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Psychedelics – Mushrooms, LSD, Salvia

Psychedelics, while they can cause pleasurable side effects, are mostly Schedule I classified drugs that are not only illegal but dangerous. While psychedelics can cause a person to feel a sense of oneness with the universe and experience spiritual or enjoyable hallucinations and distorted perceptions, they can also cause intense fear, paranoia, and panic.

Whether or not a person has a good trip or a bad tripall depends on many variables, and there is no assurance that even the same individual will experience a positive reaction twice. This is only one of the dangers of psychedelics which, while they have been used in spiritual rituals for centuries, can cause many harmful effects.

We can help you quit using psychedelic drugs. Call 800-895-1695 today.

The effects of psychedelics are extremely hard to predict. As stated by CESAR, psilocybin or psychedelic mushrooms are one of the most popularly abused psychedelics to this day, and the effects produced by psilocybin are highly variable and depend on several factors including the age, type, and dosage amount of the mushroom used, the setting the mushroom is used in, the users expectations, past drug experiences, and personality.

This is what makes psychedelic drugs so different from other commonly abused substances; it is very difficult to pinpoint how a person will react to these drugs or what they should even expect. While some effects like hallucinations, nausea, and an altered perception of space and time can all be expected to be experienced by the user, psychedelics may cause a different type of high in every user (each and every time) and their effects could last anywhere from an hour to six or more.

While there isnt a strong amount of research on the issue of psychedelic drug addiction, it is possible in some instances. Especially with a drug like MDMA, some users report symptoms of dependence, including continued use despite knowledge of physical or psychological harm, tolerance (or diminished response), and withdrawal effects (NIDA).

Some other drugs (like LSDand peyote) only cause tolerance while the effects of salvia divinorum have not yet been researched enough to provide any conclusive results. The question of whether or not addiction to certain psychedelic drugs exists can be puzzling. In many cases, though, treatment may still be necessary to help with the effects abusing psychedelic drugs can cause.We can help you find the treatment you need. Call 800-895-1695 toll free today.

If you are concerned about your psychedelic drug abuse or that of another individual, here are some steps to follow in order to better the situation.

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Psychedelics – Mushrooms, LSD, Salvia

Psychedelics – Pharmacological Reviews

I. Introduction

I was delighted when the editors invited me to write a review on psychedelics, perhaps a watershed moment, representing a shift in opinion that has been developing for more than 3 decades with respect to research and understanding of psychedelics. When I began my graduate studies in 1969, it was politically correct in scientific circles to refer to these substances only as psychotomimetics, a negative term suggesting that they fostered a mental state resembling psychosis (Hoffer, 1967). Later, as it was realized that these compounds did not provide very realistic models of psychosis or mental illness, it became more correct to refer to them as hallucinogens, again a pejorative term suggesting that they principally produce hallucinations. Yet that is not what they do in most users at ordinary doses, so this term likewise is not particularly descriptive or useful, although it is still widely used and seems to remain the preferred name for these substances in most scientific writing. In addition, the term hallucinogen is often used as a rather broad category to include all kinds of psychoactive molecules, including cannabinoids, ecstasy, dissociative agents, and others.

This review will focus exclusively on the so-called classic serotonergic hallucinogens (psychedelics), which are substances that exert their effects primarily by an agonist (or partial agonist) action on brain serotonin 5-hydroxytryptamine (5-HT) 2A receptors, as discussed later. The discussion will not consider cannabinoids, dissociatives such as ketamine, salvinorin A (a specific opioid agonist), or entactogens such as 3,4-methylenedioxymethamphetamine (MDMA). In certain contexts, all of these and some related agents have been swept into the catchall category hallucinogens. Although they all can produce profound changes in consciousness, they have a different mechanism of action and will not be discussed unless there is a specific reason to do so.

The name psychedelics for these substances was coined by Humphrey Osmond in 1957, connoting that they have a mind-manifesting capability, revealing useful or beneficial properties of the mind (Osmond, 1957). This name has been popular among the lay public for more than 5 decades, but it has generally been frowned upon by the scientific community because it implies that these substances have useful properties. The notion that psychedelics can have beneficial effects has thus far not been embraced in most medical or scientific circles; indeed, federal funding agencies (e.g., the National Institutes of Health National Institute on Drug Abuse and the National Institute of Mental Health) have no mission to support research on potentially useful properties of psychedelics. Yet this term has remained popular with the public and even appears to be gaining popularity. As I intend to show in this discussion, however, the idea that psychedelics may have useful properties is not at all farfetched, and very recent clinical studies have reinforced the belief by many that psychedelics are well worth studying from a number of different perspectives. Indeed, one of the most striking developments in this field has been the initiation and successful completion of a variety of clinical studies of psychedelics in the past 15 years, most of which have been targeted to specific medical indications. As will be discussed later, the results have been, in the main, remarkably positive.

It should be kept in mind that the relative dearth of research on psychedelics in the past half century did not result from a lack of scientific interest, but rather occurred as a consequence of political forces that manifested principally in the United States in the 1960s and 1970s (Grinspoon and Bakalar, 1979). Use of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD) and marijuana by so-called hippies who demonstrated against the Vietnam War during the 1960s created great consternation among authorities and legislative bodies, both at the federal and state levels. Antiwar attitudes and rejection of conventional social norms by adolescents and college students were often perceived by the mainstream culture to be a consequence of drug use; hence, these substances were often believed to be perverting the minds of our youth. Furthermore, the outspoken Harvard University professor and firebrand Timothy Leary encouraged young people to turn on, tune in, and drop out, essentially coaching them to take drugs, discover their true selves, and abandon convention. Such messages did not play well with the mainstream culture, all while the mass media fanned the flames of public hysteria with greatly exaggerated reports of drug-induced insanity, chromosomal damage, attempts to fly, and so forth.

Strict laws were quickly passed. After the passage of the Controlled Substances Act of 1970, LSD and other psychedelics known at the time were placed into the most restrictive category of drugs, Schedule 1. This classification made them virtually impossible to study clinically and effectively ended any significant research into the pharmacology and medical value of psychedelics for more than 3 decades. Nevertheless, there can be no doubt that psychedelics played a substantial role in defining the youth culture of the 1960s and 1970s, with books and essays too numerous to cite being written on this topic. It is believed that more than 30 million people have used LSD, psilocybin, or mescaline (Krebs and Johansen, 2013). One suspects that had LSD never been discovered, the world might look very different today than it does now, for better or worse, depending on ones perspective.

Despite the recreational use of psychedelics, a quote from a book by Grinspoon and Bakalar (1979 Pg 192) needs to be kept in mind:Many people remember vaguely that LSD and other psychedelic drugs were once used experimentally in psychiatry, but few realize how much and how long they were used. This was not a quickly rejected and forgotten fad. Between 1950 and the mid-1960s there were more than a thousand clinical papers discussing 40,000 patients, several dozen books, and six international conferences on psychedelic drug therapy. It aroused the interest of many psychiatrists who were in no sense cultural rebels or especially radical in their attitudes.

One very important scientific consequence of the discovery of LSD also is often overlooked. The powerful psychologic effect of LSD was accidently discovered in 1943 (Hofmann, 1979a), followed only a decade later in 1953 by the detection of serotonin in the mammalian brain (Twarog and Page, 1953). The presence of the tryptamine moiety within LSD was also quickly seen to be the scaffold for the chemical structure of serotonin (Fig. 1).

Chemical structures of serotonin and LSD.

This recognition led to a proposal only 1 year later by Woolley and Shaw (1954) that mental disturbances caused by lysergic acid diethylamide were to be attributed to an interference with the action of serotonin in the brain. Therefore, one could reasonably argue that the whole field of serotonin neuroscience, and especially the role of serotonin in brain function, was catalyzed by the discovery of LSD! By way of illustration, in 1952, there were only 10 publications in the National Library of Medicine concerning serotonin, nearly all of them dealing with some aspect of its ability to constrict blood vessels. Only 8 years later, in 1960, there were 300 publications on serotonin, 35 of which were now focused on studies of serotonin in the brain. For comparison, in 1960, there were only 197 publications about norepinephrine (NE)/noradrenaline, a neurotransmitter that had been discovered and studied in the mid-1940s. Green (2008) provides an interesting overview of the 19501970 period of intense research activity after the discovery of serotonin in the brain.

There have been numerous recent reviews on this topic, usually titled as hallucinogens, and the reader is encouraged to consult these works for further details (Nichols, 2004; Nichols and Chemel, 2006; Fantegrossi et al., 2008a; Green, 2008; Passie et al., 2008; Winter, 2009; Griffiths and Grob, 2010; Vollenweider and Kometer, 2010; Brandt and Passie, 2012; Beck and Bonnet, 2013; Halberstadt and Geyer, 2013b; Baumeister et al., 2014; Halberstadt, 2014; Tyl et al., 2014). I wrote a comprehensive review on the subject in 2004, so the literature considered for this review will focus primarily, but not exclusively, on the years from 2004 to the present.

Psychedelics are a class of drug that cannot be fully understood without reference to a number of other fields of research, including anthropology, ethnopharmacology, psychiatry, psychology, sociology, and others. This review will focus mostly on pharmacology, both preclinical and clinical, but on occasion reference will be made to aspects of some of those other areas.

Psychedelics may be the oldest class of psychopharmacological agents known to man. Important examples of these substances include a substance used in ancient India known as Soma, which was highly revered and is frequently mentioned in the Rigveda, with numerous Vedic hymns written in praise of Soma (Wasson and Ingalls, 1971). In the ancient village of Eleusis, outside Athens, for more than 2000 years there was an annual all-night secret ceremony that is believed to have involved ingestion of a hallucinogenic brew known as (Wasson et al., 1978). We know almost nothing about the ceremony other than that profound insights about life could be achieved, and it was apparently a treasured once-in-a-lifetime opportunity for any Greek citizen who had not been convicted of murder.

Psilocybin mushrooms were used by the Aztec shaman in healing and in a variety of religious and divinatory rituals. These mushrooms were known as teonanacatl, meaning gods flesh (Ott and Bigwood, 1978; Schultes and Hofmann, 1979). The use of various psychoactive plant materials and substances was common in pre-Columbian Mesoamerican societies, including the Olmec, Zapotec, Maya, and Aztec cultures (Carod-Artal, 2015). In the Bradshaw rock art in the Kimberly region of Australia and in the Sandawe rock art in the Kolo region of Eastern Tanzania, one finds uniquely shared images such as the mushroom head symbol of psilocybin use, suggesting that the two cultures were linked and had shamanic practices that used psychoactive mushrooms (Pettigrew, 2011).

Peyote (Lophophora williamsii) is a small cactus native to the American Southwest and Northern Mexico that has been used for millennia and is consumed as a sacrament during services of the Native American Church. Two peyote samples from a cave on the Rio Grande River in Texas were analyzed and subjected to radiocarbon dating. The average age of the samples, both of which contained mescaline, dated to 37803660 BCE (El-Seedi et al., 2005). This evidence supports the use of peyote by Native North Americans as long ago as 5700 years (Bruhn et al., 2002). Classic psychedelics that have been extensively studied include LSD, shown earlier, mescaline, psilocybin, and N,N-dimethyltryptamine (DMT) (Fig. 2).

Chemical structures of classic psychadelics mescaline, psilocybin, and DMT.

Ayahuasca, also known as yag or hoasca, has a long history of use by natives in the Amazon valley of South America (Dobkin de Rios, 1971; Schultes and Hofmann, 1979). Ayahuasca is a decoction prepared from an admixture of two plants: the pounded bark from Banisteriopsis caapi vines and leaves from Psychotria viridis. The latter contains the hallucinogen DMT, a Schedule 1 controlled substance under U.S. law, and it is generally considered that the psychoactive effects of ayahuasca can be attributed to its DMT content. Although DMT is not orally active, B. caapi contains -carboline alkaloids that inhibit the liver monoamine oxidase (MAO) that normally breaks down DMT; thus, ayahuasca is taken orally as a tea. Its use has been incorporated as a sacrament into the religious practices of two syncretic Brazilian churches [Unio do Vegetal (UDV) and the Santo Daime] that have branches in the United States, with the U.S. Supreme Court rendering a 2006 decision to allow the use of ayahuasca by the UDV under the Religious Freedom Restoration Act.

In view of the widespread historical use of psychedelics as sacraments in a variety of other cultures, Jaffes (1990) definition for the class of psychedelics can perhaps be appreciated: the feature that distinguishes the psychedelic agents from other classes of drug is their capacity reliably to induce states of altered perception, thought, and feeling that are not experienced otherwise except in dreams or at times of religious exaltation. All pharmacologists will recognize that this definition for a class of psychoactive drugs is indeed quite unique!

One of the pioneers of LSD research, the late Daniel X. Freedman, noted that one basic dimension of behavior compellingly revealed in LSD states is portentousness the capacity of the mind to see more than it can tell, to experience more than it can explicate, to believe in and be impressed with more than it can rationally justify, to experience boundlessness and boundaryless events, from the banal to the profound (Freedman, 1968). Freedmans observation is completely consistent with Jaffes definition.

The use of psychedelics as a central feature of many religious practices, as well as the profound and unique psychopharmacological effects suggested by Jaffes definition and the observations of Freedman, surely makes us aware that psychedelics are an exceptional category of mind-altering substances. Indeed, this knowledge prompted Ruck et al. (1979) to coin the word entheogen as a replacement for the terms hallucinogen and psychedelic, both of which they felt had negative connotations. Entheogen is derived from the Greek roots entheos, meaning God (theos) within, and genesthe, meaning to generate. The word entheogen thus essentially refers to a substance or material that generates God or the divine within someone. Although the term entheogen is now seeing fairly wide acceptance within the culture of those who use these substances recreationally, a search of the term in the National Library of Medicine finds only five hits. Although it seems unlikely that the term entheogen will be adopted within the formal scientific community, the reader should realize that in some circles entheogen is generally synonymous with psychedelic. Nonetheless, it should be appreciated that the effects produced by psychedelics are highly dependent on the set (mental expectation) of the user and the setting (environment). A set and setting designed to facilitate a mystical experience will increase the probability of such an occurrence, whereas an unstructured or party-type setting is less likely to lead to a positive outcome.

Studerus et al. (2012) investigated the importance of 24 predictor variables on the acute response to psilocybin and confirmed that nonpharmacological factors play an important role in the effects of psilocybin. Variables examined included age, sex, education, personality traits, drug pre-experience, mental state before drug intake, experimental setting, and drug dose. Their analysis was based on pooled data from 23 controlled experimental studies involving 261 healthy volunteers who had participated in 409 psilocybin administrations over a 19-year period in the authors laboratory. Multiple linear mixed-effects models were fitted for each of 15 response variables. Drug dose was shown to be the most important predictor for all measured response variables, but several nonpharmacological variables significantly contributed to the effects of psilocybin. Specifically, having a high score in the personality trait of absorption, being in an emotionally excitable and active state immediately before drug intake, and having experienced few psychologic problems in past weeks were most strongly associated with pleasant and mystical-type experiences. High emotional excitability, young age, and an experimental setting involving positron emission tomography (PET) most strongly predicted unpleasant and/or anxious reactions to psilocybin. Interestingly, in addition to confirming that nonpharmacological variables play an important role in the effects of psilocybin, an experimental setting involving PET most strongly predicted unpleasant and/or anxious reactions to psilocybin.

Two instruments have been most widely used to assess the subjective effects of hallucinogenic drugs. The first of these, the Hallucinogen Rating Scale (HRS) was developed by Strassman et al. (1994) during their studies of the intravenous administration of DMT. The HRS was first drafted based on interviews with 19 experienced DMT users and was modified during the early stages of their study. The final version, used for their double-blind study, contained 126 individual items. HRS items were placed into six conceptually coherent clusters: somaesthesia (interoceptive, visceral, and cutaneous/tactile effects), affect (emotional/affective responses), perception (visual, auditory, gustatory, and olfactory experiences), cognition (alteration in thought processes or content), volition (a change in capacity to interact willfully with themselves, the environment, or certain aspects of the experience), and intensity (strength of the various aspects of the experience). Subjects were asked to recall their experiences from the immediately preceding session. Most questions were scored on a 04 scale (0, not at all; 1, slightly; 2, moderately; 3, quite a bit; and 4, extremely).

The second assessment instrument widely used to quantify the subjective effects of hallucinogens is the Abnormal Mental States (APZ) questionnaire, first developed by Dittrich (1994, 1998) to measure altered states of consciousness (ASCs). In a series of 11 experiments using different induction methods in 393 healthy subjects, the hypothesis was tested that ASCs have major dimensions in common, irrespective of their mode of induction. The original version contained 158 items covering a range of phenomena potentially occurring during an ASC. The common denominator of ASCs was described by three primary oblique dimensions, designated as oceanic boundlessness (OSE, later as OBN), dread of ego dissolution (AIA, and later as DED), and visionary restructuralization (VUS, later as VRS). The APZ questionnaire became the international validated standard for the assessment of ASCs and the name was further revised to the OAV scales (Bodmer et al., 1994) and later to the five-dimensional altered states of consciousness (5D-ASC) (Dittrich et al., 2006). Details of the development of the original APZ questionnaire and its further refinements were summarized by Studerus et al. (2010). To overcome a variety of methodological limitations, Studerus et al. (2010) carried out a psychometric evaluation of the OAV and 5D-ASC in a relatively large sample from 43 pooled experimental studies of healthy subjects who had received psilocybin, ketamine, or MDMA. The total sample was composed of 591 drug sessions. After comprehensive and detailed statistical analyses, the authors found that the original OAV scales were multidimensional constructs, and arrived at an improved final model that had 11 factors: experience of unity, spiritual experience, blissful state, insightfulness, disembodiment, impaired control and cognition, anxiety, complex imagery, elementary imagery, audio-visual synesthesia, and changed meaning of percepts. Correlations between the 11 factors and their association with the original OAV scales were presented. The new lower-order scales were proposed to be better suited to assess drug-induced ASCs.

Mechanistically, psychedelics have agonist or partial agonist activity at brain serotonin 5-HT2A receptors. This molecular characterization will be elaborated in some detail later in this review, and aspects of the anatomic and functional importance of this receptor type will also be extensively explored. Discussions over the years with many colleagues working in the pharmaceutical industry have informed me that if upon screening a potential new drug is found to have serotonin 5-HT2A agonist activity, it nearly always signals the end to any further development of that molecule.

A recent study by Turton et al. (2014) reported on the subjective experience of intravenous psilocybin administered during a functional magnetic resonance imaging (fMRI) examination. Fifteen volunteers were administered an intravenous infusion of either placebo or 2 mg psilocybin and were blinded as to whether they would receive placebo or drug for a particular experiment. Drug infusion began 6 minutes after the start of a scan in a magnetic resonance imaging scanner. Subjects completed a visual analog scale rating the intensity of the drug experience at the start of the scan and prior to drug infusion, 5 minutes postinfusion, and 12 minutes postinfusion. All subjects subsequently were interviewed about the drug effects, and interviews were analyzed using interpretative phenomenological analysis, a qualitative method. All subjects reported that the onset of drug effect was very rapid and intense, with a duration of effect lasting 1015 minutes. The investigators identified nine broad categories of phenomenology. Altered somatosensory, visual, auditory, and proprioceptive sensations were reported, with 14 of 15 subjects describing perceptual changes as the primary effect of the drug. Thirteen subjects reported changes in perception of time, either speeding up or slowing down. The report describes a variety of effects on cognition, mood, memory, and spiritual or mystical experiences. Overall, subjects found the experience difficult to describe, yet most found it pleasant and positive.

In a new study by Schmid et al. (2015), LSD (200 g) was administered orally to 16 healthy subjects in a double-blind, randomized, placebo-controlled, crossover study. LSD produced a pronounced alteration in waking consciousness that lasted for 12 hours and included visual hallucinations, audio-visual synesthesia, and positively experienced derealization and depersonalization phenomena. Compared with placebo, LSD increased subjective well-being, happiness, closeness to others, openness, and trust. Increases in blood pressure, heart rate, body temperature, pupil size, plasma cortisol, prolactin, oxytocin, and epinephrine also were measured. On the 5D-ASC scale, LSD produced higher scores than did psilocybin or DMT. The authors also described subjective effects on mood that were similar to those reported for MDMA that might be useful in psychotherapy. No severe acute adverse effects were observed and the effects subsided completely within 72 hours.

In a very recent study by Carhart-Harris et al. (2015a), LSD was shown to enhance responsiveness to suggestion. Their study was prompted by very early reports indicating that LSD increased suggestibility (Sjobergand Hollister, 1965; Middlefell, 1967). Thus, Carhart-Harris et al. (2015a) administered LSD (4080 g, i.v.) to 10 healthy volunteers in a within-subject placebo-controlled design. Suggestibility and cued mental imagery were assessed using the Creative Imagination Scale and a mental imagery test. The two instruments were administered between 110 and 140 minutes after drug infusion, at the peak of the drug effect. Subjects scored significantly higher on the Creative Imagination Scale, but not the mental imagery test after LSD administration, compared with placebo. The magnitude of suggestibility enhancement was positively correlated with the subjects baseline trait conscientiousness. This enhanced suggestibility may have implications for the use of LSD as an adjunct to psychotherapy, but it also indicates that individuals with a high trait conscientiousness are particularly sensitive to the suggestibility-enhancement effect of LSD.

It has been axiomatic among users of psychedelics that music takes on an intensified and more enjoyable quality under the effects of LSD or other psychedelics, yet no modern placebo-controlled study had ever been carried out to confirm that widely held belief. Early studies at the Maryland Psychiatric Research Center found that music was a very effective stimulus and complement to the effect of LSD (Bonny and Pahnke, 1972). Gaston and Eagle (1970) also reported that the presence of music was much preferable to its absence in alcoholic patients undergoing treatment using LSD therapy, both by patient preference and treatment results. Numerous other studies had been reported on the value of music in the context of various shamanic and therapeutic approaches (see references in Kaelen et al., 2015). Very recently, therefore, Kaelen et al. (2015) tested the hypothesis that the emotional response to music is enhanced by LSD. Ten participants were administered placebo or various doses of LSD, including 40, 50, 70, or 80 g, infused intravenously over 3 minutes. They then listened to five different instrumental music tracks on each of two study days: a placebo day followed by an LSD day, separated by 57 days. Music tracks were chosen that produced the highest liking and lowest familiarity by a separate sample of nine participants. The question How emotionally affected were you by the music? was asked immediately after each track and served as the studys primary outcome. The nine-category Geneva Emotional Music Scale (Zentner et al., 2008) was also used. Mean scores for all music stimuli in response to the question how emotionally affected were you by the music? were significantly higher for the LSD condition than for placebo. In addition, all nine factors on the Geneva Emotional Music Scale were scored higher after LSD administration than after placebo. Emotions related to transcendence also were enhanced by LSD. Specific emotions showing the strongest enhancement included wonder, transcendence, tenderness, and power. Furthermore, there was a significant positive relationship between ratings of the intensity of the LSD effect and emotional arousal to music. The results of Zentner et al. (2008) support the hypothesis that LSD enhances music-evoked emotion.

The experimental study of mystical or ecstatic states engendered by psychedelics perhaps began with the so-called Good Friday experiment, carried out at Boston Universitys Marsh Chapel in 1962 by Walter Pahnke as his research for the Ph.D. in religion and society at the Harvard Divinity School. Pahnke (1963) examined the similarities and differences between experiences described by mystics and those induced by psilocybin. On Good Friday in 1962, 20 Christian theological student volunteers attended a 2.5-hour religious service in Boston Universitys Marsh Chapel. The setting and preparation of the subjects was designed to optimize a spiritual or mystical experience. In a double-blind procedure, subjects were given either an oral dose of 30 mg psilocybin, or a 200-mg placebo dose of nicotinic acid, administered in identical capsules. Based on responses to a variety of instruments and questionnaires, subjects who received psilocybin had experiences that were indistinguishable from those experienced by mystics. The experiences were powerful and personally meaningful. Doblin (1991) reported a follow-up to the Pahnke study in 1989 and was able to locate and interview 19 of the original 20 experimental participants. All of the psilocybin subjects felt that the experience had significantly affected their lives in a positive way and they expressed appreciation for having participated in the experiment.

An extension of the Good Friday experiment was recently carried out by Griffiths et al. (2006). The investigators used rigorous double-blind clinical methods to evaluate acute and longer-term effects of psilocybin (30 mg/70 kg) compared with an active comparator compound (40 mg/70 kg methylphenidate). A complex design was used to obscure which treatments were administered from the study participants and the monitors, and the study was designed to minimize adverse effects. Thirty-six healthy volunteers were enrolled, all of whom indicated some participation in regular religious or spiritual activities. Instruments used to assess effects 7 hours after drug administration were the HRS, the Addiction Research Center Inventory, the States of Consciousness questionnaire, and the Mysticism Scale. Seven to 8 weeks after each session, and before any additional session, subjects completed the Persisting Effects Questionnaire, the Mysticism ScaleLifetime, the Spiritual Transcendence Scale, the NEO Personality Inventory, and the Positive and Negative Affect Schedule Expanded Form. Based on measures of mystical experience, 22 of the 36 volunteers had a complete mystical experience after psilocybin administration, whereas only 4 did after the methylphenidate (placebo) sessions. Based on ratings of personal meaningfulness and spiritual experience, 67% of the volunteers rated the psilocybin experience to be either the single most meaningful experience of their lives or among the top five most meaningful experiences in their lives. Based on community observer ratings, psilocybin sessions were associated with significant positive changes in the volunteers behavior and attitudes.

Thus, when psilocybin was administered under structured conditions to well prepared volunteers, it occasioned experiences that had marked similarities to classic mystical experiences, imparting to the participants substantial personal meaning and spiritual significance. The investigators point out that the high value some subjects placed on the psilocybin experience may in part explain the long-term historical use of psychedelics within some cultures for divinatory or religious purposes. Griffiths et al. (2006) conclude with the statement that, The ability to prospectively occasion mystical experiences should permit rigorous scientific investigations about their causes and consequences.

Griffiths et al. (2008) subsequently conducted a 14-month follow-up of the subjects from their earlier study. Subjects were asked to identify in which session they experienced the most pronounced changes in your ordinary mental process. It was found that the 14-month retrospective follow-up ratings for the psilocybin session did not differ significantly from the immediate postsession ratings. Compared with methylphenidate, the psilocybin experience produced significant increases in ratings of positive attitudes, mood, social effects, and behavior at 14 months of follow-up. At the 14-month follow-up, 58% of the 36 volunteers still rated the psilocybin experience as among the five most personally meaningful experiences of their lives and 67% rated it as among the five most spiritually significant experiences of their lives.

A second study using a similar protocol with 18 volunteers examined dose effects of psilocybin, using 0, 5, 10, 20, and 30 mg/70 kg (Griffiths et al., 2011). The percentage of subjects who met the criteria for having a complete mystical-type experience increased with dose. Overall, 72.2% of volunteers had complete mystical experiences at either or both doses of 20 and 30 mg/70 kg. Positive ratings about life, attitudes about self, mood, social effects, and behavior also increased as a function of dose. Ratings at the 14-month follow-up were undiminished compared with ratings at 1 month after the sessions.

MacLean et al. (2011) analyzed the data from the two double-blind controlled studies of psilocybin reported by Griffiths et al. (2006, 2011). In particular, their goal was to use the NEO Personality Inventory to analyze possible personality changes that might have occurred after the high-dose psilocybin sessions in those studies. It is generally believed that personality traits are relatively enduring and that an individuals personality is predominantly stable across the lifespan. Yet evidence also exists that significant life events may dramatically change adult personality (see references in MacLean et al., 2011). The most widely accepted model of personality structure is the five-factor model, which describes five broad domains of personality: neuroticism, extroversion, openness, agreeableness, and conscientiousness (see references in MacLean et al., 2011). The authors suggest that numerous subjective claims of long-term changes after hallucinogen use appear to align with the personality trait of openness, which encompasses aesthetic appreciation and sensitivity, imagination and fantasy, and broad-minded tolerance of others viewpoints and values. Thus, they hypothesize that the mystical experiences reported in the studies by Griffiths et al. might lead to enduring increases in openness. Analysis of personality was assessed 1 to 2 months after a high-dose psilocybin session and again 16 months later to determine the persistence of any personality change(s). Consistent with their hypothesis, a mystical experience after psilocybin administration was significantly correlated with increases in openness. No such effect was seen after methylphenidate treatment. In addition, there were no significant changes in any of the other four personality factors after psilocybin administration. At the 16-month follow-up, openness levels still remained significantly elevated. The authors note that This is the first study to demonstrate changes in personality in healthy adults after an experimentally manipulated discrete event.

Studerus et al. (2011) pooled raw data from eight double-blind placebo-controlled experimental psilocybin studies conducted between 1999 and 2008. The data were analyzed for acute, short- and long-term subjective effects of psilocybin in 110 healthy human subjects who had received between one and four doses of 45315 g/kg psilocybin. Studerus et al. (2011) reported that nearly 40% of the participants in their laboratory studies of psilocybin claimed positive long-term changes in aesthetic experience and in their relationship with the environment (i.e., nature) after their psilocybin sessions. At 816 months after psilocybin sessions, more than 60% of subjects rated the experience as very enriching, and more than 90% described it as enriching to at least a medium degree. These effects occurred despite the fact that no attempt was made in their experiments to optimize conditions for a spiritual or mystical experience, which contrasts with the setting and preparations used in the two Griffiths studies cited above.

Bouso et al. (2012) compared 127 regular ayahuasca users with 115 actively religious controls who did not use ayahuasca. Baseline measurements were taken of general psychologic well-being, mental health, and cognition and the groups were then compared 1 year later to determine whether regular ayahuasca use had an effect on these measurements. Regular ayahuasca users showed lower scores on all psychopathology scales as assessed by the Symptom Checklist 90Revised, as well as on measures of harm avoidance and self-directedness. Participants scored higher on a measure of psychosocial well-being and performed better on the Stroop test (an indicator of resistance to emotional interference) and the Wisconsin Card Sorting Task (a measure of working memory). No evidence of psychologic maladjustment, mental health deterioration, or cognitive impairment was found in the ayahuasca-using group.

Lerner and Lyvers (2006) compared users of psychedelic drugs with users of nonpsychedelic drugs and nonillicit drugusing social drinkers. Samples were drawn from Israel and Australia. Compared with the other two groups, psychedelic drug users scored significantly higher on mystical beliefs (e.g., oneness with God and the universe), life values of spirituality, and concern for others, and scored lower on the value of financial prosperity, irrespective of culture of origin.

Lyvers and Meester (2012) carried out a website survey of 337 adults who used a variety of drugs, including psychedelics. Only about 25% reported spiritual motives for using psychedelics, yet use of high doses of LSD and psilocybin was significantly correlated in a dose-related manner with scores on two well known indices of mystical experiences; use of MDMA, cannabis, cocaine, opiates, or alcohol was not. Thus, even when taken recreationally, psychedelics have the potential to induce mystical experiences.

Quite interestingly, the underlying neuronal basis for mystical/spiritual experiences has recently been the subject of scientific investigation. Kometer et al. (2015) studied the neuronal basis of spiritual experiences and insightfulness after administration of psilocybin to human subjects. They conducted a double-blind, placebo-controlled study and administered psilocybin (170 or 215 g/kg, p.o.) to 50 healthy human volunteers. Electroencephalography (EEG) data were recorded from 64 scalp electrodes. Exact low-resolution brain electromagnetic tomography was applied to compute the three-dimensional intracerebral current density values of the scalp-recorded EEG rhythms. They used lagged phase synchronization, a new measure that can capture nonlinear neuronal relationships to assess dynamic functional connectivity (Pascual-Marqui et al., 2011).

The 11-dimension 5D-ASC questionnaire was used to quantify the subjective psychologic effects of psilocybin, with a particular interest in the spiritual experience subscale, and the related subscales of experience of unity, comprising experience of oneness with the environment and the self, insightfulness, measuring profound insights into life and existence, blissful state, measuring experiences of pleasure, inner peace, and love. Voxel-wise product-moment correlations between current source density in the psilocybin condition and the 11-dimension 5D-ASC subscale scores were computed by regression analysis.

Psilocybin significantly increased scores of all subscales on the 5D-ASC but significantly decreased current source density of oscillations in all frequency bands up to 20 Hz (eyes-closed condition) or up to 30 Hz (eyes-open condition). There was a significant and consistent psilocybin-induced reduction of current source density across low frequency bands (

The extent of lagged phase synchronization within a network of deep cortical structures strongly and positively correlated with score on the insightfulness subscale of the 5D-ASC and spiritual experiences subscales of the 5D-ASC during the eyes-closed condition. Lagged phase synchronization of 1.5- to 4-Hz oscillations within a network comprising the RSC, parahippocampus, and lateral orbitofrontal area was associated with spiritual experiences and insightfulness.

These findings of Kometer et al. (2015) provide further evidence that decreased ongoing oscillations below 20 Hz, particularly / oscillations, may be a common mechanism of action of psychedelics. The decrease in lower frequency oscillations was found to be localized within an extended network that included the PCC, RSC, ACC, and parahippocampal regions, a network that strongly overlaps with the default mode network (DMN). Thus, psilocybin may modulate default mode functions by decreasing ongoing lower frequency oscillations within this network.

Lower frequency oscillations, particularly in the range, mediate rhythmic cortical inhibition of neuronal ensembles (see references in Kometer et al., 2015). The marked decrease in lower frequency oscillations observed in this study may indicate that psilocybin induces a shift of the resting excitation/inhibition balance toward excitation, which would be expected to disrupt the ordinary temporal structure of neuronal processes within the extended DMN.

Lagged phase synchronization was strongly associated with the psilocybin-induced state of consciousness, supporting the view that neural integration, rather than activity, underlies the state of consciousness. Scores of the spiritual experiences subscale of the 5D-ASC questionnaire were also associated with increased lagged phase synchronization of oscillations between parahippocampal regions and the RSC. Kometer et al., (2015) speculate that the neuronal network processes they identified may constitute a crucial pathway that can be modulated by serotonergic receptors to regulate mental health, a conclusion that would be consistent with some of the potential positive mental health outcomes discussed earlier in this section.

For decades, the media have largely portrayed psychedelics as extremely dangerous drugs; in fact, the classic serotoninergic psychedelics are generally considered very physiologically safe, certainly compared with opiates and psychostimulants. Jaffe (1985) stated, In man, deaths attributable to direct effects of LSD are unknown, and this statement remains true even today. Nonetheless, despite the relative physiologic safety of psychedelics, they can lead to serious psychologic consequences. In addition, as will be discussed later, some of the newer highly potent synthetic phenethylamine hallucinogens have proven to be unexpectedly toxic. This section will detail studies indicating that psychedelics can be safely used under supervision, and that few documented serious adverse effects occur even after recreational use. The discussion will then turn to some generally recognized adverse reactions, followed by case reports of some more serious and even fatal reactions to psychedelics. It should be emphasized that these latter fatalities, which are rare, have occurred after use of newer synthetic phenethylamine compounds, and not as a result of ingestion of LSD, psilocybin, mescaline, or DMT.

Analysis of early published reports on adverse reactions and long-term negative sequelae induced by classic psychedelics failed to identify significant adverse events; if long-term adverse effects from repeated use did occur, they were subtle or nonsignificant (Strassman, 1984; Halpern and Pope, 1999). Their reviews were based on reports from supervised clinical studies using pure drugs, so the same conclusions might not apply to recreational use of drugs with unknown identities or purity.

These substances do not lead to addiction or dependence and are not considered to be reinforcing (O’Brien, 2001). This is understandable when one realizes that the serotonergic hallucinogens do not have direct effects on brain dopaminergic systems, a pharmacology that appears essential for nearly all drugs that can engender dependence. Attempts to train animals to self-administer hallucinogens, an animal model that can predict abuse liability, have generally been unsuccessful.

Using 20012004 data drawn from the National Survey on Drug Use and Health (NSDUH), Krebs and Johansen (2013) recently evaluated possible associations between lifetime use of psychedelics and current mental health in the U.S. adult population. In a large sample of respondents, 13.4% reported lifetime psychedelic use. No significant associations were found between lifetime use of any psychedelic or past-year use of LSD and increased rate of any mental health outcome. Surprisingly, in several cases, use of psychedelics was associated with a lower mental health problem rate.

A statewide survey of the adult population in Colorado sought to determine whether psychedelic use was correlated with the lifetime risk of panic attacks (Bonn-Miller et al., 2007). No association was found between psychedelic use and panic attacks, but psychedelic abuse and dependence were significantly related to an increased lifetime risk of panic attacks. It should be noted that in this study, however, phencyclidine (PCP) was included in their survey as a psychedelic, and this substance, in contrast with the classic serotonergic psychedelics, can cause dependence.

Peyote (L. williamsii) is a small cactus that grows in the Southwestern United States and Northern Mexico. It contains the psychedelic compound mescaline and has been used for centuries by Native American populations in rituals and ceremonies. Mescaline is also found in the San Pedro and Peruvian Torch cacti, and these have also been used ceremonially. Although peyote is classified as a Schedule 1 controlled substance, members of the Native American Church have a legal exemption to use it in their religious services. Halpern et al. (2005) compared 61 Navajo Native American Church members who regularly ingested peyote with 79 individuals reporting minimal use of peyote, alcohol, or other substances. Cognitive function was assessed using the Rand Mental Health Inventory and 10 standard neuropsychological tests of memory and attentional/executive functions. The peyote-using group showed no significant deficits on the Rand Mental Health Inventory or on any of the 10 other tests used. For the peyote-using group, total lifetime peyote exposure was not associated with neuropsychological performance.

By contrast, recreational use of peyote has led to adverse events, although peyote exposures reported to poison control centers are relatively rare compared with other drugs of abuse. In 2007, for example, only 116 peyote or mescaline exposures were reported to U.S. poison control centers out of more than 2.4 million total drug exposures (Bronstein et al., 2008). Carstairs and Cantrell (2010) retrospectively reviewed the California Poison Control System electronic database between the years 1997 and 2008 for reports of cases involving adverse reactions to peyote or mescaline ingestion when it was the sole intoxicating agent. A total of 31 cases were identified that met their inclusion criteria. Life-threatening symptoms did not occur, and most exposures were associated with only mild to moderate clinical effects, which most commonly included tachycardia and central nervous system (CNS) effects. Symptoms typically resolved within 24 hours or less and did not usually require anything more than supportive measures or sedation. One case of a prolonged peyote-induced psychosis was reported by Lu et al. (2004), in which the psychosis resolved after sleep. The case involved a 54-year-old Native American man with no prior history of psychosis. He drank peyote juice during a healing ceremony and within a few hours became convinced that he was hunted by animal spirits. He was unable to sleep for 2 weeks, at which time he developed visual and auditory hallucinations of the spirits and became increasingly depressed. He was persuaded to enter a hospital, where he received trazodone to help him sleep. He fell asleep and slept for 15 hours, which led to complete resolution of his psychotic symptoms. The authors speculated that his psychosis was a result of his prolonged sleep deprivation.

Hasler et al. (2004) studied eight subjects given either placebo or 45, 115, 215, or 315 g/kg psilocybin (a very low, low medium, or high dose, respectively). Instruments used to assess psilocybin effects included the 5D-ASC, the Frankfurt Attention Inventory (FAIR), and the Adjective Mood Rating Scale (AMRS). Several physiologic and plasma hormones were also measured. Psilocybin dose-dependently increased all measures on the 5D-ASC. The medium and high doses of psilocybin led to a 50% reduction in performance on the FAIR test. The only scores that were increased on the AMRS were general inactivation, emotional excitability, and dreaminess. Hasler et al. (2004) found no evidence that psilocybin is hazardous with respect to somatic health.

Bouso et al. (2015) used magnetic resonance imaging to examine potential differences in cortical thickness in 22 Spanish regular users of ayahuasca, compared with 22 matched controls. Inclusion criterion for ayahuasca users was that they had used it at least 50 times in the 2 previous years. Subjects also were assessed using three neuropsychological tests, including the two-back test to assess working memory, the Wisconsin Card Sorting Test to assess executive function, and a switching task to assess set shifting. Personality was also assessed by self-report using the Spanish version of the Temperament and Character InventoryRevised questionnaire. Ayahuasca users scored significantly better than controls on several variables derived from the neuropsychological tests. No increased psychopathology or worse neuropsychological performance was observed in the ayahuasca group, consistent with findings reported earlier by Grob et al. (1996) for ayahuasca users who were members of the Brazilian church, the UDV. Indeed, ayahuasca users scored significantly better than controls on harm avoidance, and its subscale anticipatory worry, and significantly higher on self-transcendence. Cortical thinning was found for six brain areas in the ayahuasca group: the middle frontal gyrus, the inferior frontal gyrus, the precuneus, the superior frontal gyrus, and the PCC. By contrast, cortical thickening was seen in the precentral gyrus and the ACC. Correlation analysis revealed that lifetime use of ayahuasca was inversely correlated to cortical thickness in the PCC.

Although there is a general public perception that psychedelic drugs are dangerous, from a physiologic standpoint they are in fact one of the safest known classes of CNS drugs. They do not cause addiction, and no overdose deaths have occurred after ingestion of typical doses of LSD, psilocybin, or mescaline. Cohen (1967) and Jaffe (1985) have both stated that death due to direct LSD toxicity is unknown. Indeed, recreational users who have consumed massive doses of LSD have survived. For example, eight individuals who believed they had cocaine accidentally insufflated an extremely high dose of LSD. Their plasma LSD levels were reported as between 1000 and 7000 g/100 ml (recall that a typical total oral dose of LSD might be 100200 g). These individuals all became comatose, with hyperthermia, vomiting, light gastric bleeding, and respiratory problems. With hospital treatment, however, all eight survived and without apparent residual effects (Klock et al., 1974).

Although the classic psychedelics have not been directly responsible for causing death, the judgment of users is certainly impaired while under the influence of these drugs. This is a particular concern when hallucinogens are used in unsupervised settings. Users may believe that they are invincible or possess superpowers and may do things they would not normally consider, such as believing they can fly (Reynolds and Jindrich, 1985), jumping from buildings (Keeler and Reifler, 1967), or incurring severe ocular damage by prolonged staring at the sun (Schatz and Mendelblatt, 1973; Fuller, 1976).

Studerus et al. (2010) analyzed acute, short-, and long-term subjective effects of psilocybin in healthy humans. Again, using pooled raw data from eight double-blind placebo-controlled experimental studies conducted between 1999 and 2008, their analysis included 110 healthy subjects who had received between one and four oral doses of psilocybin (45315 g/kg body weight). Psilocybin dose-dependently induced profound changes in mood, perception, thought, and self-experience, but most subjects described the experience as pleasurable, enriching, and nonthreatening. Acute adverse reactions were characterized by strong dysphoria and/or anxiety/panic, but occurred only at the two highest doses of psilocybin in a relatively small number of subjects. All acute adverse drug reactions were successfully managed through interpersonal support and did not require psychopharmacological intervention. Follow-up questionnaires indicated no subsequent drug abuse, persisting perception disorders, prolonged psychosis, or other long-term impairment of functioning in any of the subjects. The results indicate that the administration of modest psilocybin doses to healthy, high-functioning, and well prepared subjects in the context of a carefully monitored research environment carries an acceptable level of risk.

The recent resurgence of interest in the clinical uses of psychedelics led Johnson et al. (2008) to propose appropriate procedures for using them in clinical practice. The guidelines they outline have certain parallels with ritual uses of hallucinogens by older indigenous cultures. In particular, Johnson et al. (2008) cite the need for structured use (expressed as ritual in indigenous use) and restrictions on use, including the need for guidance and appreciation of the powerful psychologic effects of hallucinogens (expressed as reverence in indigenous use). Psychedelic administration in humans results in a unique profile of effects and potential adverse reactions that need to be appropriately addressed to maximize safety. The primary safety concerns with psychedelics are largely psychologic rather than physiologic in nature. Somatic effects vary but are relatively insignificant, even at doses that elicit powerful psychologic effects. The proposed guidelines extend and complement the recommendations of Fischman and Johanson (1998) for high-dose hallucinogen research. The guidelines include 1) the presence of two monitors with some medical knowledge, knowledge of ASCs, and a degree of clinical sensitivity; 2) a physical environment that is safe, aesthetically pleasing, and comfortable; 3) careful subject preparation, including several meetings to establish rapport and trust with the monitors; 4) a detailed consent form and explanations of the study procedures, detailed discussions about the range of potential experiences, and time of onset and duration of the effects; and 5) an available physician in the event of an untoward medical reaction. Anyone contemplating carrying out a clinical research program with a psychedelic is strongly encouraged to read the detailed guidelines presented by Johnson et al. (2008).

Krebs and Johansen (2013) evaluated any association between lifetime use of psychedelics and current mental health in the adult population. Data were analyzed for 20012004 for 130,152 randomly selected NSDUH respondents; 21,967 respondents (13.4% weighted) reported lifetime psychedelic use. The authors found no significant association between lifetime use of any psychedelic and increased rate of any mental health outcomes. Indeed, they discovered that psychedelic use was associated with a lower rate of mental health problems in several cases. Johansen and Krebs (2015) subsequently analyzed a new data set of 135,095 randomly selected U.S. adults that included 19,299 users of psychedelics. Data were from the NSDUH for 20082011. As in their earlier study, the authors found no significant associations between lifetime use of psychedelics and increased likelihood of past-year serious psychologic distress, mental health treatment, depression, anxiety, or suicidal thoughts, plans, or attempts. Johansen and Krebs (2015) failed to find any evidence that use of psychedelics is an independent risk factor for mental health problems. Indeed, they report that lifetime use of psychedelics was associated with decreased inpatient psychiatric treatment.

Hendricks et al. (2014) analyzed data from 20022007 for 25,622 individuals charged with a felony in the Southeastern United States and under community corrections supervision in the Treatment Accountability for Safer Communities program, which is a case management intervention program for individuals with a history of substance involvement. The authors examined relationships between any hallucinogen use disorder (versus no hallucinogen use disorder) and all available sociodemographic and psychosocial variables. They report that any hallucinogen use disorder was associated with a decreased probability of supervision failure. They note the contrast with any cannabis, cocaine, alcohol, opiate, or amphetamine use disorder, each of which was associated with an increased probability of supervision failure. Their results suggest that hallucinogens may promote alcohol and other drug abstinence and prosocial behavior in a population with high rates of recidivism.

In a more recent report by Hendricks et al. (2015), the authors evaluated any relationship between use of a classic psychedelic and psychologic distress and suicidality among more than 190,000 U.S. respondents pooled from the NSDUH for 20082012. Lifetime use of a psychedelic was associated with significantly reduced odds of past-month psychologic distress, past-year suicidal thinking, past-year suicidal planning, or past-year suicide attempt. By contrast, lifetime use of other illicit drugs was associated with an increased likelihood of these outcomes. The authors suggest that classic psychedelics may hold promise in the prevention of suicide. These findings are consistent with the surveys of Krebs and Johansen (2013) and Johansen and Krebs (2015); in all three studies, the authors suggest that their data are not compatible with the highly restricted legal status of psychedelics and that more extensive clinical research is warranted.

Use of high doses of psychedelics can lead to vascular problems because the 5-HT2A receptor is associated with vascular smooth muscle contraction, platelet aggregation, thrombus formation, and coronary artery spasms (Nagatomo et al., 2004). Acute vasoconstriction caused by serotonin is usually shared by activation of 5-HT1B and 5-HT2A receptors; however, in intracranial arteries, only the 5-HT1B receptor mediates constriction (Kaumann and Levy, 2006). Both 5-HT2A and 5-HT1B receptors can mediate coronary artery spasm. 5-HT2A receptors also constrict the portal venous system, including esophageal collaterals in cirrhosis. Data from studies by Ootsuka et al. (2004) suggest that spinal 5-HT2A receptors contribute to sympathetically induced cutaneous vasoconstriction regulated by the raphe/parapyramidal neurons in the brainstem.

Balkov (2005) reports a fatal and nonfatal overdose after ingestion of the psychedelic phenethylamine 2,5-dimethoxy-4-bromoamphetamine (DOB) by two male individuals. Gas chromatographymass spectrometry was used to detect the presence of DOB in both gastric and urine samples of the two men. Although one subject survived, the other suffered convulsions and metabolic acidosis and died 6 days after admission.

Psilocybin, when administered in a controlled setting, has frequently been reported to cause transient, delayed headache, with incidence, duration, and severity increased in a dose-related manner (Johnson et al., 2012). Bickel et al. (2005) reported the case of a 25-year-old hepatitis Cinfected man, who presented with severe rhabdomyolysis and acute renal failure after Psilocybe mushroom ingestion. He later developed encephalopathy with cortical blindness. Respiratory and cardiovascular support, mechanical ventilation, continuous venovenous hemodialysis, and corticosteroid treatment led to improvement and the patient recovered completely over several months.

Psilocin was identified in the urine of a subject who was investigated for driving under the influence (Tiscione and Miller, 2006). The subject apparently did not exhibit any response to the crash of his automobile, seemingly unaware of the severity of his situation or immediate surroundings.

Although very rare, there have been reports of rhabdomyolysis after ingestion of LSD (Berrens et al., 2010). A newer tryptamine, 5-methoxy-N,N-diisopropyltryptamine (foxy) also produced rhabdomyolysis and transient acute renal failure in an otherwise healthy 23-year-old man (Alatrash et al., 2006).

Although many ergot alkaloids are known to produce vasospasm, especially after chronic use, LSD has rarely been associated with this adverse effect. Nevertheless, Raval et al. (2008) reported on a 19-year-old woman who experienced severe lower-extremity ischemia related to a single use of LSD 3 days prior to presentation. After intra-arterial nitroglycerin and verapamil failed, balloon percutaneous transluminal angioplasty therapy led to rapid clinical improvement in lower-extremity perfusion. As of the date of the report, the patient had not required a major amputation.

Sunness (2004) described a 15-year-old female patient with a 2-year history of afterimages and photophobia after a history of drug use that included LSD, marijuana, and other illicit drugs. She had discontinued LSD 1 year prior to examination. Although the author connected her visual problems with her prior LSD use, it is not at all clear from the report that her LSD use was the cause of her visual problem.

Bernhard and Ulrich (2009) reported a case of cortical blindness in a 15-year-old girl. She had headache and nausea 5 days after taking LSD and suddenly developed complete blindness in both eyes. The blindness persisted for 48 hours. Over the next 3 months, the subject had three more episodes of complete blindness that lasted 1236 hours, with no visual disturbances between episodes. The authors suggested that the temporary blindness might be a correlate of flashbacks caused by LSD.

Toxicity also has been noted for several of the so-called designer drugs. For example, Jovel et al. (2014) reported the case of a healthy young male individual who ingested 5-methoxy-N,N-diallytryptamine, one of the emerging new tryptamine-type research chemicals. The patient was admitted with extreme agitation, tachycardia, diaphoresis, and combativeness that required physical restraint and intravenous sedation, but the patient did recover.

Andreasen et al. (2009) reported a fatality involving the potent synthetic psychedelic phenethylamine compound 1-(8-bromobenzo[1,2-b; 4,5-b]difuran-4-yl)-2-aminopropane, known commonly as Bromo-Dragonfly. An 18-year-old woman was found dead after ingesting 1 ml of a hallucinogenic liquid. She and her boyfriend had ingested it between 10 and 11 PM on the previous evening and then they both fell asleep. On awakening at 5 AM the next morning, the womans boyfriend discovered that she was dead. Autopsy findings 3 days after her death included edema of the lungs, slight edema of the brain, spleen enlargement, irritation of the mucous membrane in the stomach, and ischemic changes in the kidneys. Her femoral blood concentration of the drug was 4.7 g/kg. The bottle containing the hallucinogenic liquid was recovered and analyzed by ultraperformance liquid chromatography time-of-flight mass spectrometry, high-performance liquid chromatography diode array detection, 1H nuclear magnetic resonance, and 13C nuclear magnetic resonance and found to contain a solution of almost pure Bromo-Dragonfly. Based on the solution concentration and the amount of solution consumed, it was estimated that she had ingested approximately 700 g. Although that would seem to be a relatively small dose, no other drugs were discovered in her system, including the absence of ethanol.

It is often difficult to establish whether the drug is pure or has been coingested with other unknown drugs of unknown purity. For example, Ovaska et al. (2008) reported a case of sympathomimetic toxicity in a patient who was reported to have ingested 2,5-dimethoxy-4-chloroamphetamine (DOC), yet toxicological screening showed the patient had ingested both DOC and MDMA.

Data for 2005 to 2006 from the Texas Poison Control Centers were reviewed for mushroom exposures (Barbee et al., 2009). There were a total of 742 exposures, which were all acute and intentional. Of those, 59 individuals were admitted to a hospital, with 17 requiring admission to a critical care unit. Nonetheless, only 10 of the admissions that were identified involved psilocybin. Of all of the admissions, major toxic reactions were uncommon, with no deaths reported.

One adverse effect of hallucinogen use, particularly associated with LSD use, is hallucinogen persisting perception disorder (HPPD). This term has displaced an earlier somewhat more nonspecific one known as flashbacks, which was a re-experiencing of one or more of the perceptual effects induced by a hallucinogen at some later time, after the acute drug effects had worn off. HPPD is composed of afterimages, perception of movement in peripheral visual fields, blurring of small patterns, halo effects, and macro- and micropsia long after the drug has been used.

The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV), Text Revision lists the following three criteria for HPPD: A) re-experiencing, after the use of a hallucinogen, of one or more of the perceptual symptoms that were experienced while intoxicated with the hallucinogen; B) the symptoms in criterion A cause clinically significant distress or impairment in social, occupational, or other important areas of functioning; and C) the symptoms are not due to a general medical condition and are not better accounted for by another mental disorder.

Halpern and Pope (2003) noted that when LSD was used in a therapeutic or research setting, HPPD appeared less frequently than when LSD was used recreationally. The authors concluded, however, that some individuals, especially users of LSD, can experience a long-lasting HPPD syndrome with symptoms of persistent perceptual abnormalities reminiscent of acute intoxication. Nevertheless, the incidence of HPPD is very small given the many tens of millions of persons who have taken LSD, most often in a recreational setting. Litjens et al. (2014) provided a recent comprehensive review on the subject of HPPD. The actual incidence of HPPD is not known and depends on the prevalence of use in different countries, but epidemiologic information is scarce.

Hermle et al. (2008) reviewed MEDLINE data for 19972007, searching for reports of hallucinogen-induced psychosis, flashbacks, and HPPD. The authors reported that adolescent intoxication with psychedelic drugs rarely produced acute psychotic syndromes, further stating that The clinical relevance of flashback phenomena as a post-hallucinogenic psychiatric disorder has to be disputed.

Although LSD was most widely used and therefore has led to the greatest number of HPPD cases, it is clear that other hallucinogens also can evoke the syndrome. For example, Espiard et al. (2005) reported HPPD in an 18-year-old man after mixed intoxication with psilocybin and cannabis. The symptoms persisted for more than 8 months. Ikeda et al. (2005) reported flashbacks after use of 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) by a 35-year-old man without a previous psychiatric history. He had used the substance six or seven times over 5 months but discontinued it after he had a bad trip, with anxiety, palpitations, auditory oversensitiveness, and visual distortions. Treatment with oral risperidone ameliorated his symptoms. Another case study described a 33-year-old woman who developed HPPD after LSD use for a year. Although treatment with antidepressants and risperidone did not ameliorate her symptoms, treatment with the antiseizure drug lamotrigine almost completely abolished her visual disturbances (Hermle et al., 2012).

Although the classic serotonergic hallucinogens are not recognized to be particularly toxic, a new class of substituted phenethylamines with toxic properties has recently become very popular as recreational drugs (Nikolaou et al., 2014). Unfortunately, there are now several reports of hospitalizations and fatalities attributed to these compounds (Poklis et al., 2013, 2014; Rose et al., 2013; Nikolaou et al., 2014; Tang et al., 2014; Walterscheid et al., 2014), but it is not clear whether deaths resulted from ingestion of lethal amounts of pure bulk drug or whether the drug has some inherent toxicity that is not normally associated with other psychedelics.

Suzuki et al. (2015) provided a comprehensive literature review of toxicities associated with NBOMe ingestion. The most common adverse reactions were agitation (including aggressiveness), tachycardia, and hypertension, with seizures reported in 40% of the patients. In the 20 individual cases they reviewed, 3 (15%) were fatalities.

The most potent of these new recreational chemicals are shown in Fig. 3, with potency increasing going from X = H to X = I.

For purposes of law enforcement the iodo compound (X = I; 25I-NBOMe) is presently considered by the U.S. Drug Enforcement Administration to be an analog of 2C-I [2-(4-iodo-2,5-dimethoxy)aminoethane], which is currently a Schedule 1 controlled substance. The procedure to classify 25I-NBOMe as a Schedule 1 substance has been initiated and it has been placed temporarily into Schedule 1 (Drug Enforcement Administration, 2013). Global interest in these compounds and closely related analogs has attracted increasing interest. For example, the European Monitoring Centre for Drugs and Drug Addiction has received a range of notifications from European Union member states about analytically confirmed nonfatal and fatal intoxications associated with 25I-NBOMe. This was followed by a risk assessment conducted by the European Monitoring Centre for Drugs and Drug Addiction Scientific Committee to assess health and social risks associated with the iodo analog (European Monitoring Centre for Drugs and Drug Addiction, 2014). In addition, the World Health Organizations Expert Committee on Drug Dependence reviewed the status of a range of new substances for its 36th meeting in June 2014, which included 25I-NBOMe and its 4-bromo and 4-chloro analogs (World Health Organization, 2014).

In the mouse head-twitch assay, 25I-NBOMe and a related analog were extremely potent in inducing this behavior, which was blocked by preadministration of the selective 5-HT2A antagonist M100907 [(R)-(+)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-pipidinemethanol] (Halberstadt and Geyer, 2014). As discussed in the section on mouse models later in this review, the mouse head twitch has shown a high correlation with human psychedelic activity.

A relatively large series of 48 NBOMe-type compounds has been evaluated for affinity and function at 5-HT2 family receptors (Hansen et al., 2014). Their work was directed toward development of potential radioligands for in vivo PET imaging of 5-HT2A receptors that would be selective over 5-HT2C receptors. One compound was discovered that had approximately 100-fold selectivity for both affinity and function at the 5-HT2A versus 5-HT2C receptor. Their high affinity and relative selectivity for the 5-HT2A receptor has made some of these compounds useful as agonist ligands for in vivo PET imaging (Ettrup et al., 2010; Finnema et al., 2014).

Curiously, the NBOMe-type compounds do not appear to be orally active and are typically administered bucally, or by nasal insufflation. Their potency is so high that they are often distributed on blotter papers and marketed as being LSD. Users place the blotters against their gums to effect absorption. One hypothesis put forward to explain the lack of oral activity for these highly active compounds is a significant first-pass metabolic effect (Leth-Petersen et al., 2014). In that study, the microsomal stability of 11 phenethylamines and their N-benzylated congeners was studied using human liver microsomes. It was found that the N-benzylated compounds had a much higher intrinsic clearance than did the simple phenethylamines, and the authors hypothesized that their low hepatic stability was the reason for their lack of oral activity.

Stellpflug et al. (2014) reported a clinical case of a nonfatal overdose with 25I-NBOMe. They identified a major metabolite of the compound in the urine that had a concentration 80-fold higher than the parent drug. The subjects urine was treated with -glucuronidase and then analyzed using ultraperformance liquid chromatography electrospray ionization plus tandem mass spectrometry to identify a major metabolite with a mass that was one methyl group lower than the parent compound. Comparison of the full fragmentation pattern was then assessed and concluded to be an O-demethylated metabolite at the 2- or 5-position of the trisubstituted ring, but the investigators were not able to determine which position had been metabolized. They detected two other very minor metabolites that also appeared to be O-demethylated. The concentration of the unmetabolized parent 25I-NBOMe in the urine was 7.5 ng/ml, whereas the desmethyl metabolite was 600 ng/ml. This metabolite and the two other minor metabolites were not present in the urine in the absence of prior enzymatic treatment, indicating that they were all glucuronidated.

Most recently, Leth-Petersen et al. (2015) identified the basis for the high first-pass effect of NBOMe compounds and the likely basis for their inactivity after oral administration. Using in vivo studies in pigs, they determined that the 5-methoxy of the trisubstituted phenyl ring is rapidly O-demethylated. After intravenous administration of 25B-NBOMe [N-(2-[11C]methoxybenzyl)-2,5-dimethoxy-4-bromophenethylamine (Cimbi-36)] to a pig, analysis revealed that plasma levels of the parent drug rapidly declined, with a new metabolite rapidly appearing and accumulating in plasma. At the 30-minute mark, there was more than twice as much of this metabolite present in plasma as there was of the parent compound. This metabolite was definitively identified as the 5-O-glucuronide using liquid chromatography/mass spectrometry and chemical synthesis. Evidently, the highly hydrophobic nature of the N-benzyl phenethylamines readily targets them to the mixed function oxidases in the endoplasmic reticulum, where they are efficiently 5-O-demethylated and then very quickly glucuronidated.

Stanislov Grof characterized LSD as a powerful nonspecific amplifier of the unconscious (Grof, 1975). This empirical observation was based on his personal supervision of more than a thousand clinical administrations of LSD. Barr et al. (1972) also stated that the phenomena induced by LSD cannot be predicted or understood in purely pharmacological terms; the personality of the drug taker plays an enormous and critical role in determining how much effect there will be and of what particular type.

However, until we understand the fundamental nature of consciousness and its underlying neuronal substrates, as well as the unconscious, it will not be possible to scientifically test Grofs hypothesis. What can be discussed are the findings that point to involvement of specific receptors in certain brain areas that lead to the overt effects of psychedelics. In addition, recent brain scanning technologies, including PET, fMRI, EEG, magnetoencephalography (MEG), and pharmacological magnetic resonance imaging (phMRI), have also allowed the identification of key brain areas that must be involved in the actions of psychedelics.

One should keep in mind that the effects of psychedelics are highly variable and are not necessarily dose dependent. At low doses of LSD (e.g.,

By contrast, high doses have a greater propensity to transport the user to an alternate reality, where they lose contact with their everyday environment. These occasions are often described as peak experiences, transcendent, or mystical and are profoundly altered states of consciousness. Users may feel that they have transcended time and space or encountered their concept of God, or they may feel that they have encountered otherworldly beings, feelings of being at one with the universe, reliving past memories, and so forth. With respect to medical value, this state of consciousness is most closely associated with dramatic therapeutic improvement. Although this phenomenon is more likely to occur after high doses of psychedelics, it can occur at nearly any dose if the set and setting have been optimized to promote such an ASC. These experiences are often characterized as among the most meaningful of the subjects life (e.g., see Griffiths et al., 2006) and can lead to persisting positive effects on attitudes, mood, and behavior.

It was only a decade after the discovery of the remarkable psychopharmacology of LSD that the presence of serotonin was demonstrated in the mammalian brain (Twarog and Page, 1953). A comparison of the chemical structures of LSD and serotonin (shown earlier) led to early hypotheses that the action of LSD was due to an interaction with serotonin systems in the brain. Ten years after the discovery of LSD, Gaddum (1953) reported that LSD antagonized the action of serotonin in peripheral tissues. Only 1 year later, Gaddum and Hameed (1954) and Woolley and Shaw (1954) independently proposed that the effects of LSD might result from serotonin receptor blockade in the CNS. Shaw and Woolley (1956) later modified their hypothesis to include the possibility that LSD might mimic the actions of serotonin. Numerous studies in the subsequent decade examined the possibility that LSD blocked the actions of serotonin, but it was a concept that proved untenable. It was clear, however, that LSD did have a potent effect on brain serotonin systems, elevating whole brain serotonin content (Freedman, 1961) and reducing brain levels of the major metabolite of serotonin, 5-hydroxyindole acetic acid (Rosecrans et al., 1967).

Ultimately, Andn et al. (1968) suggested that LSD might have direct agonist actions at serotonin receptors in the brain. Subsequently, studies from numerous laboratories provided support for that idea, with an initial focus on serotonin 5-HT1A receptors (see discussion in Nichols, 2004). When serotonin receptorselective antagonists became available, it was Glennon et al. (1983, 1984) who demonstrated in a rat drug discrimination model that the 5-HT2 antagonists ketanserin and pirenperone blocked the discriminative cue of a psychedelic. Further studies in numerous laboratories over the next 2 decades, primarily with rodents, then focused attention on the 5-HT2A receptor as the primary target for psychedelics. Agonist or partial agonist activity at the serotonin 5-HT2A receptor was ultimately concluded to be a necessary pharmacology for psychedelic effects, but it may not be sufficient to explain all of the qualitative differences between different drugs. As Ray (2010) pointed out, different molecules may also have significant affinity for other types of brain receptors.

The first definitive experiment pointing to the central role of the 5-HT2A receptor for the action of psychedelics in humans came from a clinical study by Vollenweider et al. (1998), who showed that the effects of psilocybin were blocked by the 5-HT2A receptorselective antagonist ketanserin or the atypical antipsychotic risperidone but were enhanced by the dopamine antagonist and typical antipsychotic haloperidol. These data provided the first evidence that psilocybin-induced effects in humans were due to 5-HT2A receptor activation. Subsequently, Vollenweider and colleagues have carried out several additional clinical studies, discussed later, of various aspects of the action of psilocybin and have shown that ketanserin can block most of those effects.

Kometer et al. (2012) carried out a randomized, double-blind study in 17 healthy human subjects. On 4 separate days, subjects received placebo, psilocybin (215 g/kg), the 5-HT2A antagonist ketanserin (50 mg, p.o.), or psilocybin plus ketanserin. Mood states were assessed, and behavioral and event-related potential measurements were used to quantify facial emotional recognition and goal-directed behavior toward emotional cues. Psilocybin was found to enhance positive mood and attenuate negative facial expression recognition. Furthermore, psilocybin increased goal-directed behavior toward positive compared with negative cues, facilitated positive but inhibited negative sequential emotional effects, and valence-dependently attenuated the P300 component. Ketanserin given alone had no effect but blocked the psilocybin-induced mood enhancement and decreased recognition of negative facial expression. This study demonstrated that psilocybin shifts the emotional bias across various psychologic domains and that activation of 5-HT2A receptors is central in mood regulation and emotional face recognition in healthy subjects. The authors suggest that their findings have implications not only for the pathophysiology of dysfunctional emotional biases, but they may also provide a framework to delineate the mechanisms underlying psilocybins putative antidepressant effects.

Quednow et al. (2012) investigated the role of 5-HT2A receptors in automatic (sensorimotor gating) and controlled (Stroop interference) inhibition processes in a model psychosis approach using psilocybin (260 g/kg) in 16 healthy humans pretreated either with the 5-HT2Aselective receptor antagonist ketanserin (40 mg) or placebo, using a placebo-controlled, crossover, counterbalanced, and double-blind design. They found that psilocybin-induced deficits in automatic and controlled inhibition were significantly attenuated by ketanserin. They also replicated their previous findings that most of the subjective hallucinogenic effects of psilocybin were abolished by ketanserin.

Kometer et al. (2013) assessed the effects of psilocybin (215 g/kg) on both oscillations that regulate cortical excitability and early visual evoked P1 and N170 potentials in 16 healthy human subjects. They employed a double-blind, placebo-controlled, within-subject, randomized design. Psilocybin generally significantly increased 5D-ASC scores after placebo pretreatment, but not after ketanserin pretreatment. Psilocybin strongly decreased both prestimulus parieto-occipatal power and decreased N170 potentials associated with the appearance of visual perceptual alterations, including visual hallucinations. Preadministration of the 5-HT2A antagonist ketanserin (50 mg) blocked all of these effects. The authors conclude that 5-HT2A receptor activation by psilocybin profoundly modulates the neurophysiological and phenomenological indices of visual processing. They further propose that 5-HT2A receptor activation may induce a processing mode in which stimulus-driven cortical excitation is overwhelmed by spontaneous neuronal excitation through modulation of oscillations.

Indirect evidence for a role of 5-HT2A receptors in mediating psychedelic-induced hallucinations comes from a study by Huot et al. (2010). In that study, [3H]ketanserin binding was used to compare 5-HT2A receptor density in postmortem brains of patients with Parkinsons disease (PD) who experienced visual hallucinations with the brains of PD patients who did not experience hallucinations. Six brains from patients with idiopathic PD who experienced visual hallucinations were compared with six PD patients without visual hallucinations and five healthy, age-matched controls. In PD patients with visual hallucinations, [3H]ketanserin binding was increased 45.6% in inferolateral temporal cortex compared with PD patients who did not have visual hallucinations. The authors suggest that increased 5-HT2A density in the inferolateral temporal cortex may be the basis for visual hallucinations in PD patients and that 5HT2A antagonists may alleviate this symptom.

Similarly, Ballanger et al. (2010) measured 5-HT2A binding in vivo using [18F]setoperone PET in brains of seven PD patients with visual hallucinations and seven age-matched PD patients without visual hallucinations. Patients with visual hallucinations had significantly increased 5-HT2A receptor binding in several cortical regions and one subcortical region. These increased levels of 5-HT2A receptor expression were clustered mainly in the ventral visual pathway. With the evidence of increased 5-HT2A receptor expression as a possible basis for visual hallucinations in PD patients, a serotonin 5-HT2A inverse agonist, perhaps not surprisingly, demonstrated phase 3 clinical efficacy in treating several symptoms of PD psychosis, including visual hallucinations (Hacksell et al., 2014).

Halberstadt et al. (2011a) examined the effects of several psychedelics on the mouse head twitch response (HTR) in wild-type (WT) male C57BL/6J or 5-HT2A knockout (KO) mice. They also assessed investigatory and locomotor activity in the mouse behavioral pattern monitor (BPM). Psilocin and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) produced the HTR in WT mice but not in KO mice. Psilocin and 5-MeO-DMT reduced locomotor activity, investigatory behavior, and center duration in the BPM, and these effects were blocked by the selective 5-HT1A antagonist WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- N-(2-pyridyl)cyclohexanecarboxamide), indicating that psilocin and 5-MeO-DMT act as mixed 5-HT1A/5-HT2A agonists. Halberstadt and Geyer (2011) reviewed the extensive literature covering various indoleamines as well as LSD and concluded that although the phenethylamines primarily exert their effects through activation of 5-HT2A receptors, indoleamines can have a significant behavioral component mediated by activation of 5-HT1A receptors.

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Psychedelics – Pharmacological Reviews

Psychedelics – Pharmacological Reviews

I. Introduction

I was delighted when the editors invited me to write a review on psychedelics, perhaps a watershed moment, representing a shift in opinion that has been developing for more than 3 decades with respect to research and understanding of psychedelics. When I began my graduate studies in 1969, it was politically correct in scientific circles to refer to these substances only as psychotomimetics, a negative term suggesting that they fostered a mental state resembling psychosis (Hoffer, 1967). Later, as it was realized that these compounds did not provide very realistic models of psychosis or mental illness, it became more correct to refer to them as hallucinogens, again a pejorative term suggesting that they principally produce hallucinations. Yet that is not what they do in most users at ordinary doses, so this term likewise is not particularly descriptive or useful, although it is still widely used and seems to remain the preferred name for these substances in most scientific writing. In addition, the term hallucinogen is often used as a rather broad category to include all kinds of psychoactive molecules, including cannabinoids, ecstasy, dissociative agents, and others.

This review will focus exclusively on the so-called classic serotonergic hallucinogens (psychedelics), which are substances that exert their effects primarily by an agonist (or partial agonist) action on brain serotonin 5-hydroxytryptamine (5-HT) 2A receptors, as discussed later. The discussion will not consider cannabinoids, dissociatives such as ketamine, salvinorin A (a specific opioid agonist), or entactogens such as 3,4-methylenedioxymethamphetamine (MDMA). In certain contexts, all of these and some related agents have been swept into the catchall category hallucinogens. Although they all can produce profound changes in consciousness, they have a different mechanism of action and will not be discussed unless there is a specific reason to do so.

The name psychedelics for these substances was coined by Humphrey Osmond in 1957, connoting that they have a mind-manifesting capability, revealing useful or beneficial properties of the mind (Osmond, 1957). This name has been popular among the lay public for more than 5 decades, but it has generally been frowned upon by the scientific community because it implies that these substances have useful properties. The notion that psychedelics can have beneficial effects has thus far not been embraced in most medical or scientific circles; indeed, federal funding agencies (e.g., the National Institutes of Health National Institute on Drug Abuse and the National Institute of Mental Health) have no mission to support research on potentially useful properties of psychedelics. Yet this term has remained popular with the public and even appears to be gaining popularity. As I intend to show in this discussion, however, the idea that psychedelics may have useful properties is not at all farfetched, and very recent clinical studies have reinforced the belief by many that psychedelics are well worth studying from a number of different perspectives. Indeed, one of the most striking developments in this field has been the initiation and successful completion of a variety of clinical studies of psychedelics in the past 15 years, most of which have been targeted to specific medical indications. As will be discussed later, the results have been, in the main, remarkably positive.

It should be kept in mind that the relative dearth of research on psychedelics in the past half century did not result from a lack of scientific interest, but rather occurred as a consequence of political forces that manifested principally in the United States in the 1960s and 1970s (Grinspoon and Bakalar, 1979). Use of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD) and marijuana by so-called hippies who demonstrated against the Vietnam War during the 1960s created great consternation among authorities and legislative bodies, both at the federal and state levels. Antiwar attitudes and rejection of conventional social norms by adolescents and college students were often perceived by the mainstream culture to be a consequence of drug use; hence, these substances were often believed to be perverting the minds of our youth. Furthermore, the outspoken Harvard University professor and firebrand Timothy Leary encouraged young people to turn on, tune in, and drop out, essentially coaching them to take drugs, discover their true selves, and abandon convention. Such messages did not play well with the mainstream culture, all while the mass media fanned the flames of public hysteria with greatly exaggerated reports of drug-induced insanity, chromosomal damage, attempts to fly, and so forth.

Strict laws were quickly passed. After the passage of the Controlled Substances Act of 1970, LSD and other psychedelics known at the time were placed into the most restrictive category of drugs, Schedule 1. This classification made them virtually impossible to study clinically and effectively ended any significant research into the pharmacology and medical value of psychedelics for more than 3 decades. Nevertheless, there can be no doubt that psychedelics played a substantial role in defining the youth culture of the 1960s and 1970s, with books and essays too numerous to cite being written on this topic. It is believed that more than 30 million people have used LSD, psilocybin, or mescaline (Krebs and Johansen, 2013). One suspects that had LSD never been discovered, the world might look very different today than it does now, for better or worse, depending on ones perspective.

Despite the recreational use of psychedelics, a quote from a book by Grinspoon and Bakalar (1979 Pg 192) needs to be kept in mind:Many people remember vaguely that LSD and other psychedelic drugs were once used experimentally in psychiatry, but few realize how much and how long they were used. This was not a quickly rejected and forgotten fad. Between 1950 and the mid-1960s there were more than a thousand clinical papers discussing 40,000 patients, several dozen books, and six international conferences on psychedelic drug therapy. It aroused the interest of many psychiatrists who were in no sense cultural rebels or especially radical in their attitudes.

One very important scientific consequence of the discovery of LSD also is often overlooked. The powerful psychologic effect of LSD was accidently discovered in 1943 (Hofmann, 1979a), followed only a decade later in 1953 by the detection of serotonin in the mammalian brain (Twarog and Page, 1953). The presence of the tryptamine moiety within LSD was also quickly seen to be the scaffold for the chemical structure of serotonin (Fig. 1).

Chemical structures of serotonin and LSD.

This recognition led to a proposal only 1 year later by Woolley and Shaw (1954) that mental disturbances caused by lysergic acid diethylamide were to be attributed to an interference with the action of serotonin in the brain. Therefore, one could reasonably argue that the whole field of serotonin neuroscience, and especially the role of serotonin in brain function, was catalyzed by the discovery of LSD! By way of illustration, in 1952, there were only 10 publications in the National Library of Medicine concerning serotonin, nearly all of them dealing with some aspect of its ability to constrict blood vessels. Only 8 years later, in 1960, there were 300 publications on serotonin, 35 of which were now focused on studies of serotonin in the brain. For comparison, in 1960, there were only 197 publications about norepinephrine (NE)/noradrenaline, a neurotransmitter that had been discovered and studied in the mid-1940s. Green (2008) provides an interesting overview of the 19501970 period of intense research activity after the discovery of serotonin in the brain.

There have been numerous recent reviews on this topic, usually titled as hallucinogens, and the reader is encouraged to consult these works for further details (Nichols, 2004; Nichols and Chemel, 2006; Fantegrossi et al., 2008a; Green, 2008; Passie et al., 2008; Winter, 2009; Griffiths and Grob, 2010; Vollenweider and Kometer, 2010; Brandt and Passie, 2012; Beck and Bonnet, 2013; Halberstadt and Geyer, 2013b; Baumeister et al., 2014; Halberstadt, 2014; Tyl et al., 2014). I wrote a comprehensive review on the subject in 2004, so the literature considered for this review will focus primarily, but not exclusively, on the years from 2004 to the present.

Psychedelics are a class of drug that cannot be fully understood without reference to a number of other fields of research, including anthropology, ethnopharmacology, psychiatry, psychology, sociology, and others. This review will focus mostly on pharmacology, both preclinical and clinical, but on occasion reference will be made to aspects of some of those other areas.

Psychedelics may be the oldest class of psychopharmacological agents known to man. Important examples of these substances include a substance used in ancient India known as Soma, which was highly revered and is frequently mentioned in the Rigveda, with numerous Vedic hymns written in praise of Soma (Wasson and Ingalls, 1971). In the ancient village of Eleusis, outside Athens, for more than 2000 years there was an annual all-night secret ceremony that is believed to have involved ingestion of a hallucinogenic brew known as (Wasson et al., 1978). We know almost nothing about the ceremony other than that profound insights about life could be achieved, and it was apparently a treasured once-in-a-lifetime opportunity for any Greek citizen who had not been convicted of murder.

Psilocybin mushrooms were used by the Aztec shaman in healing and in a variety of religious and divinatory rituals. These mushrooms were known as teonanacatl, meaning gods flesh (Ott and Bigwood, 1978; Schultes and Hofmann, 1979). The use of various psychoactive plant materials and substances was common in pre-Columbian Mesoamerican societies, including the Olmec, Zapotec, Maya, and Aztec cultures (Carod-Artal, 2015). In the Bradshaw rock art in the Kimberly region of Australia and in the Sandawe rock art in the Kolo region of Eastern Tanzania, one finds uniquely shared images such as the mushroom head symbol of psilocybin use, suggesting that the two cultures were linked and had shamanic practices that used psychoactive mushrooms (Pettigrew, 2011).

Peyote (Lophophora williamsii) is a small cactus native to the American Southwest and Northern Mexico that has been used for millennia and is consumed as a sacrament during services of the Native American Church. Two peyote samples from a cave on the Rio Grande River in Texas were analyzed and subjected to radiocarbon dating. The average age of the samples, both of which contained mescaline, dated to 37803660 BCE (El-Seedi et al., 2005). This evidence supports the use of peyote by Native North Americans as long ago as 5700 years (Bruhn et al., 2002). Classic psychedelics that have been extensively studied include LSD, shown earlier, mescaline, psilocybin, and N,N-dimethyltryptamine (DMT) (Fig. 2).

Chemical structures of classic psychadelics mescaline, psilocybin, and DMT.

Ayahuasca, also known as yag or hoasca, has a long history of use by natives in the Amazon valley of South America (Dobkin de Rios, 1971; Schultes and Hofmann, 1979). Ayahuasca is a decoction prepared from an admixture of two plants: the pounded bark from Banisteriopsis caapi vines and leaves from Psychotria viridis. The latter contains the hallucinogen DMT, a Schedule 1 controlled substance under U.S. law, and it is generally considered that the psychoactive effects of ayahuasca can be attributed to its DMT content. Although DMT is not orally active, B. caapi contains -carboline alkaloids that inhibit the liver monoamine oxidase (MAO) that normally breaks down DMT; thus, ayahuasca is taken orally as a tea. Its use has been incorporated as a sacrament into the religious practices of two syncretic Brazilian churches [Unio do Vegetal (UDV) and the Santo Daime] that have branches in the United States, with the U.S. Supreme Court rendering a 2006 decision to allow the use of ayahuasca by the UDV under the Religious Freedom Restoration Act.

In view of the widespread historical use of psychedelics as sacraments in a variety of other cultures, Jaffes (1990) definition for the class of psychedelics can perhaps be appreciated: the feature that distinguishes the psychedelic agents from other classes of drug is their capacity reliably to induce states of altered perception, thought, and feeling that are not experienced otherwise except in dreams or at times of religious exaltation. All pharmacologists will recognize that this definition for a class of psychoactive drugs is indeed quite unique!

One of the pioneers of LSD research, the late Daniel X. Freedman, noted that one basic dimension of behavior compellingly revealed in LSD states is portentousness the capacity of the mind to see more than it can tell, to experience more than it can explicate, to believe in and be impressed with more than it can rationally justify, to experience boundlessness and boundaryless events, from the banal to the profound (Freedman, 1968). Freedmans observation is completely consistent with Jaffes definition.

The use of psychedelics as a central feature of many religious practices, as well as the profound and unique psychopharmacological effects suggested by Jaffes definition and the observations of Freedman, surely makes us aware that psychedelics are an exceptional category of mind-altering substances. Indeed, this knowledge prompted Ruck et al. (1979) to coin the word entheogen as a replacement for the terms hallucinogen and psychedelic, both of which they felt had negative connotations. Entheogen is derived from the Greek roots entheos, meaning God (theos) within, and genesthe, meaning to generate. The word entheogen thus essentially refers to a substance or material that generates God or the divine within someone. Although the term entheogen is now seeing fairly wide acceptance within the culture of those who use these substances recreationally, a search of the term in the National Library of Medicine finds only five hits. Although it seems unlikely that the term entheogen will be adopted within the formal scientific community, the reader should realize that in some circles entheogen is generally synonymous with psychedelic. Nonetheless, it should be appreciated that the effects produced by psychedelics are highly dependent on the set (mental expectation) of the user and the setting (environment). A set and setting designed to facilitate a mystical experience will increase the probability of such an occurrence, whereas an unstructured or party-type setting is less likely to lead to a positive outcome.

Studerus et al. (2012) investigated the importance of 24 predictor variables on the acute response to psilocybin and confirmed that nonpharmacological factors play an important role in the effects of psilocybin. Variables examined included age, sex, education, personality traits, drug pre-experience, mental state before drug intake, experimental setting, and drug dose. Their analysis was based on pooled data from 23 controlled experimental studies involving 261 healthy volunteers who had participated in 409 psilocybin administrations over a 19-year period in the authors laboratory. Multiple linear mixed-effects models were fitted for each of 15 response variables. Drug dose was shown to be the most important predictor for all measured response variables, but several nonpharmacological variables significantly contributed to the effects of psilocybin. Specifically, having a high score in the personality trait of absorption, being in an emotionally excitable and active state immediately before drug intake, and having experienced few psychologic problems in past weeks were most strongly associated with pleasant and mystical-type experiences. High emotional excitability, young age, and an experimental setting involving positron emission tomography (PET) most strongly predicted unpleasant and/or anxious reactions to psilocybin. Interestingly, in addition to confirming that nonpharmacological variables play an important role in the effects of psilocybin, an experimental setting involving PET most strongly predicted unpleasant and/or anxious reactions to psilocybin.

Two instruments have been most widely used to assess the subjective effects of hallucinogenic drugs. The first of these, the Hallucinogen Rating Scale (HRS) was developed by Strassman et al. (1994) during their studies of the intravenous administration of DMT. The HRS was first drafted based on interviews with 19 experienced DMT users and was modified during the early stages of their study. The final version, used for their double-blind study, contained 126 individual items. HRS items were placed into six conceptually coherent clusters: somaesthesia (interoceptive, visceral, and cutaneous/tactile effects), affect (emotional/affective responses), perception (visual, auditory, gustatory, and olfactory experiences), cognition (alteration in thought processes or content), volition (a change in capacity to interact willfully with themselves, the environment, or certain aspects of the experience), and intensity (strength of the various aspects of the experience). Subjects were asked to recall their experiences from the immediately preceding session. Most questions were scored on a 04 scale (0, not at all; 1, slightly; 2, moderately; 3, quite a bit; and 4, extremely).

The second assessment instrument widely used to quantify the subjective effects of hallucinogens is the Abnormal Mental States (APZ) questionnaire, first developed by Dittrich (1994, 1998) to measure altered states of consciousness (ASCs). In a series of 11 experiments using different induction methods in 393 healthy subjects, the hypothesis was tested that ASCs have major dimensions in common, irrespective of their mode of induction. The original version contained 158 items covering a range of phenomena potentially occurring during an ASC. The common denominator of ASCs was described by three primary oblique dimensions, designated as oceanic boundlessness (OSE, later as OBN), dread of ego dissolution (AIA, and later as DED), and visionary restructuralization (VUS, later as VRS). The APZ questionnaire became the international validated standard for the assessment of ASCs and the name was further revised to the OAV scales (Bodmer et al., 1994) and later to the five-dimensional altered states of consciousness (5D-ASC) (Dittrich et al., 2006). Details of the development of the original APZ questionnaire and its further refinements were summarized by Studerus et al. (2010). To overcome a variety of methodological limitations, Studerus et al. (2010) carried out a psychometric evaluation of the OAV and 5D-ASC in a relatively large sample from 43 pooled experimental studies of healthy subjects who had received psilocybin, ketamine, or MDMA. The total sample was composed of 591 drug sessions. After comprehensive and detailed statistical analyses, the authors found that the original OAV scales were multidimensional constructs, and arrived at an improved final model that had 11 factors: experience of unity, spiritual experience, blissful state, insightfulness, disembodiment, impaired control and cognition, anxiety, complex imagery, elementary imagery, audio-visual synesthesia, and changed meaning of percepts. Correlations between the 11 factors and their association with the original OAV scales were presented. The new lower-order scales were proposed to be better suited to assess drug-induced ASCs.

Mechanistically, psychedelics have agonist or partial agonist activity at brain serotonin 5-HT2A receptors. This molecular characterization will be elaborated in some detail later in this review, and aspects of the anatomic and functional importance of this receptor type will also be extensively explored. Discussions over the years with many colleagues working in the pharmaceutical industry have informed me that if upon screening a potential new drug is found to have serotonin 5-HT2A agonist activity, it nearly always signals the end to any further development of that molecule.

A recent study by Turton et al. (2014) reported on the subjective experience of intravenous psilocybin administered during a functional magnetic resonance imaging (fMRI) examination. Fifteen volunteers were administered an intravenous infusion of either placebo or 2 mg psilocybin and were blinded as to whether they would receive placebo or drug for a particular experiment. Drug infusion began 6 minutes after the start of a scan in a magnetic resonance imaging scanner. Subjects completed a visual analog scale rating the intensity of the drug experience at the start of the scan and prior to drug infusion, 5 minutes postinfusion, and 12 minutes postinfusion. All subjects subsequently were interviewed about the drug effects, and interviews were analyzed using interpretative phenomenological analysis, a qualitative method. All subjects reported that the onset of drug effect was very rapid and intense, with a duration of effect lasting 1015 minutes. The investigators identified nine broad categories of phenomenology. Altered somatosensory, visual, auditory, and proprioceptive sensations were reported, with 14 of 15 subjects describing perceptual changes as the primary effect of the drug. Thirteen subjects reported changes in perception of time, either speeding up or slowing down. The report describes a variety of effects on cognition, mood, memory, and spiritual or mystical experiences. Overall, subjects found the experience difficult to describe, yet most found it pleasant and positive.

In a new study by Schmid et al. (2015), LSD (200 g) was administered orally to 16 healthy subjects in a double-blind, randomized, placebo-controlled, crossover study. LSD produced a pronounced alteration in waking consciousness that lasted for 12 hours and included visual hallucinations, audio-visual synesthesia, and positively experienced derealization and depersonalization phenomena. Compared with placebo, LSD increased subjective well-being, happiness, closeness to others, openness, and trust. Increases in blood pressure, heart rate, body temperature, pupil size, plasma cortisol, prolactin, oxytocin, and epinephrine also were measured. On the 5D-ASC scale, LSD produced higher scores than did psilocybin or DMT. The authors also described subjective effects on mood that were similar to those reported for MDMA that might be useful in psychotherapy. No severe acute adverse effects were observed and the effects subsided completely within 72 hours.

In a very recent study by Carhart-Harris et al. (2015a), LSD was shown to enhance responsiveness to suggestion. Their study was prompted by very early reports indicating that LSD increased suggestibility (Sjobergand Hollister, 1965; Middlefell, 1967). Thus, Carhart-Harris et al. (2015a) administered LSD (4080 g, i.v.) to 10 healthy volunteers in a within-subject placebo-controlled design. Suggestibility and cued mental imagery were assessed using the Creative Imagination Scale and a mental imagery test. The two instruments were administered between 110 and 140 minutes after drug infusion, at the peak of the drug effect. Subjects scored significantly higher on the Creative Imagination Scale, but not the mental imagery test after LSD administration, compared with placebo. The magnitude of suggestibility enhancement was positively correlated with the subjects baseline trait conscientiousness. This enhanced suggestibility may have implications for the use of LSD as an adjunct to psychotherapy, but it also indicates that individuals with a high trait conscientiousness are particularly sensitive to the suggestibility-enhancement effect of LSD.

It has been axiomatic among users of psychedelics that music takes on an intensified and more enjoyable quality under the effects of LSD or other psychedelics, yet no modern placebo-controlled study had ever been carried out to confirm that widely held belief. Early studies at the Maryland Psychiatric Research Center found that music was a very effective stimulus and complement to the effect of LSD (Bonny and Pahnke, 1972). Gaston and Eagle (1970) also reported that the presence of music was much preferable to its absence in alcoholic patients undergoing treatment using LSD therapy, both by patient preference and treatment results. Numerous other studies had been reported on the value of music in the context of various shamanic and therapeutic approaches (see references in Kaelen et al., 2015). Very recently, therefore, Kaelen et al. (2015) tested the hypothesis that the emotional response to music is enhanced by LSD. Ten participants were administered placebo or various doses of LSD, including 40, 50, 70, or 80 g, infused intravenously over 3 minutes. They then listened to five different instrumental music tracks on each of two study days: a placebo day followed by an LSD day, separated by 57 days. Music tracks were chosen that produced the highest liking and lowest familiarity by a separate sample of nine participants. The question How emotionally affected were you by the music? was asked immediately after each track and served as the studys primary outcome. The nine-category Geneva Emotional Music Scale (Zentner et al., 2008) was also used. Mean scores for all music stimuli in response to the question how emotionally affected were you by the music? were significantly higher for the LSD condition than for placebo. In addition, all nine factors on the Geneva Emotional Music Scale were scored higher after LSD administration than after placebo. Emotions related to transcendence also were enhanced by LSD. Specific emotions showing the strongest enhancement included wonder, transcendence, tenderness, and power. Furthermore, there was a significant positive relationship between ratings of the intensity of the LSD effect and emotional arousal to music. The results of Zentner et al. (2008) support the hypothesis that LSD enhances music-evoked emotion.

The experimental study of mystical or ecstatic states engendered by psychedelics perhaps began with the so-called Good Friday experiment, carried out at Boston Universitys Marsh Chapel in 1962 by Walter Pahnke as his research for the Ph.D. in religion and society at the Harvard Divinity School. Pahnke (1963) examined the similarities and differences between experiences described by mystics and those induced by psilocybin. On Good Friday in 1962, 20 Christian theological student volunteers attended a 2.5-hour religious service in Boston Universitys Marsh Chapel. The setting and preparation of the subjects was designed to optimize a spiritual or mystical experience. In a double-blind procedure, subjects were given either an oral dose of 30 mg psilocybin, or a 200-mg placebo dose of nicotinic acid, administered in identical capsules. Based on responses to a variety of instruments and questionnaires, subjects who received psilocybin had experiences that were indistinguishable from those experienced by mystics. The experiences were powerful and personally meaningful. Doblin (1991) reported a follow-up to the Pahnke study in 1989 and was able to locate and interview 19 of the original 20 experimental participants. All of the psilocybin subjects felt that the experience had significantly affected their lives in a positive way and they expressed appreciation for having participated in the experiment.

An extension of the Good Friday experiment was recently carried out by Griffiths et al. (2006). The investigators used rigorous double-blind clinical methods to evaluate acute and longer-term effects of psilocybin (30 mg/70 kg) compared with an active comparator compound (40 mg/70 kg methylphenidate). A complex design was used to obscure which treatments were administered from the study participants and the monitors, and the study was designed to minimize adverse effects. Thirty-six healthy volunteers were enrolled, all of whom indicated some participation in regular religious or spiritual activities. Instruments used to assess effects 7 hours after drug administration were the HRS, the Addiction Research Center Inventory, the States of Consciousness questionnaire, and the Mysticism Scale. Seven to 8 weeks after each session, and before any additional session, subjects completed the Persisting Effects Questionnaire, the Mysticism ScaleLifetime, the Spiritual Transcendence Scale, the NEO Personality Inventory, and the Positive and Negative Affect Schedule Expanded Form. Based on measures of mystical experience, 22 of the 36 volunteers had a complete mystical experience after psilocybin administration, whereas only 4 did after the methylphenidate (placebo) sessions. Based on ratings of personal meaningfulness and spiritual experience, 67% of the volunteers rated the psilocybin experience to be either the single most meaningful experience of their lives or among the top five most meaningful experiences in their lives. Based on community observer ratings, psilocybin sessions were associated with significant positive changes in the volunteers behavior and attitudes.

Thus, when psilocybin was administered under structured conditions to well prepared volunteers, it occasioned experiences that had marked similarities to classic mystical experiences, imparting to the participants substantial personal meaning and spiritual significance. The investigators point out that the high value some subjects placed on the psilocybin experience may in part explain the long-term historical use of psychedelics within some cultures for divinatory or religious purposes. Griffiths et al. (2006) conclude with the statement that, The ability to prospectively occasion mystical experiences should permit rigorous scientific investigations about their causes and consequences.

Griffiths et al. (2008) subsequently conducted a 14-month follow-up of the subjects from their earlier study. Subjects were asked to identify in which session they experienced the most pronounced changes in your ordinary mental process. It was found that the 14-month retrospective follow-up ratings for the psilocybin session did not differ significantly from the immediate postsession ratings. Compared with methylphenidate, the psilocybin experience produced significant increases in ratings of positive attitudes, mood, social effects, and behavior at 14 months of follow-up. At the 14-month follow-up, 58% of the 36 volunteers still rated the psilocybin experience as among the five most personally meaningful experiences of their lives and 67% rated it as among the five most spiritually significant experiences of their lives.

A second study using a similar protocol with 18 volunteers examined dose effects of psilocybin, using 0, 5, 10, 20, and 30 mg/70 kg (Griffiths et al., 2011). The percentage of subjects who met the criteria for having a complete mystical-type experience increased with dose. Overall, 72.2% of volunteers had complete mystical experiences at either or both doses of 20 and 30 mg/70 kg. Positive ratings about life, attitudes about self, mood, social effects, and behavior also increased as a function of dose. Ratings at the 14-month follow-up were undiminished compared with ratings at 1 month after the sessions.

MacLean et al. (2011) analyzed the data from the two double-blind controlled studies of psilocybin reported by Griffiths et al. (2006, 2011). In particular, their goal was to use the NEO Personality Inventory to analyze possible personality changes that might have occurred after the high-dose psilocybin sessions in those studies. It is generally believed that personality traits are relatively enduring and that an individuals personality is predominantly stable across the lifespan. Yet evidence also exists that significant life events may dramatically change adult personality (see references in MacLean et al., 2011). The most widely accepted model of personality structure is the five-factor model, which describes five broad domains of personality: neuroticism, extroversion, openness, agreeableness, and conscientiousness (see references in MacLean et al., 2011). The authors suggest that numerous subjective claims of long-term changes after hallucinogen use appear to align with the personality trait of openness, which encompasses aesthetic appreciation and sensitivity, imagination and fantasy, and broad-minded tolerance of others viewpoints and values. Thus, they hypothesize that the mystical experiences reported in the studies by Griffiths et al. might lead to enduring increases in openness. Analysis of personality was assessed 1 to 2 months after a high-dose psilocybin session and again 16 months later to determine the persistence of any personality change(s). Consistent with their hypothesis, a mystical experience after psilocybin administration was significantly correlated with increases in openness. No such effect was seen after methylphenidate treatment. In addition, there were no significant changes in any of the other four personality factors after psilocybin administration. At the 16-month follow-up, openness levels still remained significantly elevated. The authors note that This is the first study to demonstrate changes in personality in healthy adults after an experimentally manipulated discrete event.

Studerus et al. (2011) pooled raw data from eight double-blind placebo-controlled experimental psilocybin studies conducted between 1999 and 2008. The data were analyzed for acute, short- and long-term subjective effects of psilocybin in 110 healthy human subjects who had received between one and four doses of 45315 g/kg psilocybin. Studerus et al. (2011) reported that nearly 40% of the participants in their laboratory studies of psilocybin claimed positive long-term changes in aesthetic experience and in their relationship with the environment (i.e., nature) after their psilocybin sessions. At 816 months after psilocybin sessions, more than 60% of subjects rated the experience as very enriching, and more than 90% described it as enriching to at least a medium degree. These effects occurred despite the fact that no attempt was made in their experiments to optimize conditions for a spiritual or mystical experience, which contrasts with the setting and preparations used in the two Griffiths studies cited above.

Bouso et al. (2012) compared 127 regular ayahuasca users with 115 actively religious controls who did not use ayahuasca. Baseline measurements were taken of general psychologic well-being, mental health, and cognition and the groups were then compared 1 year later to determine whether regular ayahuasca use had an effect on these measurements. Regular ayahuasca users showed lower scores on all psychopathology scales as assessed by the Symptom Checklist 90Revised, as well as on measures of harm avoidance and self-directedness. Participants scored higher on a measure of psychosocial well-being and performed better on the Stroop test (an indicator of resistance to emotional interference) and the Wisconsin Card Sorting Task (a measure of working memory). No evidence of psychologic maladjustment, mental health deterioration, or cognitive impairment was found in the ayahuasca-using group.

Lerner and Lyvers (2006) compared users of psychedelic drugs with users of nonpsychedelic drugs and nonillicit drugusing social drinkers. Samples were drawn from Israel and Australia. Compared with the other two groups, psychedelic drug users scored significantly higher on mystical beliefs (e.g., oneness with God and the universe), life values of spirituality, and concern for others, and scored lower on the value of financial prosperity, irrespective of culture of origin.

Lyvers and Meester (2012) carried out a website survey of 337 adults who used a variety of drugs, including psychedelics. Only about 25% reported spiritual motives for using psychedelics, yet use of high doses of LSD and psilocybin was significantly correlated in a dose-related manner with scores on two well known indices of mystical experiences; use of MDMA, cannabis, cocaine, opiates, or alcohol was not. Thus, even when taken recreationally, psychedelics have the potential to induce mystical experiences.

Quite interestingly, the underlying neuronal basis for mystical/spiritual experiences has recently been the subject of scientific investigation. Kometer et al. (2015) studied the neuronal basis of spiritual experiences and insightfulness after administration of psilocybin to human subjects. They conducted a double-blind, placebo-controlled study and administered psilocybin (170 or 215 g/kg, p.o.) to 50 healthy human volunteers. Electroencephalography (EEG) data were recorded from 64 scalp electrodes. Exact low-resolution brain electromagnetic tomography was applied to compute the three-dimensional intracerebral current density values of the scalp-recorded EEG rhythms. They used lagged phase synchronization, a new measure that can capture nonlinear neuronal relationships to assess dynamic functional connectivity (Pascual-Marqui et al., 2011).

The 11-dimension 5D-ASC questionnaire was used to quantify the subjective psychologic effects of psilocybin, with a particular interest in the spiritual experience subscale, and the related subscales of experience of unity, comprising experience of oneness with the environment and the self, insightfulness, measuring profound insights into life and existence, blissful state, measuring experiences of pleasure, inner peace, and love. Voxel-wise product-moment correlations between current source density in the psilocybin condition and the 11-dimension 5D-ASC subscale scores were computed by regression analysis.

Psilocybin significantly increased scores of all subscales on the 5D-ASC but significantly decreased current source density of oscillations in all frequency bands up to 20 Hz (eyes-closed condition) or up to 30 Hz (eyes-open condition). There was a significant and consistent psilocybin-induced reduction of current source density across low frequency bands (

The extent of lagged phase synchronization within a network of deep cortical structures strongly and positively correlated with score on the insightfulness subscale of the 5D-ASC and spiritual experiences subscales of the 5D-ASC during the eyes-closed condition. Lagged phase synchronization of 1.5- to 4-Hz oscillations within a network comprising the RSC, parahippocampus, and lateral orbitofrontal area was associated with spiritual experiences and insightfulness.

These findings of Kometer et al. (2015) provide further evidence that decreased ongoing oscillations below 20 Hz, particularly / oscillations, may be a common mechanism of action of psychedelics. The decrease in lower frequency oscillations was found to be localized within an extended network that included the PCC, RSC, ACC, and parahippocampal regions, a network that strongly overlaps with the default mode network (DMN). Thus, psilocybin may modulate default mode functions by decreasing ongoing lower frequency oscillations within this network.

Lower frequency oscillations, particularly in the range, mediate rhythmic cortical inhibition of neuronal ensembles (see references in Kometer et al., 2015). The marked decrease in lower frequency oscillations observed in this study may indicate that psilocybin induces a shift of the resting excitation/inhibition balance toward excitation, which would be expected to disrupt the ordinary temporal structure of neuronal processes within the extended DMN.

Lagged phase synchronization was strongly associated with the psilocybin-induced state of consciousness, supporting the view that neural integration, rather than activity, underlies the state of consciousness. Scores of the spiritual experiences subscale of the 5D-ASC questionnaire were also associated with increased lagged phase synchronization of oscillations between parahippocampal regions and the RSC. Kometer et al., (2015) speculate that the neuronal network processes they identified may constitute a crucial pathway that can be modulated by serotonergic receptors to regulate mental health, a conclusion that would be consistent with some of the potential positive mental health outcomes discussed earlier in this section.

For decades, the media have largely portrayed psychedelics as extremely dangerous drugs; in fact, the classic serotoninergic psychedelics are generally considered very physiologically safe, certainly compared with opiates and psychostimulants. Jaffe (1985) stated, In man, deaths attributable to direct effects of LSD are unknown, and this statement remains true even today. Nonetheless, despite the relative physiologic safety of psychedelics, they can lead to serious psychologic consequences. In addition, as will be discussed later, some of the newer highly potent synthetic phenethylamine hallucinogens have proven to be unexpectedly toxic. This section will detail studies indicating that psychedelics can be safely used under supervision, and that few documented serious adverse effects occur even after recreational use. The discussion will then turn to some generally recognized adverse reactions, followed by case reports of some more serious and even fatal reactions to psychedelics. It should be emphasized that these latter fatalities, which are rare, have occurred after use of newer synthetic phenethylamine compounds, and not as a result of ingestion of LSD, psilocybin, mescaline, or DMT.

Analysis of early published reports on adverse reactions and long-term negative sequelae induced by classic psychedelics failed to identify significant adverse events; if long-term adverse effects from repeated use did occur, they were subtle or nonsignificant (Strassman, 1984; Halpern and Pope, 1999). Their reviews were based on reports from supervised clinical studies using pure drugs, so the same conclusions might not apply to recreational use of drugs with unknown identities or purity.

These substances do not lead to addiction or dependence and are not considered to be reinforcing (O’Brien, 2001). This is understandable when one realizes that the serotonergic hallucinogens do not have direct effects on brain dopaminergic systems, a pharmacology that appears essential for nearly all drugs that can engender dependence. Attempts to train animals to self-administer hallucinogens, an animal model that can predict abuse liability, have generally been unsuccessful.

Using 20012004 data drawn from the National Survey on Drug Use and Health (NSDUH), Krebs and Johansen (2013) recently evaluated possible associations between lifetime use of psychedelics and current mental health in the U.S. adult population. In a large sample of respondents, 13.4% reported lifetime psychedelic use. No significant associations were found between lifetime use of any psychedelic or past-year use of LSD and increased rate of any mental health outcome. Surprisingly, in several cases, use of psychedelics was associated with a lower mental health problem rate.

A statewide survey of the adult population in Colorado sought to determine whether psychedelic use was correlated with the lifetime risk of panic attacks (Bonn-Miller et al., 2007). No association was found between psychedelic use and panic attacks, but psychedelic abuse and dependence were significantly related to an increased lifetime risk of panic attacks. It should be noted that in this study, however, phencyclidine (PCP) was included in their survey as a psychedelic, and this substance, in contrast with the classic serotonergic psychedelics, can cause dependence.

Peyote (L. williamsii) is a small cactus that grows in the Southwestern United States and Northern Mexico. It contains the psychedelic compound mescaline and has been used for centuries by Native American populations in rituals and ceremonies. Mescaline is also found in the San Pedro and Peruvian Torch cacti, and these have also been used ceremonially. Although peyote is classified as a Schedule 1 controlled substance, members of the Native American Church have a legal exemption to use it in their religious services. Halpern et al. (2005) compared 61 Navajo Native American Church members who regularly ingested peyote with 79 individuals reporting minimal use of peyote, alcohol, or other substances. Cognitive function was assessed using the Rand Mental Health Inventory and 10 standard neuropsychological tests of memory and attentional/executive functions. The peyote-using group showed no significant deficits on the Rand Mental Health Inventory or on any of the 10 other tests used. For the peyote-using group, total lifetime peyote exposure was not associated with neuropsychological performance.

By contrast, recreational use of peyote has led to adverse events, although peyote exposures reported to poison control centers are relatively rare compared with other drugs of abuse. In 2007, for example, only 116 peyote or mescaline exposures were reported to U.S. poison control centers out of more than 2.4 million total drug exposures (Bronstein et al., 2008). Carstairs and Cantrell (2010) retrospectively reviewed the California Poison Control System electronic database between the years 1997 and 2008 for reports of cases involving adverse reactions to peyote or mescaline ingestion when it was the sole intoxicating agent. A total of 31 cases were identified that met their inclusion criteria. Life-threatening symptoms did not occur, and most exposures were associated with only mild to moderate clinical effects, which most commonly included tachycardia and central nervous system (CNS) effects. Symptoms typically resolved within 24 hours or less and did not usually require anything more than supportive measures or sedation. One case of a prolonged peyote-induced psychosis was reported by Lu et al. (2004), in which the psychosis resolved after sleep. The case involved a 54-year-old Native American man with no prior history of psychosis. He drank peyote juice during a healing ceremony and within a few hours became convinced that he was hunted by animal spirits. He was unable to sleep for 2 weeks, at which time he developed visual and auditory hallucinations of the spirits and became increasingly depressed. He was persuaded to enter a hospital, where he received trazodone to help him sleep. He fell asleep and slept for 15 hours, which led to complete resolution of his psychotic symptoms. The authors speculated that his psychosis was a result of his prolonged sleep deprivation.

Hasler et al. (2004) studied eight subjects given either placebo or 45, 115, 215, or 315 g/kg psilocybin (a very low, low medium, or high dose, respectively). Instruments used to assess psilocybin effects included the 5D-ASC, the Frankfurt Attention Inventory (FAIR), and the Adjective Mood Rating Scale (AMRS). Several physiologic and plasma hormones were also measured. Psilocybin dose-dependently increased all measures on the 5D-ASC. The medium and high doses of psilocybin led to a 50% reduction in performance on the FAIR test. The only scores that were increased on the AMRS were general inactivation, emotional excitability, and dreaminess. Hasler et al. (2004) found no evidence that psilocybin is hazardous with respect to somatic health.

Bouso et al. (2015) used magnetic resonance imaging to examine potential differences in cortical thickness in 22 Spanish regular users of ayahuasca, compared with 22 matched controls. Inclusion criterion for ayahuasca users was that they had used it at least 50 times in the 2 previous years. Subjects also were assessed using three neuropsychological tests, including the two-back test to assess working memory, the Wisconsin Card Sorting Test to assess executive function, and a switching task to assess set shifting. Personality was also assessed by self-report using the Spanish version of the Temperament and Character InventoryRevised questionnaire. Ayahuasca users scored significantly better than controls on several variables derived from the neuropsychological tests. No increased psychopathology or worse neuropsychological performance was observed in the ayahuasca group, consistent with findings reported earlier by Grob et al. (1996) for ayahuasca users who were members of the Brazilian church, the UDV. Indeed, ayahuasca users scored significantly better than controls on harm avoidance, and its subscale anticipatory worry, and significantly higher on self-transcendence. Cortical thinning was found for six brain areas in the ayahuasca group: the middle frontal gyrus, the inferior frontal gyrus, the precuneus, the superior frontal gyrus, and the PCC. By contrast, cortical thickening was seen in the precentral gyrus and the ACC. Correlation analysis revealed that lifetime use of ayahuasca was inversely correlated to cortical thickness in the PCC.

Although there is a general public perception that psychedelic drugs are dangerous, from a physiologic standpoint they are in fact one of the safest known classes of CNS drugs. They do not cause addiction, and no overdose deaths have occurred after ingestion of typical doses of LSD, psilocybin, or mescaline. Cohen (1967) and Jaffe (1985) have both stated that death due to direct LSD toxicity is unknown. Indeed, recreational users who have consumed massive doses of LSD have survived. For example, eight individuals who believed they had cocaine accidentally insufflated an extremely high dose of LSD. Their plasma LSD levels were reported as between 1000 and 7000 g/100 ml (recall that a typical total oral dose of LSD might be 100200 g). These individuals all became comatose, with hyperthermia, vomiting, light gastric bleeding, and respiratory problems. With hospital treatment, however, all eight survived and without apparent residual effects (Klock et al., 1974).

Although the classic psychedelics have not been directly responsible for causing death, the judgment of users is certainly impaired while under the influence of these drugs. This is a particular concern when hallucinogens are used in unsupervised settings. Users may believe that they are invincible or possess superpowers and may do things they would not normally consider, such as believing they can fly (Reynolds and Jindrich, 1985), jumping from buildings (Keeler and Reifler, 1967), or incurring severe ocular damage by prolonged staring at the sun (Schatz and Mendelblatt, 1973; Fuller, 1976).

Studerus et al. (2010) analyzed acute, short-, and long-term subjective effects of psilocybin in healthy humans. Again, using pooled raw data from eight double-blind placebo-controlled experimental studies conducted between 1999 and 2008, their analysis included 110 healthy subjects who had received between one and four oral doses of psilocybin (45315 g/kg body weight). Psilocybin dose-dependently induced profound changes in mood, perception, thought, and self-experience, but most subjects described the experience as pleasurable, enriching, and nonthreatening. Acute adverse reactions were characterized by strong dysphoria and/or anxiety/panic, but occurred only at the two highest doses of psilocybin in a relatively small number of subjects. All acute adverse drug reactions were successfully managed through interpersonal support and did not require psychopharmacological intervention. Follow-up questionnaires indicated no subsequent drug abuse, persisting perception disorders, prolonged psychosis, or other long-term impairment of functioning in any of the subjects. The results indicate that the administration of modest psilocybin doses to healthy, high-functioning, and well prepared subjects in the context of a carefully monitored research environment carries an acceptable level of risk.

The recent resurgence of interest in the clinical uses of psychedelics led Johnson et al. (2008) to propose appropriate procedures for using them in clinical practice. The guidelines they outline have certain parallels with ritual uses of hallucinogens by older indigenous cultures. In particular, Johnson et al. (2008) cite the need for structured use (expressed as ritual in indigenous use) and restrictions on use, including the need for guidance and appreciation of the powerful psychologic effects of hallucinogens (expressed as reverence in indigenous use). Psychedelic administration in humans results in a unique profile of effects and potential adverse reactions that need to be appropriately addressed to maximize safety. The primary safety concerns with psychedelics are largely psychologic rather than physiologic in nature. Somatic effects vary but are relatively insignificant, even at doses that elicit powerful psychologic effects. The proposed guidelines extend and complement the recommendations of Fischman and Johanson (1998) for high-dose hallucinogen research. The guidelines include 1) the presence of two monitors with some medical knowledge, knowledge of ASCs, and a degree of clinical sensitivity; 2) a physical environment that is safe, aesthetically pleasing, and comfortable; 3) careful subject preparation, including several meetings to establish rapport and trust with the monitors; 4) a detailed consent form and explanations of the study procedures, detailed discussions about the range of potential experiences, and time of onset and duration of the effects; and 5) an available physician in the event of an untoward medical reaction. Anyone contemplating carrying out a clinical research program with a psychedelic is strongly encouraged to read the detailed guidelines presented by Johnson et al. (2008).

Krebs and Johansen (2013) evaluated any association between lifetime use of psychedelics and current mental health in the adult population. Data were analyzed for 20012004 for 130,152 randomly selected NSDUH respondents; 21,967 respondents (13.4% weighted) reported lifetime psychedelic use. The authors found no significant association between lifetime use of any psychedelic and increased rate of any mental health outcomes. Indeed, they discovered that psychedelic use was associated with a lower rate of mental health problems in several cases. Johansen and Krebs (2015) subsequently analyzed a new data set of 135,095 randomly selected U.S. adults that included 19,299 users of psychedelics. Data were from the NSDUH for 20082011. As in their earlier study, the authors found no significant associations between lifetime use of psychedelics and increased likelihood of past-year serious psychologic distress, mental health treatment, depression, anxiety, or suicidal thoughts, plans, or attempts. Johansen and Krebs (2015) failed to find any evidence that use of psychedelics is an independent risk factor for mental health problems. Indeed, they report that lifetime use of psychedelics was associated with decreased inpatient psychiatric treatment.

Hendricks et al. (2014) analyzed data from 20022007 for 25,622 individuals charged with a felony in the Southeastern United States and under community corrections supervision in the Treatment Accountability for Safer Communities program, which is a case management intervention program for individuals with a history of substance involvement. The authors examined relationships between any hallucinogen use disorder (versus no hallucinogen use disorder) and all available sociodemographic and psychosocial variables. They report that any hallucinogen use disorder was associated with a decreased probability of supervision failure. They note the contrast with any cannabis, cocaine, alcohol, opiate, or amphetamine use disorder, each of which was associated with an increased probability of supervision failure. Their results suggest that hallucinogens may promote alcohol and other drug abstinence and prosocial behavior in a population with high rates of recidivism.

In a more recent report by Hendricks et al. (2015), the authors evaluated any relationship between use of a classic psychedelic and psychologic distress and suicidality among more than 190,000 U.S. respondents pooled from the NSDUH for 20082012. Lifetime use of a psychedelic was associated with significantly reduced odds of past-month psychologic distress, past-year suicidal thinking, past-year suicidal planning, or past-year suicide attempt. By contrast, lifetime use of other illicit drugs was associated with an increased likelihood of these outcomes. The authors suggest that classic psychedelics may hold promise in the prevention of suicide. These findings are consistent with the surveys of Krebs and Johansen (2013) and Johansen and Krebs (2015); in all three studies, the authors suggest that their data are not compatible with the highly restricted legal status of psychedelics and that more extensive clinical research is warranted.

Use of high doses of psychedelics can lead to vascular problems because the 5-HT2A receptor is associated with vascular smooth muscle contraction, platelet aggregation, thrombus formation, and coronary artery spasms (Nagatomo et al., 2004). Acute vasoconstriction caused by serotonin is usually shared by activation of 5-HT1B and 5-HT2A receptors; however, in intracranial arteries, only the 5-HT1B receptor mediates constriction (Kaumann and Levy, 2006). Both 5-HT2A and 5-HT1B receptors can mediate coronary artery spasm. 5-HT2A receptors also constrict the portal venous system, including esophageal collaterals in cirrhosis. Data from studies by Ootsuka et al. (2004) suggest that spinal 5-HT2A receptors contribute to sympathetically induced cutaneous vasoconstriction regulated by the raphe/parapyramidal neurons in the brainstem.

Balkov (2005) reports a fatal and nonfatal overdose after ingestion of the psychedelic phenethylamine 2,5-dimethoxy-4-bromoamphetamine (DOB) by two male individuals. Gas chromatographymass spectrometry was used to detect the presence of DOB in both gastric and urine samples of the two men. Although one subject survived, the other suffered convulsions and metabolic acidosis and died 6 days after admission.

Psilocybin, when administered in a controlled setting, has frequently been reported to cause transient, delayed headache, with incidence, duration, and severity increased in a dose-related manner (Johnson et al., 2012). Bickel et al. (2005) reported the case of a 25-year-old hepatitis Cinfected man, who presented with severe rhabdomyolysis and acute renal failure after Psilocybe mushroom ingestion. He later developed encephalopathy with cortical blindness. Respiratory and cardiovascular support, mechanical ventilation, continuous venovenous hemodialysis, and corticosteroid treatment led to improvement and the patient recovered completely over several months.

Psilocin was identified in the urine of a subject who was investigated for driving under the influence (Tiscione and Miller, 2006). The subject apparently did not exhibit any response to the crash of his automobile, seemingly unaware of the severity of his situation or immediate surroundings.

Although very rare, there have been reports of rhabdomyolysis after ingestion of LSD (Berrens et al., 2010). A newer tryptamine, 5-methoxy-N,N-diisopropyltryptamine (foxy) also produced rhabdomyolysis and transient acute renal failure in an otherwise healthy 23-year-old man (Alatrash et al., 2006).

Although many ergot alkaloids are known to produce vasospasm, especially after chronic use, LSD has rarely been associated with this adverse effect. Nevertheless, Raval et al. (2008) reported on a 19-year-old woman who experienced severe lower-extremity ischemia related to a single use of LSD 3 days prior to presentation. After intra-arterial nitroglycerin and verapamil failed, balloon percutaneous transluminal angioplasty therapy led to rapid clinical improvement in lower-extremity perfusion. As of the date of the report, the patient had not required a major amputation.

Sunness (2004) described a 15-year-old female patient with a 2-year history of afterimages and photophobia after a history of drug use that included LSD, marijuana, and other illicit drugs. She had discontinued LSD 1 year prior to examination. Although the author connected her visual problems with her prior LSD use, it is not at all clear from the report that her LSD use was the cause of her visual problem.

Bernhard and Ulrich (2009) reported a case of cortical blindness in a 15-year-old girl. She had headache and nausea 5 days after taking LSD and suddenly developed complete blindness in both eyes. The blindness persisted for 48 hours. Over the next 3 months, the subject had three more episodes of complete blindness that lasted 1236 hours, with no visual disturbances between episodes. The authors suggested that the temporary blindness might be a correlate of flashbacks caused by LSD.

Toxicity also has been noted for several of the so-called designer drugs. For example, Jovel et al. (2014) reported the case of a healthy young male individual who ingested 5-methoxy-N,N-diallytryptamine, one of the emerging new tryptamine-type research chemicals. The patient was admitted with extreme agitation, tachycardia, diaphoresis, and combativeness that required physical restraint and intravenous sedation, but the patient did recover.

Andreasen et al. (2009) reported a fatality involving the potent synthetic psychedelic phenethylamine compound 1-(8-bromobenzo[1,2-b; 4,5-b]difuran-4-yl)-2-aminopropane, known commonly as Bromo-Dragonfly. An 18-year-old woman was found dead after ingesting 1 ml of a hallucinogenic liquid. She and her boyfriend had ingested it between 10 and 11 PM on the previous evening and then they both fell asleep. On awakening at 5 AM the next morning, the womans boyfriend discovered that she was dead. Autopsy findings 3 days after her death included edema of the lungs, slight edema of the brain, spleen enlargement, irritation of the mucous membrane in the stomach, and ischemic changes in the kidneys. Her femoral blood concentration of the drug was 4.7 g/kg. The bottle containing the hallucinogenic liquid was recovered and analyzed by ultraperformance liquid chromatography time-of-flight mass spectrometry, high-performance liquid chromatography diode array detection, 1H nuclear magnetic resonance, and 13C nuclear magnetic resonance and found to contain a solution of almost pure Bromo-Dragonfly. Based on the solution concentration and the amount of solution consumed, it was estimated that she had ingested approximately 700 g. Although that would seem to be a relatively small dose, no other drugs were discovered in her system, including the absence of ethanol.

It is often difficult to establish whether the drug is pure or has been coingested with other unknown drugs of unknown purity. For example, Ovaska et al. (2008) reported a case of sympathomimetic toxicity in a patient who was reported to have ingested 2,5-dimethoxy-4-chloroamphetamine (DOC), yet toxicological screening showed the patient had ingested both DOC and MDMA.

Data for 2005 to 2006 from the Texas Poison Control Centers were reviewed for mushroom exposures (Barbee et al., 2009). There were a total of 742 exposures, which were all acute and intentional. Of those, 59 individuals were admitted to a hospital, with 17 requiring admission to a critical care unit. Nonetheless, only 10 of the admissions that were identified involved psilocybin. Of all of the admissions, major toxic reactions were uncommon, with no deaths reported.

One adverse effect of hallucinogen use, particularly associated with LSD use, is hallucinogen persisting perception disorder (HPPD). This term has displaced an earlier somewhat more nonspecific one known as flashbacks, which was a re-experiencing of one or more of the perceptual effects induced by a hallucinogen at some later time, after the acute drug effects had worn off. HPPD is composed of afterimages, perception of movement in peripheral visual fields, blurring of small patterns, halo effects, and macro- and micropsia long after the drug has been used.

The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV), Text Revision lists the following three criteria for HPPD: A) re-experiencing, after the use of a hallucinogen, of one or more of the perceptual symptoms that were experienced while intoxicated with the hallucinogen; B) the symptoms in criterion A cause clinically significant distress or impairment in social, occupational, or other important areas of functioning; and C) the symptoms are not due to a general medical condition and are not better accounted for by another mental disorder.

Halpern and Pope (2003) noted that when LSD was used in a therapeutic or research setting, HPPD appeared less frequently than when LSD was used recreationally. The authors concluded, however, that some individuals, especially users of LSD, can experience a long-lasting HPPD syndrome with symptoms of persistent perceptual abnormalities reminiscent of acute intoxication. Nevertheless, the incidence of HPPD is very small given the many tens of millions of persons who have taken LSD, most often in a recreational setting. Litjens et al. (2014) provided a recent comprehensive review on the subject of HPPD. The actual incidence of HPPD is not known and depends on the prevalence of use in different countries, but epidemiologic information is scarce.

Hermle et al. (2008) reviewed MEDLINE data for 19972007, searching for reports of hallucinogen-induced psychosis, flashbacks, and HPPD. The authors reported that adolescent intoxication with psychedelic drugs rarely produced acute psychotic syndromes, further stating that The clinical relevance of flashback phenomena as a post-hallucinogenic psychiatric disorder has to be disputed.

Although LSD was most widely used and therefore has led to the greatest number of HPPD cases, it is clear that other hallucinogens also can evoke the syndrome. For example, Espiard et al. (2005) reported HPPD in an 18-year-old man after mixed intoxication with psilocybin and cannabis. The symptoms persisted for more than 8 months. Ikeda et al. (2005) reported flashbacks after use of 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) by a 35-year-old man without a previous psychiatric history. He had used the substance six or seven times over 5 months but discontinued it after he had a bad trip, with anxiety, palpitations, auditory oversensitiveness, and visual distortions. Treatment with oral risperidone ameliorated his symptoms. Another case study described a 33-year-old woman who developed HPPD after LSD use for a year. Although treatment with antidepressants and risperidone did not ameliorate her symptoms, treatment with the antiseizure drug lamotrigine almost completely abolished her visual disturbances (Hermle et al., 2012).

Although the classic serotonergic hallucinogens are not recognized to be particularly toxic, a new class of substituted phenethylamines with toxic properties has recently become very popular as recreational drugs (Nikolaou et al., 2014). Unfortunately, there are now several reports of hospitalizations and fatalities attributed to these compounds (Poklis et al., 2013, 2014; Rose et al., 2013; Nikolaou et al., 2014; Tang et al., 2014; Walterscheid et al., 2014), but it is not clear whether deaths resulted from ingestion of lethal amounts of pure bulk drug or whether the drug has some inherent toxicity that is not normally associated with other psychedelics.

Suzuki et al. (2015) provided a comprehensive literature review of toxicities associated with NBOMe ingestion. The most common adverse reactions were agitation (including aggressiveness), tachycardia, and hypertension, with seizures reported in 40% of the patients. In the 20 individual cases they reviewed, 3 (15%) were fatalities.

The most potent of these new recreational chemicals are shown in Fig. 3, with potency increasing going from X = H to X = I.

For purposes of law enforcement the iodo compound (X = I; 25I-NBOMe) is presently considered by the U.S. Drug Enforcement Administration to be an analog of 2C-I [2-(4-iodo-2,5-dimethoxy)aminoethane], which is currently a Schedule 1 controlled substance. The procedure to classify 25I-NBOMe as a Schedule 1 substance has been initiated and it has been placed temporarily into Schedule 1 (Drug Enforcement Administration, 2013). Global interest in these compounds and closely related analogs has attracted increasing interest. For example, the European Monitoring Centre for Drugs and Drug Addiction has received a range of notifications from European Union member states about analytically confirmed nonfatal and fatal intoxications associated with 25I-NBOMe. This was followed by a risk assessment conducted by the European Monitoring Centre for Drugs and Drug Addiction Scientific Committee to assess health and social risks associated with the iodo analog (European Monitoring Centre for Drugs and Drug Addiction, 2014). In addition, the World Health Organizations Expert Committee on Drug Dependence reviewed the status of a range of new substances for its 36th meeting in June 2014, which included 25I-NBOMe and its 4-bromo and 4-chloro analogs (World Health Organization, 2014).

In the mouse head-twitch assay, 25I-NBOMe and a related analog were extremely potent in inducing this behavior, which was blocked by preadministration of the selective 5-HT2A antagonist M100907 [(R)-(+)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-pipidinemethanol] (Halberstadt and Geyer, 2014). As discussed in the section on mouse models later in this review, the mouse head twitch has shown a high correlation with human psychedelic activity.

A relatively large series of 48 NBOMe-type compounds has been evaluated for affinity and function at 5-HT2 family receptors (Hansen et al., 2014). Their work was directed toward development of potential radioligands for in vivo PET imaging of 5-HT2A receptors that would be selective over 5-HT2C receptors. One compound was discovered that had approximately 100-fold selectivity for both affinity and function at the 5-HT2A versus 5-HT2C receptor. Their high affinity and relative selectivity for the 5-HT2A receptor has made some of these compounds useful as agonist ligands for in vivo PET imaging (Ettrup et al., 2010; Finnema et al., 2014).

Curiously, the NBOMe-type compounds do not appear to be orally active and are typically administered bucally, or by nasal insufflation. Their potency is so high that they are often distributed on blotter papers and marketed as being LSD. Users place the blotters against their gums to effect absorption. One hypothesis put forward to explain the lack of oral activity for these highly active compounds is a significant first-pass metabolic effect (Leth-Petersen et al., 2014). In that study, the microsomal stability of 11 phenethylamines and their N-benzylated congeners was studied using human liver microsomes. It was found that the N-benzylated compounds had a much higher intrinsic clearance than did the simple phenethylamines, and the authors hypothesized that their low hepatic stability was the reason for their lack of oral activity.

Stellpflug et al. (2014) reported a clinical case of a nonfatal overdose with 25I-NBOMe. They identified a major metabolite of the compound in the urine that had a concentration 80-fold higher than the parent drug. The subjects urine was treated with -glucuronidase and then analyzed using ultraperformance liquid chromatography electrospray ionization plus tandem mass spectrometry to identify a major metabolite with a mass that was one methyl group lower than the parent compound. Comparison of the full fragmentation pattern was then assessed and concluded to be an O-demethylated metabolite at the 2- or 5-position of the trisubstituted ring, but the investigators were not able to determine which position had been metabolized. They detected two other very minor metabolites that also appeared to be O-demethylated. The concentration of the unmetabolized parent 25I-NBOMe in the urine was 7.5 ng/ml, whereas the desmethyl metabolite was 600 ng/ml. This metabolite and the two other minor metabolites were not present in the urine in the absence of prior enzymatic treatment, indicating that they were all glucuronidated.

Most recently, Leth-Petersen et al. (2015) identified the basis for the high first-pass effect of NBOMe compounds and the likely basis for their inactivity after oral administration. Using in vivo studies in pigs, they determined that the 5-methoxy of the trisubstituted phenyl ring is rapidly O-demethylated. After intravenous administration of 25B-NBOMe [N-(2-[11C]methoxybenzyl)-2,5-dimethoxy-4-bromophenethylamine (Cimbi-36)] to a pig, analysis revealed that plasma levels of the parent drug rapidly declined, with a new metabolite rapidly appearing and accumulating in plasma. At the 30-minute mark, there was more than twice as much of this metabolite present in plasma as there was of the parent compound. This metabolite was definitively identified as the 5-O-glucuronide using liquid chromatography/mass spectrometry and chemical synthesis. Evidently, the highly hydrophobic nature of the N-benzyl phenethylamines readily targets them to the mixed function oxidases in the endoplasmic reticulum, where they are efficiently 5-O-demethylated and then very quickly glucuronidated.

Stanislov Grof characterized LSD as a powerful nonspecific amplifier of the unconscious (Grof, 1975). This empirical observation was based on his personal supervision of more than a thousand clinical administrations of LSD. Barr et al. (1972) also stated that the phenomena induced by LSD cannot be predicted or understood in purely pharmacological terms; the personality of the drug taker plays an enormous and critical role in determining how much effect there will be and of what particular type.

However, until we understand the fundamental nature of consciousness and its underlying neuronal substrates, as well as the unconscious, it will not be possible to scientifically test Grofs hypothesis. What can be discussed are the findings that point to involvement of specific receptors in certain brain areas that lead to the overt effects of psychedelics. In addition, recent brain scanning technologies, including PET, fMRI, EEG, magnetoencephalography (MEG), and pharmacological magnetic resonance imaging (phMRI), have also allowed the identification of key brain areas that must be involved in the actions of psychedelics.

One should keep in mind that the effects of psychedelics are highly variable and are not necessarily dose dependent. At low doses of LSD (e.g.,

By contrast, high doses have a greater propensity to transport the user to an alternate reality, where they lose contact with their everyday environment. These occasions are often described as peak experiences, transcendent, or mystical and are profoundly altered states of consciousness. Users may feel that they have transcended time and space or encountered their concept of God, or they may feel that they have encountered otherworldly beings, feelings of being at one with the universe, reliving past memories, and so forth. With respect to medical value, this state of consciousness is most closely associated with dramatic therapeutic improvement. Although this phenomenon is more likely to occur after high doses of psychedelics, it can occur at nearly any dose if the set and setting have been optimized to promote such an ASC. These experiences are often characterized as among the most meaningful of the subjects life (e.g., see Griffiths et al., 2006) and can lead to persisting positive effects on attitudes, mood, and behavior.

It was only a decade after the discovery of the remarkable psychopharmacology of LSD that the presence of serotonin was demonstrated in the mammalian brain (Twarog and Page, 1953). A comparison of the chemical structures of LSD and serotonin (shown earlier) led to early hypotheses that the action of LSD was due to an interaction with serotonin systems in the brain. Ten years after the discovery of LSD, Gaddum (1953) reported that LSD antagonized the action of serotonin in peripheral tissues. Only 1 year later, Gaddum and Hameed (1954) and Woolley and Shaw (1954) independently proposed that the effects of LSD might result from serotonin receptor blockade in the CNS. Shaw and Woolley (1956) later modified their hypothesis to include the possibility that LSD might mimic the actions of serotonin. Numerous studies in the subsequent decade examined the possibility that LSD blocked the actions of serotonin, but it was a concept that proved untenable. It was clear, however, that LSD did have a potent effect on brain serotonin systems, elevating whole brain serotonin content (Freedman, 1961) and reducing brain levels of the major metabolite of serotonin, 5-hydroxyindole acetic acid (Rosecrans et al., 1967).

Ultimately, Andn et al. (1968) suggested that LSD might have direct agonist actions at serotonin receptors in the brain. Subsequently, studies from numerous laboratories provided support for that idea, with an initial focus on serotonin 5-HT1A receptors (see discussion in Nichols, 2004). When serotonin receptorselective antagonists became available, it was Glennon et al. (1983, 1984) who demonstrated in a rat drug discrimination model that the 5-HT2 antagonists ketanserin and pirenperone blocked the discriminative cue of a psychedelic. Further studies in numerous laboratories over the next 2 decades, primarily with rodents, then focused attention on the 5-HT2A receptor as the primary target for psychedelics. Agonist or partial agonist activity at the serotonin 5-HT2A receptor was ultimately concluded to be a necessary pharmacology for psychedelic effects, but it may not be sufficient to explain all of the qualitative differences between different drugs. As Ray (2010) pointed out, different molecules may also have significant affinity for other types of brain receptors.

The first definitive experiment pointing to the central role of the 5-HT2A receptor for the action of psychedelics in humans came from a clinical study by Vollenweider et al. (1998), who showed that the effects of psilocybin were blocked by the 5-HT2A receptorselective antagonist ketanserin or the atypical antipsychotic risperidone but were enhanced by the dopamine antagonist and typical antipsychotic haloperidol. These data provided the first evidence that psilocybin-induced effects in humans were due to 5-HT2A receptor activation. Subsequently, Vollenweider and colleagues have carried out several additional clinical studies, discussed later, of various aspects of the action of psilocybin and have shown that ketanserin can block most of those effects.

Kometer et al. (2012) carried out a randomized, double-blind study in 17 healthy human subjects. On 4 separate days, subjects received placebo, psilocybin (215 g/kg), the 5-HT2A antagonist ketanserin (50 mg, p.o.), or psilocybin plus ketanserin. Mood states were assessed, and behavioral and event-related potential measurements were used to quantify facial emotional recognition and goal-directed behavior toward emotional cues. Psilocybin was found to enhance positive mood and attenuate negative facial expression recognition. Furthermore, psilocybin increased goal-directed behavior toward positive compared with negative cues, facilitated positive but inhibited negative sequential emotional effects, and valence-dependently attenuated the P300 component. Ketanserin given alone had no effect but blocked the psilocybin-induced mood enhancement and decreased recognition of negative facial expression. This study demonstrated that psilocybin shifts the emotional bias across various psychologic domains and that activation of 5-HT2A receptors is central in mood regulation and emotional face recognition in healthy subjects. The authors suggest that their findings have implications not only for the pathophysiology of dysfunctional emotional biases, but they may also provide a framework to delineate the mechanisms underlying psilocybins putative antidepressant effects.

Quednow et al. (2012) investigated the role of 5-HT2A receptors in automatic (sensorimotor gating) and controlled (Stroop interference) inhibition processes in a model psychosis approach using psilocybin (260 g/kg) in 16 healthy humans pretreated either with the 5-HT2Aselective receptor antagonist ketanserin (40 mg) or placebo, using a placebo-controlled, crossover, counterbalanced, and double-blind design. They found that psilocybin-induced deficits in automatic and controlled inhibition were significantly attenuated by ketanserin. They also replicated their previous findings that most of the subjective hallucinogenic effects of psilocybin were abolished by ketanserin.

Kometer et al. (2013) assessed the effects of psilocybin (215 g/kg) on both oscillations that regulate cortical excitability and early visual evoked P1 and N170 potentials in 16 healthy human subjects. They employed a double-blind, placebo-controlled, within-subject, randomized design. Psilocybin generally significantly increased 5D-ASC scores after placebo pretreatment, but not after ketanserin pretreatment. Psilocybin strongly decreased both prestimulus parieto-occipatal power and decreased N170 potentials associated with the appearance of visual perceptual alterations, including visual hallucinations. Preadministration of the 5-HT2A antagonist ketanserin (50 mg) blocked all of these effects. The authors conclude that 5-HT2A receptor activation by psilocybin profoundly modulates the neurophysiological and phenomenological indices of visual processing. They further propose that 5-HT2A receptor activation may induce a processing mode in which stimulus-driven cortical excitation is overwhelmed by spontaneous neuronal excitation through modulation of oscillations.

Indirect evidence for a role of 5-HT2A receptors in mediating psychedelic-induced hallucinations comes from a study by Huot et al. (2010). In that study, [3H]ketanserin binding was used to compare 5-HT2A receptor density in postmortem brains of patients with Parkinsons disease (PD) who experienced visual hallucinations with the brains of PD patients who did not experience hallucinations. Six brains from patients with idiopathic PD who experienced visual hallucinations were compared with six PD patients without visual hallucinations and five healthy, age-matched controls. In PD patients with visual hallucinations, [3H]ketanserin binding was increased 45.6% in inferolateral temporal cortex compared with PD patients who did not have visual hallucinations. The authors suggest that increased 5-HT2A density in the inferolateral temporal cortex may be the basis for visual hallucinations in PD patients and that 5HT2A antagonists may alleviate this symptom.

Similarly, Ballanger et al. (2010) measured 5-HT2A binding in vivo using [18F]setoperone PET in brains of seven PD patients with visual hallucinations and seven age-matched PD patients without visual hallucinations. Patients with visual hallucinations had significantly increased 5-HT2A receptor binding in several cortical regions and one subcortical region. These increased levels of 5-HT2A receptor expression were clustered mainly in the ventral visual pathway. With the evidence of increased 5-HT2A receptor expression as a possible basis for visual hallucinations in PD patients, a serotonin 5-HT2A inverse agonist, perhaps not surprisingly, demonstrated phase 3 clinical efficacy in treating several symptoms of PD psychosis, including visual hallucinations (Hacksell et al., 2014).

Halberstadt et al. (2011a) examined the effects of several psychedelics on the mouse head twitch response (HTR) in wild-type (WT) male C57BL/6J or 5-HT2A knockout (KO) mice. They also assessed investigatory and locomotor activity in the mouse behavioral pattern monitor (BPM). Psilocin and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) produced the HTR in WT mice but not in KO mice. Psilocin and 5-MeO-DMT reduced locomotor activity, investigatory behavior, and center duration in the BPM, and these effects were blocked by the selective 5-HT1A antagonist WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- N-(2-pyridyl)cyclohexanecarboxamide), indicating that psilocin and 5-MeO-DMT act as mixed 5-HT1A/5-HT2A agonists. Halberstadt and Geyer (2011) reviewed the extensive literature covering various indoleamines as well as LSD and concluded that although the phenethylamines primarily exert their effects through activation of 5-HT2A receptors, indoleamines can have a significant behavioral component mediated by activation of 5-HT1A receptors.

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Psychedelics – Pharmacological Reviews

Psychedelics – Mushrooms, LSD, Salvia

Psychedelics, while they can cause pleasurable side effects, are mostly Schedule I classified drugs that are not only illegal but dangerous. While psychedelics can cause a person to feel a sense of oneness with the universe and experience spiritual or enjoyable hallucinations and distorted perceptions, they can also cause intense fear, paranoia, and panic.

Whether or not a person has a good trip or a bad tripall depends on many variables, and there is no assurance that even the same individual will experience a positive reaction twice. This is only one of the dangers of psychedelics which, while they have been used in spiritual rituals for centuries, can cause many harmful effects.

We can help you quit using psychedelic drugs. Call 800-895-1695 today.

The effects of psychedelics are extremely hard to predict. As stated by CESAR, psilocybin or psychedelic mushrooms are one of the most popularly abused psychedelics to this day, and the effects produced by psilocybin are highly variable and depend on several factors including the age, type, and dosage amount of the mushroom used, the setting the mushroom is used in, the users expectations, past drug experiences, and personality.

This is what makes psychedelic drugs so different from other commonly abused substances; it is very difficult to pinpoint how a person will react to these drugs or what they should even expect. While some effects like hallucinations, nausea, and an altered perception of space and time can all be expected to be experienced by the user, psychedelics may cause a different type of high in every user (each and every time) and their effects could last anywhere from an hour to six or more.

While there isnt a strong amount of research on the issue of psychedelic drug addiction, it is possible in some instances. Especially with a drug like MDMA, some users report symptoms of dependence, including continued use despite knowledge of physical or psychological harm, tolerance (or diminished response), and withdrawal effects (NIDA).

Some other drugs (like LSDand peyote) only cause tolerance while the effects of salvia divinorum have not yet been researched enough to provide any conclusive results. The question of whether or not addiction to certain psychedelic drugs exists can be puzzling. In many cases, though, treatment may still be necessary to help with the effects abusing psychedelic drugs can cause.We can help you find the treatment you need. Call 800-895-1695 toll free today.

If you are concerned about your psychedelic drug abuse or that of another individual, here are some steps to follow in order to better the situation.

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Psychedelics – Mushrooms, LSD, Salvia

Horizons: Perspectives on Psychedelics

In recent years, a growing community of scientists, doctors, artists, activists, seekers and scholars have orchestrated a renaissance in psychedelic thought and practice.

Horizons brings together the brightest minds and the boldest voices of this movement to share their research, insights, and dreams for the future.

Horizons Media, Inc. is a 501c(3) not-for-profit educational charity led by Kevin Balktick, Neal M. Goldsmith, Ph.D., Ingmar Gorman, Ph.D., and James Vasile, Esq.

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Horizons: Perspectives on Psychedelics

Using Psychedelics to Address End of Life and Chronic Illness

Psychedlic drugs allow people to face their deepest and most troubling fear with a level of openness and honesty that is often impossible otherwise. In a very general sense, psychedelics can remove the painful, fearful, and reactionary associations that we all have with traumatic events.

If you are struggling with the mental pain of a terminal or debilitating illness, loss of a loved one, or other trauma, you mind find relief in conscious use of psychedlics. After treatment, many individuals find that they can face the obstacles in their life with a new honesty and openness and can embrace the path they are on, regardless of how difficult it may be for themselves and their loved ones.

Heres one womans story of being treated with mushrooms as she was facing death, described in a New York Times article (see below):

Before Pam Sakuda died, she described her psilocybin experience on video: I felt this lump of emotions welling up . . . almost like an entity, Sakuda said, as she spoke straight into the camera. I started to cry. . . . Everything was concentrated and came welling up and then . . . it started to dissipate, and I started to look at it differently. . . . I began to realize that all of this negative fear and guilt was such a hindrance . . . to making the most of and enjoying the healthy time that Im having. Sakuda went on to explain that, under the influence of the psilocybin, she came to a very visceral understanding that there was a present, a now, and that it was hers to have.

Two weeks after Sakudas psilocybin session, Grob (the researcher) readministered the depression and anxiety assessments. Over all among his subjects, he found that their scores on the anxiety scale at one and three months after treatment demonstrated a sustained reduction in anxiety, the researchers wrote in The Archives of General Psychiatry. They also found that their subjects scores on the Beck Depression Inventory dropped significantly at the six-month follow-up.

To learn how to use mushrooms for treating depression and anxiety, please see our step-by-step Mushroom Guide.

Psychedelic Psychotherapy for Life-Threatening Illness Anxiety Panel

from MAPS: Psychedelic Science Vimeo Channel.

Psychedelics have been misunderstood and misrepresented for decades. That’s changing. Please help us share safe, responsible information on using psychedelics by sending this page to friends, and posting to Facebook, Twitter, and Google:

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Using Psychedelics to Address End of Life and Chronic Illness

Psychedelics in problem-solving experiment – Wikipedia

Psychedelic agents in creative problem-solving experiment was a study designed to evaluate whether the use of a psychedelic substance with supportive setting can lead to improvement of performance in solving professional problems. The altered performance was measured by subjective reports, questionnaires, the obtained solutions for the professional problems and psychometric data using the Purdue Creativity, the Miller Object Visualization, and the Witkins Embedded Figures tests.[1] This experiment was a pilot that was to be followed by control studies as part of exploratory studies on uses for psychedelic drugs, that were interrupted early in 1966 when the Food and Drug Administration declared a moratorium on research with human subjects, as a strategy in combating illicit use.[2]

Some weeks before the actual experiment, a preliminary experiment was conducted. It consisted of two sessions with four participants in each. The groups worked on two problems chosen by the research personnel. The first group consisted of four people with professional experience in electrical engineering, engineering design, engineering management and psychology. They were given 50 micrograms of LSD. The second group consisted of four research engineers, three with a background in electronics and one in mechanics. They were given 100 milligrams of mescaline. Both groups were productive in ideation but, according to Fadiman, the fact that the participants didn’t have actual personal stake in the outcome of the session negatively affected the actualization of the ideas. This is why the actual study focused on personal professional problems that the participants were highly motivated to tackle.[3]

The experiment was carried out in 1966 in a facility of International Foundation for Advanced Study, Menlo Park, California, by a team including Willis Harman, Robert H. McKim, Robert E. Mogar, James Fadiman and Myron Stolaroff. The participants of the study consisted of 27 male subjects engaged in a variety of professions: sixteen engineers, one engineer-physicist, two mathematicians, two architects, one psychologist, one furniture designer, one commercial artist, one sales manager, and one personnel manager. Nineteen of the subjects had had no previous experience with psychedelics. Each participant was required to bring a professional problem they had been working on for at least 3 months, and to have a desire to solve it.

Commonly observed characteristics of the psychedelic experience seemed to operate both for and against the hypothesis that the drug session could be used for performance enhancement. The research was therefore planned so as to attempt to provide a setting that would maximize improved functioning, while minimizing effects that might hinder effective functioning.[4] Each group of four subjects met for an evening session several days before the experiment. They received instructions and introduced themselves and their unsolved problems to the group. Approximately one hour of pencil-and-paper tests were also administered. At the beginning of the day of the experiment session, subjects were given 200 milligrams of mescaline sulphate (a moderately light dose compared to the doses used in experiments to induce mystical experiences). After some hours of relaxation, subjects were given tests similar to the ones on the introduction day. After the tests, subjects had four hours to work on their chosen problems. After the working phase, the group would discuss their experiences and review the solutions they had come up with. After this, the participants were driven home. Within a week after the session, each participant wrote a subjective account of his experience. Six weeks further, subjects again filled in questionnaires, this time concentrating on the effects on post-session creative ability and the validity and reception of the solutions conceived during the session. This data was in addition to the psychometric data comparing results of the two testing periods.

Solutions obtained in the experiment include:[3][5][6]

The participants also reported following experiences of enhanced functioning: low inhibition and anxiety, capacity to restructure problem in larger context, enhanced fluency and flexibility of ideation, heightened capacity for visual imagery and fantasy, increased ability to concentrate, heightened empathy with external processes and objects, heightened empathy with people, subconscious data more accessible, association of dissimilar ideas, heightened motivation to obtain closure, visualizing the completed solution.

According to a recent unpublished review by Matthew J. Baggott, PhD, the experimenters co-administered methamphetamine as an “energizer” along with the mescaline. This went mysteriously unreported in Fadiman’s published work.

“[T]he preliminary report of the study indicates that participants received methamphetamine and chlordiazepoxide along with the mescaline: ‘In the individual sessions the drug regime consists of psychic energizers and a psychedelic drug (200 mg. of mescaline sulphate in these experiments), usually with additional energizer at mid-day’ (Fadiman et al. 1965, p 4). The nature of these energizers is clarified later in the report where methedrine (methamphetamine) and librium (chlordiazepoxide) are explicitly mentioned (ibid, p B-1). Because the co-administration of other drugs was not described in the peer-reviewed publication by Harman et al. in Psychological Reports, very few subsequent commentators have noted this confound (Krippner (1968) notes the use of ‘energizers’ without comment)”[7] p.8

In the overview of the experiment, Harman and Fadiman mention that experiments on specific performance enhancement through directed use of psychedelics have gone on in various countries of the world, on both sides of the Iron Curtain.[8]

In the book LSD The Problem-Solving Psychedelic, Stafford and Golightly write about a man engaged in naval research, working with a team under his direction on the design of an anti-submarine detection device for over five years without success. He contacted a small research foundation studying the use of LSD. After a few sessions of learning to control the fluidity of the LSD state (how to stop it, how to start it, how to turn it around) he directed his attention to the design problem. Within ten minutes he had the solution he had been searching for. Since then, the device has been patented by the U.S., and Navy and Naval personnel working in this area have been trained in its use.[9]

In 1999 Jeremy Narby, an anthropologist specialized in amazonian shamanism, acted as a translator for three molecular biologists who travelled to the Peruvian Amazon to see whether they could obtain bio-molecular information in the visions they had in sessions orchestrated by an indigenous shaman. Narby recounts this preliminary experiment and the exchange of methods of gaining knowledge between the biologists and indigenous people in his article Shamans and scientists.[10]

In 1991, Denise Caruso, writing a computer column for The San Francisco Examiner went to SIGGRAPH, the largest gathering of computer graphic professionals in the world. She conducted a survey; by the time she got back to San Francisco, she had talked to 180 professionals in the computer graphic field who had admitted taking psychedelics, and that psychedelics are important to their work; according to mathematician Ralph Abraham.[11][12]

James Fadiman is currently conducting a study on psychedelic micro-dosing for improving normal functioning.[13] Micro-dosing (or sub-perceptual dosing) means taking sub-threshold dose, which for LSD is 10-20 micrograms. The purpose of micro-dosing is not intoxication but enhancement of normal functionality (see nootropic). In this study the volunteers self-administer the drug approximately every third day. They then self-report perceived effects on their daily duties and relationships. Volunteers participating in the study include a wide variety of scientific and artistic professionals and students. So far the reports suggest that, in general, the subjects experience normal functioning but with increased focus, creativity and emotional clarity and slightly enhanced physical performance. Albert Hofmann was also aware of micro-dosing and has called it the most under-researched area of psychedelics.[14]

Since the 1930s, ibogaine was sold in France in 8mg tablets in the form of Lambarne, an extract of the Tabernanthe manii plant. 8mg of ibogaine could be considered a microdose since doses in ibogatherapy and -rituals vary in the range of 10mg/kg to 30mg/kg adding usually up to 1000mg.[15] Lambarne was advertised as a mental and physical stimulant and was “…indicated in cases of depression, asthenia, in convalescence, infectious disease, [and] greater than normal physical or mental efforts by healthy individuals”. The drug enjoyed some popularity among post World War II athletes, but was eventually removed from the market, when the sale of ibogaine-containing products was prohibited in 1966.[16] In the end of 1960’s The International Olympic Committee banned ibogaine as a potential doping agent.[17] Other psychedelics have also been reported to have been used in similar way as doping.[18]

In 1948, Swiss pharmacologist Peter N. Witt started his research on the effect of drugs on spiders. Witt tested spiders with a range of psychoactive drugs, including amphetamine, mescaline, strychnine, LSD, and caffeine. All the drugs tested reduced web regularity except for small doses (0.10.3g) of LSD, which increased web regularity.[19]

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Psychedelics in problem-solving experiment – Wikipedia

Safety – How to Use Psychedelics

The purpose of this site is to provide science-based information about how to safely use psychedelics. Following basic safety precautions dramatically reduces any risks.

Safety with psychedelics is important not just because these are powerful substances but also because creating a safe environment and approach will make treatment much more effective. Crucially, when psychedelics are used in a safe and comfortable setting, it becomes easier for people to relax and open themselves to the experience and gain the most benefit.

The most common psychedelics — LSD, mushrooms, MDMA — are far safer to their users and the people around them than drugs like alcohol, tobacco, and many prescription medicines. However, because of prohibition in many countries, there is far less available information and far more uncertainty about the sources and contents of psychedelic substances. Caution is very important.

We recommend psychedelics be taken only when you are in good health (unless you have decided to use it specifically to deal with an illness or in alleviating end of life anxiety). Those with heart problems should avoid psychedelics unless specifically discussed with a doctor. Pregnant women should not take psychedelics.

During a psychedelic experience, the mind/body connection is usually magnified. Any physical pain or discomfort (including something as small as hunger pangs) can affect the nature of the experience. Women should avoid tripping when experiencing menstrual cramps. If a woman typically experiences strong pre-menstrual symptoms (back aches, bloating, moodiness, headaches etc) its advisable to postpone the trip until they have subsided.

Entering a psychedelic journey with a comfortable and healthy body will help you toward a positive and meaningful experience.

For the advanced psychedelic user, a trip to deliberately investigate physical discomfort or pain may prove beneficial in understanding the mind/body connection and creating a deeper connection with your physical body.

Here are the some components of a safe psychedelic experience:

Setup the room that you will be in so that it feels cozy and pleasant. Have a comfortable place to sit or lie down, have pillows and decorations. You may want to have some music to listen to as well (music without words is recommended, as it is less likely to pull your thoughts away).

Keep in mind that going from place to place, being in a public setting, or dealing with logistical matters can be difficult while using psychedelics and can also be a source of anxiety. This is not recommended and can distract your focus.

When in doubt: be very cautious, don’t rush, and start small.

Dont take a psychedelic for the first time without someone present who has experience with that substance. Make sure this is someone who you trust to help talk you through any stressful or confusing moments. Having trusted support is incredibly helpful for letting you feel safe and open to the experience. In addition, having someone around to help with practical needs (like getting you a glass of water) will let you focus on the process. Even if you have lots of experience with psychedelics, we recommend having a trusted person present (they don’t need to be in the same room, just on hand).

We generally believe that psychedelics are most appropriate for people in their mid-20’s and older. We don’t know of research that has explored age-associated effects, but anecdotally, older individuals tend to take a more serious and intentional attitude towards psychedelic exploration.

If you have a dissociative psychological disorder, we do not recommend that you use psychedelics. Again, there is not good research on this topic and anecdotal reports are highly contradictory– some people have had their conditions healed by use of psychedelics, others have found it has made their symptoms worse. We encourage you to err on the side of caution for these types of disorders.

Be sure to very carefully research any potential interactions with other prescription or non-prescription medicines or supplements that you are taking. In particular, anti-depressants, SSRIs, anti-anxiety, and anti-psychotic medications are not safe to take with psychedelics.

Before using a particular psychedelic for the first time, you may want to gauge your sensitivity to it. Some people are much more sensitive to certain substances than others. One mushroom cap might feel strong for one person and very mild for another.

If it is your first time taking a substance, try to take a very small tester amount (less than 1/10th of a dose) a few days before your planned trip. You may not feel any effects, but you will be able to roughly judge your sensitivity if you do, and you may feel more comfortable when the time comes to take a standard dose.

Several companies make purity testing kits for various substances, including MDMA and LSD. These can be found easily on Amazon.com or with a Google search. If you are uncertain about the purity of a substance, it’s always better to test and be safe.

Psychedelics have been misunderstood and misrepresented for decades. That’s changing. Please help us share safe, responsible information on using psychedelics by sending this page to friends, and posting to Facebook, Twitter, and Google:

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Safety – How to Use Psychedelics

Famous Users of Psychedelics – How to Use Psychedelics for …

Psychedelics have been used by many of the most creative and successful individuals in our society. Because of the stigma surrounding psychedelics, only a small percentage of these people have spoken publicly about their experiences. Here are a few who have. Right now, this list is just white men! We’d love to feature some well-known people of color and women– please let us know if you have any suggestions.

Steve Jobs and his Apple co-Founder Steve Wozniak took LSD many times at the beginning of their career. Their experiences are discussed in Walter Isaacson’s biography of Steve Jobs.

“Taking LSD was a profound experience, one of the most important things in my life. LSD shows you that there’s another side to the coin, and you cant remember it when it wears off, but you know it. It reinforced my sense of what was importantcreating great things instead of making money, putting things back into the stream of history and of human consciousness as much as I could.”

Steve JobsFounder, Apple

Susan Sarandon discussed ayahuasca and mushrooms in an interview with the Daily Beast.

“Ive done Ayahuasca and Ive done mushrooms and things like that. But I like those drugs in the outdoorsIm not a city-tripper… I like doing it in the Grand Canyon, or in the woods. You want to be prepared and not have responsibilities. It does remind you of your space in the universeyour place in the universeand reframe things for you. I think you can have some very profound experiences.”

Susan SarandonActor

Frances McDormand described her experiences with LSD and psychedelic mushrooms in a 2014 interview with the Daily Beast.

“I really, really enjoyed LSD. And I really enjoyed mushrooms very much. Its unfortunate, I think, that drugs were not handled properly. Politically, theyve been used to separate the economic classes. Thankfully, its all getting fixed now with the marijuana laws. But with LSD, because it was countercultural, and because it was used as an experimental drug, it was not marketed properly. It if had been marketed properly, we would have it…. We needed a PR person for that LSD! It was very profound. Very profound.”

Frances McDormandActor

Tim Ferriss is a multi-bestselling author of the Four-Hour Workweek and the Four-Hour Body. He has spoken repeatedly about his use of psychedelics and his advice about what he considers a safe and productive approach.

“The billionaires I know, almost without exception, use hallucinogens on a regular basis,” Ferriss said. “[They’re] trying to be very disruptive and look at the problems in the world … and ask completely new questions.” – Tim Ferris, CNN.com

In this video he addresses the subject in depth:

Cary Grant was used LSD with his therapist many times and was an advocate. Vanity Fair wrote about his experiences in detail in this article from 2010.

“The Curious Story Behind the New Cary Grant headlined the September 1, 1959, issue of Look magazine, and inside was a glowing account of how, because of LSD therapy, “at last, I am close to happiness.” He later explained that “I wanted to rid myself of all my hypocrisies. I wanted to work through the events of my childhood, my relationship with my parents and my former wives. I did not want to spend years in analysis.”

Vanity Fair

Kary Mullis won the Nobel Prize in Chemistry in for dramatically improving the technique of polymerase chain reaction (PCR), which is an essential tool of modern biology research. Albert Hofmann, the inventor of LSD, was told by Kary that LSD had helped him develop his PCR invention (Wired, 2008).

“Back in the 1960s and early ’70s I took plenty of LSD. A lot of people were doing that in Berkeley back then. And I found it to be a mind-opening experience. It was certainly much more important than any courses I ever took.”

Kary MullisCalifornia Monthly, 1994

“What if I had not taken LSD ever; would I have still invented PCR?” He replied, “I don’t know. I doubt it. I seriously doubt it.”

Kary MullisBBC Horizon Interview, 1997

Psychedelics have been misunderstood and misrepresented for decades. That’s changing. Please help us share safe, responsible information on using psychedelics by sending this page to friends, and posting to Facebook, Twitter, and Google:

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Famous Users of Psychedelics – How to Use Psychedelics for …

Horizons: Perspectives on Psychedelics

In recent years, a growing community of scientists, doctors, artists, activists, seekers and scholars have orchestrated a renaissance in psychedelic thought and practice.

Horizons brings together the brightest minds and the boldest voices of this movement to share their research, insights, and dreams for the future.

Horizons Media, Inc. is a 501c(3) not-for-profit educational charity led by Kevin Balktick, Neal M. Goldsmith, Ph.D., Ingmar Gorman, Ph.D., and James Vasile, Esq.

Continued here:

Horizons: Perspectives on Psychedelics

Speakers Horizons: Perspectives on Psychedelics

Rob HeffernanAyahuasca Defense Fund Associate, Independent Researcher, ActivistGuard-en-ing the Gates of Heaven: Protecting and Cultivating the Legality, Health and Safety of Sacred Medicines

Mendel Kaelen, Ph.D.Postdoctoral Research Associate, Imperial College London”Music in Psychedelic Therapy”

Anja Loizaga-Velder, Ph.D.Postdoctoral Research Associate, Faculty of Medicine, National Autonomous University of Mexico (UNAM); Director of Psychotherapy and Research, Nierika Institute for Intercultural Medicine- Mexico New Psychotherapeutic Perspectives With Ancient Medicines

Elizabeth M. Nielson, Ph.D.Psychologist, Department of Psychiatry, NYU Langone Medical Center”What Psychedelic Therapists Don’t Talk About and Why: The Case for Research on First-hand Experience with Psychedelics”

Nicholas Byron Powers, Ph.D.Poet, journalist, and Associate Professor of English, SUNY Old Westbury”Black Masks, Rainbow Bodies: Race and Psychedelics”

Stacy B. Schaefer, Ph.D.Professor Emerita in the Department of Anthropology, California State University, Chico (CSUC) and former Co-Director of the Museum of Anthropology (CSUC)”Communing with the Gods: Peyote (Lophophora williamsii) in the Lifecycle of Huichol Indians of Mexico”

Philip E. Wolfson, M.D.Psychiatrist, psychotherapist, and Principal Investigator, MAPS MDMA-Assisted Psychotherapy for Anxiety Associated with Life-Threatening Illness Study”Ketamine Assisted Psychotherapy and the Ketamine Opportunity”

Read more:

Speakers Horizons: Perspectives on Psychedelics

Horizons: Perspectives on Psychedelics

In recent years, a growing community of scientists, doctors, artists, activists, seekers and scholars have orchestrated a renaissance in psychedelic thought and practice.

Horizons brings together the brightest minds and the boldest voices of this movement to share their research, insights, and dreams for the future.

Horizons Media, Inc. is a 501c(3) not-for-profit educational charity led by Kevin Balktick, Neal M. Goldsmith, Ph.D., Ingmar Gorman, Ph.D., and James Vasile, Esq.

Read more from the original source:

Horizons: Perspectives on Psychedelics

How to Use MDMA (Molly) – How to Use Psychedelics

MDMA is a truly remarkable medicine for working with difficult emotional experiences. The clinical results have far exceeded other interventions for a range of uses (see the research section at the bottom of this page).

MDMA is a synthetic psychedelic, first developed by the pharmaceutical company Merck in 1912. It has been widely studied since then, particularly for psychotherapeutic uses. With the rate of academic research growing rapidly, it is likely that MDMA will become FDA approved for therapeutic use within the next few years, and MAPS.org is focused on moving it through the approval process. MDMA is being widely tested for post-traumatic stress, with results that surpass any other existing treatment method.

MDMA is a particularly appealing psychedelic for therapists and researchers because the subjective mental experience feels fairly stable, while creating a dramatic increase in emotional openness and a reduction in fear and anxiety.

Before you begin, be sure to read our safety section and see the special safety considerations for MDMA at the bottom of this page.

Because MDMA has anti-anxiety and anti-fear effects, it is generally considered safe to use a full dose your first time and each time you use MDMA (generally 75mg – 125mg depending on the individual). It is important to measure the dose carefully. Milligram-precision scales cost about 20 dollars (heres an Amazon search for milligram scale).

Some therapy protocols add a booster dose of about 60mg of MDMA 2-3 hours after the first dose to extend the period of therapeutic effects and provide more time for deep exploration.

MDMA will typically be in the form of a powder, pill, or crystal. Again, be sure that you are receiving pure MDMA, not mixed with other drugs or stimulants like caffeine. ‘Molly’ is another term for pure MDMA, distinguished from ‘Ecstasy’ which often contains MDMA but is not pure MDMA. If the MDMA is in pill form, youll have to be confident of the reported dosage, as fillers are added to create a pill and weighing the pill will not indicate the MDMA content. As always, do not take any MDMA if you are unsure of quantity or purity.

Once the MDMA has worn off, be sure that you drink lots of water and get a long peaceful sleep at night. MDMA can be mentally tiring and you need to rejuvenate.

Most people find that they have an afterglow from their MDMA experience that can last days or weeks, improving their mood and outlook and keeping them very open to others.

On the other hand, some people feel mentally drained by MDMA and have a foggy headed feeling for a day or two afterwards. Others will feel emotionally drained, and have a depressed mood for up to a week after the experience. Sometimes, these feelings begin two days after the experience, but not the day after. To combat this, some people who feel sensitive to that after-effect will take 5-HTP or L-Tryptophan (both are common supplements available from any source) for a few days after MDMA in an attempt to restore their serotonin levels. People who do feel drained after an MDMA session generally report that precise the MDMA dose can affect how they feel afterwards. Too much may leave them more drained than necessary. This is another reason to start with a modest, precisely measured dose to begin.

Nearly everyone, no matter how they feel the following week, finds that the thoughts, feelings, and emotional release that they experience on MDMA persists afterwards. In particular, any realizations that they had during the experiences tend to prove real and lasting.

Most remarkably, painful emotional associations with life experiences — traumas, breakups, divorces, etc — are dramatically reduced if that issue has been explored during the experience. You will find that when you think about that same painful experience after exploring it on MDMA, you will not have the same flood of emotional pain and tension that you would have had beforehand. The memory will be intact but the emotional strings will be looser.

Even for extreme emotional trauma, this holds true. In a recent research study for patients with PTSD, 83% of patients experienced reduced symptoms after just 3 MDMA sessions combined with therapy, vs. only 25% of patients who had therapy alone. Quite simple, MDMA is the most effective treatment for PTSD ever developed. Compare this level of success to traditional anti-depressants which have strong side effects and are dosed every day for years at a time (for a total of hundreds or thousands of doses) and which have very low rates of effectiveness, often just slightly above placebo.

In addition to our standard safety suggestions, there are three particularly important precautions for MDMA use:

Psychedelics have been misunderstood and misrepresented for decades. That’s changing. Please help us share safe, responsible information on using psychedelics by sending this page to friends, and posting to Facebook, Twitter, and Google:

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How to Use MDMA (Molly) – How to Use Psychedelics

How Mushrooms Became Magic – The Atlantic

If you were an American scientist interested in hallucinogens, the 1950s and 1960s were a great time to be working. Drugs like LSD and psilocybinthe active ingredient in magic mushroomswere legal and researchers could acquire them easily. With federal funding, they ran more than a hundred studies to see if these chemicals could treat psychiatric disorders.

That heyday ended in 1970, when Richard Nixon signed the Controlled Substances Act. It completely banned the use, sale, and transport of psychedelicsand stifled research into them. There was an expectation that you could potentially derail your career if you were found to be a psychedelics researcher, says Jason Slot from Ohio State University.

For Slot, that was a shame. He tried magic mushrooms as a young adult, and credits them with pushing him into science. It helped me to think more fluidly, with fewer assumptions or acquired constraints, he says. And I developed a greater sensitivity to natural patterns. That ability inspired him to return to graduate school and study evolution, after drifting through several post-college jobs. (They are not for everyone, they entail risks, theyre prohibited by law in many countries, and only supervised use by informed adults would be advisable, he adds.)

Ironically, he became a mycologistan aficionado of fungi. And he eventually came to study the very mushrooms that he had once experienced, precisely because so few others had. I realized how pitifully little we still knew about the genetics and ecology of such a historically significant substance, he says.

Why, for example, do mushrooms make a hallucinogen at all? Its certainly not for our benefit: These mushrooms have been around since long before people existed. So why did they evolve the ability to make psilocybin in the first place?

And why do such distantly related fungi make psilocybin? Around 200 species do so, but they arent nestled within the same part of the fungal family tree. Instead, theyre scattered around it, and each one has close relatives that arent hallucinogenic. You have some little brown mushrooms, little white mushrooms … you even have a lichen, Slot says. And youre talking tens of millions of years of divergence between those groups.

Its possible that these mushrooms evolved the ability to make psilocybin independently. It could be that all mushrooms once did so, and most of them have lost that skill. But Slot thought that neither explanation was likely. Instead, he suspected that the genes for making psilocybin had jumped between different species.

These kinds of horizontal gene transfers, where genes shortcut the usual passage from parent to offspring and instead move directly between individuals, are rare in animals, but common among bacteria. They happen in fungi, too. In the last decade, Slot has found a couple of cases where different fungi have exchanged clusters of genes that allow the recipients to produce toxins and assimilate nutrients. Could a similar mobile cluster bestow the ability to make psilocybin?

To find out, Slots team first had to discover the genes responsible for making the drug. His postdoc Hannah Reynolds searched for genes that were present in various hallucinogenic mushrooms, but not in their closest non-trippy relatives. A cluster of five genes fit the bill, and they seem to produce all the enzymes necessary to make psilocybin from its chemical predecessors.

After mapping the presence of these five genes in the fungal family tree, Slots team confirmed that they most likely spread by jumping around as a unit. Thats why theyre in the same order relative to each other across the various hallucinogenic mushrooms.

These genes seem to have originated in fungi that specialize in breaking down decaying wood or animal dung. Both materials are rich in hungry insects that compete with fungi, either by eating them directly or by going after the same nutrients. So perhaps, Slot suggests, fungi first evolved psilocybin to drug these competitors.

His idea makes sense. Psilocybin affects us humans because it fits into receptor molecules that typically respond to serotonina brain-signaling chemical. Those receptors are ancient ones that insects also share, so its likely that psilocybin interferes with their nervous system, too. We dont have a way to know the subjective experience of an insect, says Slot, and its hard to say if they trip. But one thing is clear from past experiments: Psilocybin reduces insect appetites.

By evolving the ability to make this chemical, which prevents the munchies in insects, perhaps some fungi triumphed over their competitors, and dominated the delicious worlds of dung and rotting wood. And perhaps other species gained the same powers by taking up the genes for those hallucinogens. Its not clear how they did so. Some scientists think that fungi can occasionally fuse together, giving them a chance to share their DNA, while Slot prefers the idea that in times of stress, fungi can soak up DNA from their environment. Either way, the genes for psilocybin have spread.

Much of this is speculation, based on circumstantial evidence. Since psilocybin is still a controlled substance, Slot cant legally make it in his lab, which means he cant prove that the gene cluster he identified actually produces psilocybin in mushrooms. Still, his team have done as much as they can, says Jennifer Wisecaver, an evolutionary biologist from Purdue University who studies fungal genes. Given the other evidence they provide, I’d say the hypothesis is very compelling, she says.

This work is part of a resurgence of psilobycin research. Just last week, a German team led by Dirk Hoffmeister identified four enzymes that can produce the drug, paving the way to manufacture it without growing shrooms. Other scientists have shown that psilocybin could have potential for treating depression, helping smokers to quit, and relieving the anxiety felt by cancer patients. The science thats being done on [magic mushrooms] has taken on more of an air of respectability, says Slot.

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How Mushrooms Became Magic – The Atlantic

Using Mushrooms and LSD to Enhance Creativity – How to Use …

Psychedelics (specifically LSD and Mushrooms) can be extremely helpful to artists or anyone working on creative projects. Because psychedelics help us to see and think without our usual defenses, the artist’s ideas are able to sidestep their normal defensive filters (anxiety, competition, fear) resulting in truer, freer, creation. Simply put, the artist is able to hear their own voice more clearly. They know more immediately when they are being real, or being false.

Psychedelics allow us to think outside of the normal framework of time, space, language and the sensory. We may see sounds, or feel colors etc. This opens a new way of thinking about and communicating emotions and ideas. The artist is essentially given a new language. Psychedelics may also bring forth a new understanding of an individuals psyche, the physical world, emotional world, spiritual world, and the artists role in all four.

For creative work we recommend lower doses, so that you are able to focus. Wed suggest LSD doses at or under 50 mcg, and mushroom doses under .5 grams (roughly 2 small caps or an equivalent amount). As everyones sensitivity differs, you may need to experiment to find the right amount for you. When working on a low-dose your goal is not to trip but to open yourself to your own ideas.

Because you may be sitting unmoving for long periods of time as you work, your body may be very stiff toward the end of the day. To reduce stiffness or water retention drink plenty of fluids and try to take several stretching breaks. You may even want to work at a makeshift standing desk for short periods of time. Have snacks or light meals readily available. If you havent eaten all day and still dont feel hungry, eat a banana anyway — keep your energy up! Hunger affects the mood of your psychedelic experience.

Psychedelics have been misunderstood and misrepresented for decades. That’s changing. Please help us share safe, responsible information on using psychedelics by sending this page to friends, and posting to Facebook, Twitter, and Google:

Visit link:

Using Mushrooms and LSD to Enhance Creativity – How to Use …

Using Mushrooms and LSD to Enhance Creativity – How to Use …

Psychedelics (specifically LSD and Mushrooms) can be extremely helpful to artists or anyone working on creative projects. Because psychedelics help us to see and think without our usual defenses, the artist’s ideas are able to sidestep their normal defensive filters (anxiety, competition, fear) resulting in truer, freer, creation. Simply put, the artist is able to hear their own voice more clearly. They know more immediately when they are being real, or being false.

Psychedelics allow us to think outside of the normal framework of time, space, language and the sensory. We may see sounds, or feel colors etc. This opens a new way of thinking about and communicating emotions and ideas. The artist is essentially given a new language. Psychedelics may also bring forth a new understanding of an individuals psyche, the physical world, emotional world, spiritual world, and the artists role in all four.

For creative work we recommend lower doses, so that you are able to focus. Wed suggest LSD doses at or under 50 mcg, and mushroom doses under .5 grams (roughly 2 small caps or an equivalent amount). As everyones sensitivity differs, you may need to experiment to find the right amount for you. When working on a low-dose your goal is not to trip but to open yourself to your own ideas.

Because you may be sitting unmoving for long periods of time as you work, your body may be very stiff toward the end of the day. To reduce stiffness or water retention drink plenty of fluids and try to take several stretching breaks. You may even want to work at a makeshift standing desk for short periods of time. Have snacks or light meals readily available. If you havent eaten all day and still dont feel hungry, eat a banana anyway — keep your energy up! Hunger affects the mood of your psychedelic experience.

Psychedelics have been misunderstood and misrepresented for decades. That’s changing. Please help us share safe, responsible information on using psychedelics by sending this page to friends, and posting to Facebook, Twitter, and Google:

Link:

Using Mushrooms and LSD to Enhance Creativity – How to Use …

Psychedelics pioneer keeps his inner hippy in check – New Scientist

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Psychedelics pioneer keeps his inner hippy in check – New Scientist

This Philosopher Thinks Psychedelic Drugs Lead to the Truth of Experience – Big Think

Philosopher Chris Letheby believes that psychedelic drugs are a legitimate way to achieve a spiritual and therapeutic transformation. His doctoral research at the University of Adelaide was the first systematic attempt to relate psychedelic experience and 21st century philosophy of cognitive science. He argued in his thesis that psychedelics can be rightfully regarded as bringing a deeper understanding of our selves and the world around us. In fact, he says, the use of psychedelics is very much consistent with philosophical naturalism and our current scientific knowledge.

While using psychedelics, Letheby maintains, subjects gain knowledge of their own psychological potential and the fact that their selves are constructed. He expanded on these ideas in his recent interview with the 3:AM Magazine.

Letheby says that as recent scientific evidence shows, psychedelic sessions can lead to the reduction in the symptoms of anxiety, addiction and depression. Since these activities prevent people from engaging with the world, our normal way of gaining knowledge, psychedelics provide what Letheby calls epistemic benefits – allowing the patients to get reconnected and be able to once again take in information.

Chris Letheby.

The philosopher described his philosophy as physicalism or materialism that basically says the mind and consciousness emerge from the complex organisation of non-minded, non-conscious things. He thinks that from that standpoint, psychedelic states can allow the subjects to gain genuine knowledge of psychology.

Specifically, I think psychedelic subjects gain what philosophers call knowledge by acquaintance of their own vast psychological potential, says Letheby. They become directly acquaintedbecause it becomes manifestwith the modal or dispositional fact that there are vastly many, often very unusual, possible ways that their minds can be.

This is why, he claims, many spiritual seekers of the 60s ended up dedicated to meditation to expand upon the potential they realized existed while tripping.

He also thinks psychedelics can illustrate to people that the self is constructed. He thinks the drugs can offer a quicker path than meditation to having a transformative ego dissolution experience.

To those who criticize psychedelics as not providing a true experience since its not grounded in reality, Letheby says such drugs can really lead to real knowledge.

My claim is not just that psychedelic experience involves meaning, but that psychedelic transformation does, expounds Letheby. I mean something very specific by this: that the causal process leading from psychedelic ingestion to psychological benefit (be it therapeutic or cosmetic) essentially involves phenomenally conscious mental representations. This is important because it is a way of making precise the claim that psychedelic transformation is a distinctive type of psychopharmacological intervention.

In a Matrix-like twist, the philosopher also argues that psychedelic experiences can show that the ordinary waking perception is actually a controlled hallucination. What psychedelics do is disrupt this illusion and could draw peoples attention to the constructed or simulated nature of the reality in which they live. The drugs can show that the entire world they inhabit is produced by and exists within their consciousness.

Check out the full interview here, with a fascinating discussion of other topics like the role of neuroscience and antidepressants in our lives.

See the article here:

This Philosopher Thinks Psychedelic Drugs Lead to the Truth of Experience – Big Think

Using Mushrooms and LSD to Enhance Creativity – How to Use …

Psychedelics (specifically LSD and Mushrooms) can be extremely helpful to artists or anyone working on creative projects. Because psychedelics help us to see and think without our usual defenses, the artist’s ideas are able to sidestep their normal defensive filters (anxiety, competition, fear) resulting in truer, freer, creation. Simply put, the artist is able to hear their own voice more clearly. They know more immediately when they are being real, or being false.

Psychedelics allow us to think outside of the normal framework of time, space, language and the sensory. We may see sounds, or feel colors etc. This opens a new way of thinking about and communicating emotions and ideas. The artist is essentially given a new language. Psychedelics may also bring forth a new understanding of an individuals psyche, the physical world, emotional world, spiritual world, and the artists role in all four.

For creative work we recommend lower doses, so that you are able to focus. Wed suggest LSD doses at or under 50 mcg, and mushroom doses under .5 grams (roughly 2 small caps or an equivalent amount). As everyones sensitivity differs, you may need to experiment to find the right amount for you. When working on a low-dose your goal is not to trip but to open yourself to your own ideas.

Because you may be sitting unmoving for long periods of time as you work, your body may be very stiff toward the end of the day. To reduce stiffness or water retention drink plenty of fluids and try to take several stretching breaks. You may even want to work at a makeshift standing desk for short periods of time. Have snacks or light meals readily available. If you havent eaten all day and still dont feel hungry, eat a banana anyway — keep your energy up! Hunger affects the mood of your psychedelic experience.

Psychedelics have been misunderstood and misrepresented for decades. That’s changing. Please help us share safe, responsible information on using psychedelics by sending this page to friends, and posting to Facebook, Twitter, and Google:

Read the rest here:

Using Mushrooms and LSD to Enhance Creativity – How to Use …

How MDMA & Other Psychedelics Could Change Therapy | Goop

Psychedelic drugs that have been considered recreational for decadesand classified as drugs of abuse by the FDAare showing major promise as potential solutions for hard-to-treat disorders and illnesses (see this goop piece on ibogaine and addiction, as well as this one on ayahuasca). Usually associated with the street names ecstasy or molly (although its not actually the same), the drug MDMA is in new clinical trials to treat PTSD and anxiety; other possible therapeutic applications are being explored, too.

Emily Williams, M.D. is a resident psychiatrist at UCSF and trained MDMA-assisted psychotherapist working with MAPS (Multidisciplinary Association for Psychedelic Studies), a non-profit pharmaceutical research organization leading the way on MDMA research. In Williams current work, she has patients take MDMA while undergoing tailored psychotherapy sessions. MDMA is thought to enhance the efficacy of psychotherapy by reducing the fear response, and strengthening the sense of the trust between patient and therapist. MDMA seems to bring about an internal awareness that even painful feelings that arise are important to the therapeutic process, says Williams. Many people describe the experience of MDMA-assisted psychotherapy as years of therapy in one day.

Below, Williams tells us how MDMA might change the future of various therapy modalities, as well as how we think about psychedelics.

Q

Can you explain what MDMA is?

A

MDMA is not the same as ecstasy or molly, which may contain MDMA, but frequently also contain unknown and/or dangerous adulterants. (Its important to note that in clinical research trials, the MDMA used is created in a strictly regulated lab setting and monitored by both the FDA and DEA.)

In technical terms, MDMA (3, 4-methelynedioxymethamphetamine) is a monoamine releaser and re-uptake inhibitor that affects serotonin, prolactin, and oxytocin. This means that it causes an increase in serotonin and other neurotransmitters in the body, and also allows for increased serotonin activity at certain receptors in the brain.

MDMA was first synthesized in 1912 by Merck in an effort to develop a compound to stop abnormal bleeding. It wasnt thought to have a medical benefit until it was rediscovered by Alexander Shulgin, Ph.D. in Northern California in 1976 and spread by psychiatrists and psychologists who reported seeing benefits to its use as an adjunct to psychotherapy in individuals and couples.

Q

What does MDMA-assisted psychotherapy entail, and who is it meant for?

A

Clinical trials have primarily investigated MDMA as treatment for PTSD, but there have also been studies on MDMA-assisted psychotherapy for social anxiety in autistic adults, anxiety related to life-threatening illness, as well as in couples therapy. (As mentioned above, in the late 1970s and early 80s, before MDMA was reclassified as a drug of abuse, it was used with anecdotal success in individual and couples therapy.)

In MAPS clinical research trials, a course of MDMA-assisted psychotherapy begins with a series of psychotherapy sessions, sans drugs, to establish the therapeutic relationship and safe space for processing.

This preparatory phase is followed by a series of MDMA psychotherapy sessions: Each one lasts about six to eight hours and consists of the patient orally ingesting MDMA and resting in a comfortable position with eyes closed or wearing an eye mask, while listening to music thats initially relaxing and then emotionally evocative. Throughout these experimental MDMA sessions, periods of patient introspection alternate organically with periods of conversation with the therapists, largely determined by the desire of the patient.

The MDMA sessions are followed by integration sessions (no drugs involved) that last about 90 minutes, where the patient and therapist talk about insights gained during the experimental sessions, and how they relate to the trauma or other issues that were brought up during the preparatory phases.

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Q

Can you tell us about the results so far?

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The combined results from the PTSD studies are very promising: After just two sessions of MDMA-assisted psychotherapy for PTSD, 52.7% of 74 study participants no longer met criteria for PTSD, versus 22.6% of the placebo group. Among all study participants who received active dose MDMA-assisted psychotherapy, 67.4% of 86 participants no longer met criteria for PTSD at the twelve-month follow up. This shows that not only is MDMA-assisted psychotherapy effective for treating PTSD, its benefits are long-lasting. No other psychiatric medications or therapies currently available are comparable.

Q

Whats the treatment like for the patient?

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The MDMA experience itself has been described as having an enhanced mood, heightened sense of openness, sense of closeness with others, and increased connection with ones intuition or what we refer to as inner healing intelligence. A large majority of patients in the clinical trials have reported that their course of MDMA-assisted psychotherapy was profound and life-changing. Many describe it as years of therapy in one day.

Q

Would MDMA be effective on its own, without the therapy session, or does it work because of the interaction of the two?

A

MDMAs effectiveness is reliant on the accompanying psychotherapy. It is thought that MDMA increases trust and strengthens the therapeutic alliance (the relationship between patient and therapist)that relationship is actually the number-one factor determining the efficacy of psychotherapy. MDMA is thought to catalyze the healing process, which is further supported by highly trained MDMA therapists. MDMA seems to bring about an internal awareness that even painful feelings that arise are important to the therapeutic process. The MDMA and psychotherapy complement each other to foster a clearer perspective, helping the patient understand that the trauma is an event from the past, and to see the support and safety that exists for them in the present moment.

This process also relies on concepts of set and setting: Set is the intention of the patient, the preparations they have made, as well as their mental and physical characteristics. The setting is the physical/interpersonal environment that can contribute to a persons altered state of consciousness. The psychotherapeutic frame of MDMA-assisted therapy is so important; the preparatory process works towards establishing an optimal set and setting for the MDMA experience.

It is also important to stress that there are medical risks associated with MDMA use, including hyperthermia, cardiac complications, as well as a potentially fatal complication called Serotonin Syndrome, so close supervision by a physician is critical.

Q

How is MDMA/psychotherapy treatment thought to decrease the fear response in patients?

A

MDMA can reduce a patients perceived threat to their emotional integrity; it can also decrease defensiveness without blocking access to memories, or preventing a deep and genuine experience of emotion. Eliminating your conditioned fear responses can lead to more open, comfortable communication about past traumatic events and give you greater access to information about those events. Some studies show a decrease in communication between the amygdala (the fear-processing area of the brain) and hippocampus (memory storage) with MDMA compared to a placebo, however the actual mechanism of action remains unknown, which is why further research is crucial in this growing field.

Q

Could MDMA be used for other applications/to treat other conditions?

A

MDMA-psychotherapy has the potential to be used to supplement more traditional therapy modalities, such as psychodynamic or cognitive behavioral therapies, as a way to explore personal growth and overall wellbeing.

Q

Besides MDMA, which psychedelic drugs do you think are most promising in terms of potential therapeutic applications?

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There are a number of different psychedelics being studied currently for a variety of disorders, ranging from depression to addiction and tobacco cessation. At this moment, I would say that psilocybin (the active compound in psychedelic magic mushrooms) is also very promising in terms of becoming legalized for clinical use. The Amazonian brew, ayahuasca is also showing benefit in some recent research studies for a variety of disorders, including trauma and depression.

Q

MAPS work is all privately funded; do you see federal funding (or FDA approval) on the horizon?

A

The Multidisciplinary Association for Psychedelic Studies (MAPS) is undertaking a roughly $25-million effort to make MDMA into an FDA-approved prescription medication by 2021; its currently the only organization in the world thats funding clinical trials on MDMA-assisted psychotherapy. Were closer than ever before to seeing federal research funding awards to projects focusing on MDMA-assisted psychotherapy. We are experiencing a societal, cultural shift in how psychedelics are perceived and I hope that as more people express interest, the funding will follow.

Q

How did MAPS get started, and how did you become involved with the organization?

A

The Multidisciplinary Association for Psychedelic Studies (MAPS) is a 501(c)(3) non-profit organization focused on pharmaceutical research. It was founded in 1986 by Rick Doblin, Ph.D. in an effort to preserve the therapeutic use of MDMA after it was identified by the US DEA as a drug of abuse. Doblin realized that to legitimize psychedelic-assisted psychotherapy, wed have to prove its efficacy via clinical trials. Nearly a decade later the first FDA-approved, double-blind, placebo-controlled US Phase I dose-response safety study of MDMA was published; it was sponsored by MAPS. MAPS is now beginning the first Phase 3 multi-site clinical trial of MDMA-assisted psychotherapy for the treatment of PTSD, one of the last steps towards MDMA becoming an FDA-approved medication.

I first became connected with MAPS when I was in medical school in Charleston, South Carolina, which also happened to be the site of one of the original MDMA-assisted psychotherapy studies in the US. Over the last several years, I have trained as an MDMA-assisted psychotherapist with MAPS in parallel with my psychiatry residency, and I will be a therapist and team co-leader on our clinical PTSD trial. Im also working on an MDMA psychotherapy study for anxiety related to life-threatening illness.

Emily Williams, M.D., is a resident psychiatrist at UCSF where she is conducting an analysis of the effects of MDMA on therapeutic alliance, as well as serving as co-investigator on a clinical trial for MDMA-assisted psychotherapy. She is a mentor for the Center for Psychedelic Therapies and Research at the California Institute of Integral Studies, and works as the independent clinical rater for a MAPS-funded study on MDMA for end-of-life anxiety. In addition to her clinical and research work, she serves as a supervisor for the Zendo Project, which provides psychedelic harm reduction for events and festivals.

The views expressed in this article intend to highlight alternative studies and induce conversation. They are the views of the author and do not necessarily represent the views of goop, and are for informational purposes only, even if and to the extent that this article features the advice of physicians and medical practitioners. This article is not, nor is it intended to be, a substitute for professional medical advice, diagnosis, or treatment, and should never be relied upon for specific medical advice.

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How MDMA & Other Psychedelics Could Change Therapy | Goop


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