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This story is part two in a two-part series looking at thepsychedelics drug development landscape. Part one, which looks at investors' interested in psychedelics,is available here.

Psychedelic drugs are coming out of the jungle and creeping closer to the market, but developers will have to overcome a kitchen sink of regulatory issuesor, maybe more accurately, a living room couch?

Unlike modern pharmaceuticals, such as antidepressant pills or cancer-fighting infusions, the medicinesusedin psychedelics-assisted therapy arenot standalone treatments. Instead, these drugs help a patient reset their brain as they work with a psychotherapist to overcome ailments such as depression and addiction.

The FDA was unsure what to do with the therapy part of it. Do they look at the therapy training program? What is the label going to say? How much do you put in the REMS [Risk Evaluation and Mitigation Strategy] and how much do you put in the label? said Amy Emerson, CEO of MAPS Public Benefit Corporation, a subsidiary set up by the nonprofit Multidisciplinary Association for Psychedelic Studies to develop and commercialize its MDMA-assisted treatment for post-traumatic stress disorder (PTSD).

RELATED: Investors are tripping on psychedelics startups despite a murky path to commercial success

Psychedelicstreatment developers also mustovercomeintellectual property challenges, because thesedrugs are in the public domain or have been used by Indigenous peoples for millennia. They have to figure outhow to open up access to all who need treatment. And they may need to create new business modelsto develop these treatments, not only to help patients and turn a profit but also to do it ethically.

Numerous studies have shown the promise of psychedelics, such as LSD and psilocybin, but research in the field has been hindered by federallaw. The Controlled Substances Act of 1970 classified psychedelics as Schedule I drugs with no currently accepted medical use.

But the tide is turning, thanks in part to the shortcomings of traditional mental health care.Current treatments dont always work well, and they carry side effects such as an increase in alcohol cravings or an increased risk of suicide.

Research and investor interest in psychedelics-based treatment has rebounded in the last decade. Privately funded research centers have popped up at prestigious institutions like Johns Hopkins University and the University of California, Berkeley.

We have very blunt tools that are mostly focused on symptom management rather than trying to help people with their own resiliency and internal ability to make change and potentially overcome the challenges they are having in life, said Evan Wood, M.D., Ph.D., chief medical officer at Numinus, which has partnered with MAPS and Syreon on clinical trials of MDMA- and psilocybin-based therapy, respectively.

The hope is that psychedelics added to talk therapy can achieve what previous approaches haven't, especially as the COVID-19 pandemic has exacerbated mental health problems and highlighted the need for better options,said Jeeshan Chowdhury, M.D., Ph.D., CEO of Journey Colab, a biotech working on a synthetic form of mescaline, a hallucinogenic compound found in some species of cactus, to treat alcohol use disorder.

For MAPS, the stigma around psychedelics did the nonprofit no favors as it tried to get human trials off the ground in the 1990s.

RELATED:Journey Colab bags $3M from 'moonshot' fund to push new development model for psychedelic treatments

Because of a wealth of research into the potential harms of MDMA, the nonprofit didnt need to run a phase 1 study to figure out the best dose of the drug or its side effects.

The nonprofit started itsfirst phase 2 trial in 2004, nine years after it completed the required preclinical studies in 1995.

We had a hard time getting the first study approved because politics were being put in front of the science, Emerson said. Another barrier was moneyMAPS is funded by philanthropy, rather than deep-pocketed venture capitalists like many a psychedelics-focused biotech today. Instead of going full speed ahead on multiple phase 2 trials, MAPS had to carry them out slowly and sequentially, Emerson said.

The nonprofit moved into phase 3 in 2018 and is now recruiting patients for a second phase 3 trial. An FDA decision is anticipatedin 2023.

Though psychedelics research has certain requirements that other drug R&D doesnt, such as secure drug storage and monitoring patients overnight, Emerson views MAPS work as no different from other treatments that are among the first of their kind.

MAPS therapy harnesses MDMA, also known as ecstasy or molly, which was first synthesized by German pharma Merck KGaA in 1912. But other psychedelics-assisted therapies are based on compounds such as psilocybin, mescaline and N,N-dimethyltryptamine, which are found in nature and have been used by Indigenous populations for millennia.

Thats why Chowdhury of Journey Colab thinks of the companys work as translating therapies from a traditional setting to a clinical setting rather than simply drug development.

Some patients may have the means to travel to Indigenous communities to benefit from such treatments, but there are some issues there in terms of sustainability, extractive models and impact on those communities, Chowdhury said.

Some of the plant sources for these medicines are endangered, for example, while history is rife with examples of colonizers exploiting Indigenous peoples, their expertise and their lands.

We need to meet patients and families who suffer from alcohol use disorder where they are We need to bring these therapies to people in their homesnot everyone can or should go to the jungle to experience these therapies, Chowdhury added.

RELATED: From 'party drug' to PTSD treatment: Atai launches EmpathBio to develop MDMA-based therapy

Translating these therapies into a modern healthcare context includes developing synthetic versions and creating methods to deliver reliable, consistent and measurable doses to patients.

For some traditional psychedelic therapies, the 'method of administration is smoking, which is not appropriate for a clinical setting, Chowdhury said. A patient in the clinic versus in a ceremony is going to receive a different type of therapy.

These inventions could address the issue of intellectual property, where companies would patent delivery methods and treatment protocols rather than the psychedelics themselves, some of which are in the public domain and cannot be patented. Johnson & Johnson did just that with thehallucinogenicparty drug ketamine by creating a new formulation called esketamine,which was approved in 2019 as thenasal spray antidepressant Spravato.

Atai Life Sciences is working on shorter-acting psychedelics, which could lessen treatment time for patients and potentiallydeliver the benefits of psychedelics without their hallucinogenic effects.

Still, psychedelics developers remainvulnerable to competitors that could undercut them with cheaper versions.

Thats a concern for Compass Pathways, a biotech working on psilocybin-based therapy for treatment-resistant depression. The company noted competition as a risk in a recent securities filing,not just from biotech and pharma companies but also from nonprofits including the Wisconsin-based Usona Institute, which is researching psilocybin-based therapy for major depressive disorder.

RELATED: Compass plans IPO to take 'magic mushroom' drug to phase 3

To encourage psychedelics R&D, Numinus Wood thinks this class of therapies shouldnt be lumped in with modern pharmaceuticals and instead needs its own regulatory pathway.

This is not a pharmaceutical druga cancer drug, chemotherapy drug or new heart disease drugbut a naturally occurring molecule people have been using for hundreds if not thousands of years, Wood said. There probably needs to be a different regulatory regime for it.

MAPS tried to model its MDMA-assisted psychotherapy after traditional regulatory processes for other pharmaceutical drug approvals.

I wanted to make it look exactly how the FDA or any regulator would expect any other study and drug development program to look, said Emerson, who started out with MAPS as a pro bono consultant in 2003 and became the CEO of its Public Benefit Corporation in 2014.

Some players believe the field needs a new business model to develop and market the therapies. Others think current models can be tweaked, seeing as companies like J&J, GW Pharma and Jazz Pharma have brought versions of Schedule I drugs to market as new medicines for depression, epilepsy and narcolepsy.

Srinivas Rao, M.D., Ph.D., chief scientific officer of psychedelics treatment maker Atai, said in the case of Spravato,patients can self-administer the drugbut have to do sounder the supervision of a healthcare provider in a certified Spravato treatment center over several weeks.

RELATED: Jazz leaps into epilepsy with $7.2B buyout of cannabinoid drugmaker GW Pharma

Was that a markedly different business model? Id argue no, Rao said. "If we can bring it down to make [dosing] much less frequent, well be in pretty good shape.

But Emerson and Chowdhury think this type of treatment requires a bigger change.

We cant just take existing company structures and plug them into psychedelicsthe opportunity with this class of compounds is it forces us to think about different structures, different ways of approaching mental health, Chowdhury said.

For MAPS, a nonprofit dedicated to research, that meant setting up a public benefit corporation rather than a traditional for-profit structure. This allowed them price the drug to maximize patient access while also funding future research.

Journey is treading somewhere between nonprofit and for-profit by putting10% of its founding equity into a trust to share profits with employees, the therapists and caregivers who will administer the treatments, and the Indigenous communities to which the companys medicines trace their roots.

As MAPS PTSD treatment and other psychedelics-based therapies inch closer to regulatory review, the next big question will be how to translate treatments from a tightly controlled clinical trial environment to the real world.

The setting [of therapy] is very important. This is something we have guidelines around and we would have guidelines post-approval as well, Emerson said. It should be comfortable, more like a living room setting than a hospital room.

That includes music, eye shades and a comfortable couch, but the rooms could look different depending on who is providing treatment, ranging from a community-based private practice to clinics at an institution, she said.

MAPS is gaining experience in the real world through an Expanded Access Program, which is approved to treat 50 people.

For now, the MDMA-based treatment will always be given in a clinic under the eye of a therapist. But looking down the roadand if the data support thispatients may be able to take the treatment at home after a certain number of sessions in the clinic, or a therapist may administer treatment in a patients home. Rao of Atai envisions a general practitioner offering these treatments in their offices but acknowledged this would be a long way off.

We have to be negotiating really hard with payers to not only cover the drug but to have new codes to cover the therapy, Emerson said. Therapy is more expensive than the drug. Therapy is not something we get to set the price forwe cant do that, it doesnt belong to us.

But companies dont need to start from scratch: They can build on existing structures, like the 16,000 rehabilitation centers in the U.S., the millions of people already going to therapy each week, and insurance codes and reimbursement models to make this work for patients, Chowdhury said.

There are questions about how were going to pay for this, build all this, Chowdhury said. Already, we are paying for it, especially in addictions. The amount we spend on frustratingly unsuccessful therapies is enormous."

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Psychedelics are getting closer to approval, but the market may not be ready - FierceBiotech

In 1966, U.S. senators organized hearings where doctors and government officials voiced their concerns about psychedelic use. William Frosch, a professor of psychiatry at New York University and attending doctor at Bellevue Hospital, said that LSD had serious adverse effects with prolonged psychotic reactions even on normally stable persons.

The president of the New York State Council on Drug Addiction, Donald Louria (who infamously said, Gram for gram LSD is far more dangerous than heroin), brought up the psychedelic side effects seen at Bellevue, where in addition to vivid, colorful hallucinations, these include many bizarre effects such as terror. Some of the patients had developed states of anxiety so powerful that the report called them panic reactions.

These testimonies took place in the context of the war on drugs, as pointed arguments in favor of prohibition. Four years later, in 1970, Richard Nixon introduced the Controlled Substances Act, which federally banned psychedelics, with some exceptions.

The idea of the "bad trip" has persisted culturally, even as psychedelics in the past two decades have established footholds in scientific research, academic journals, and for-profit companies. Many states have proposed or passed decriminalization laws on psychedelics, FDA approval for psilocybin for depression is inching closer, and psychedelic companies that have gone public have been valued in the billions.

Psychedelics have entered a stage of mainstreaming where those who might never have considered taking psychedelics are now curious, but could be cautious or risk-averse. They want to know, beforehand, what their experience will be like: Will it be safe, will they have a bad trip"?

In June, I got an email pitch from a senior adviser at Bullseye Corporate, a communications firm, about the first psychedelic gene test, one that was created to meet this need. Want to know your reaction to psychedelics before you take them? You can nowwith the first ever Psychedelic Genetics Test kit the test kit can help people considering psychedelics assisted therapy gain personalized insights into how their genetic profile may impact treatment and outcomes. In other words, it can basically predict a 'bad trip' as genetics plays a strong role in how psychedelics are received and metabolized by each user.

Sold by HaluGen Life Sciences, a subsidiary of Entheon Biomedical Corp, the Psychedelic Genetic Test claims to help a person understand your sensitivity to classical psychedelics, like LSD and psilocybin, discover your ketamine response based on genetics and format, and explore your short- and long-term risk factors associated with psychedelics use," according to their website.

HaluGen provided Motherboard with four test kits for $1 each plus shipping; they normally cost $89. I sent in my DNA sample from a cheek swab, as did my colleague, Tim Marchman. As a measure of quality control, Motherboard also sent in DNA samples from a pair of twins to see if their results would be the same. They were. This was a small test of only two people with identical DNA, but in this instance, HaluGen produced consistent results.

The problem with HaluGens test is not their DNA processing skills but what's implied from the genes they hone in onincluding two genes that HaluGen claims to influence serious mental illness risk that have been scientifically discredited according to published literature. The conclusions drawn from the other genes are also overstated and misinterpreted, according to scientists Motherboard consulted who study those genes. In response to these statements, a spokesperson for Entheon told Motherboard that like other direct-to-consumer tests, the Psychedelic Genetics Test is designed to be educational, not diagnostic, and that a disclaimer on HaluGen's website clearly states that.

This may be the first psychedelics genetic test kit, but it almost certainly wont be the last. This test exemplifies the kinds of tactics future products will likely utilize: marketing certainty based on biology (while paired with hedging disclaimers), and using scientific jargon and, sometimes, prominent research findings to justify their interpretations. Actually, though, the amount of practical insight or knowledge they can provide from a handful of genes is woefully small.

As such, tests like these create a number of risk factors all on their own. They could lead people to make decisions about drug dosage based on a simplistic reading of single gene variations, which dont accurately predict outcomes. If a genetic test informs someone that their gene variations are "normal," it could lead them to focus less on their intentions and settingknown to be important for the experiencebefore a psychedelic trip. Finally, telling people based on outdated or misrepresented science that they are at risk for psychosis or schizophreniaas I wasis both distressing and ethically fraught.

The test looks at five genes: one that is claimed to impact how fast or slow you metabolize ketamine, one that influences the density of serotonin receptors that you have, and three gene variants that HaluGen claims influence mental health riskwith the implication that those with higher risk based on those variants should be cautious of psychedelics.

In a press release, Entheon CEO Timothy Ko said, For patients considering psychedelic-assisted psychotherapy, and providers alike, this product gives greater insight into how an individual's genetic profile could impact treatment, ultimately improving outcomes.

The boilerplate pitch for the test I got in my inboxthat the test could "basically predict a 'bad trip'"is predicated on a gene for a specific kind of serotonin receptor, 5HTR2A. The test said that a gene variation that led to a higher density of these receptors would make a person more sensitive to psychedelics. The suggestion here is that a higher density of these receptors is correlated with the quality of the trip that they're going to have.

Charles Nichols, a professor of pharmacology at LSU School of Medicine who researches serotonin receptors, put it plainly: "This really means nothing, Nichols said. The premise of trying to link one polymorphism with a behavioral predictor is just, I would say, preposterous.

There are many other gene variations that could influence serotonin receptors outside of density, Nichols said. It may not be the amount of serotonin receptors that you have to look at; it might be the function of the serotonin receptor: How is it signaling? How is it desensitizing?

It doesn't mean that these receptors are unimportant. HaluGen cites 55 references on its website, and Nichols pointed out one to me: a 2019 paper from the journal Nature that showed that psychedelic effects emerge through serotonin 2A receptors. They reported that the intensity of psychedelic effects, as reported by their participants, was related to the receptor occupancymeaning how many receptors were stimulated by psilocybins active metabolite, psilocin.

Nichols said this was significant research; the study showed without a doubt that these specific serotonin receptors are relevant to psychedelic intensity. But the exact relationship between gene variations, receptor density, and receptor occupancy still needs more research.

(Entheon wrote that "there is growing evidence that the HTR2A gene that governs receptor density has an influence on psychedelic sensitivity. The science is continuously improving as more studies are conducted and well review and monitor new evidence as it becomes available.")

But the study found that the intensity of psilocybin experience is dependent not only upon the number of receptors that a person has in the brain but also on the occupancy of those receptors, Nichols said. "If you think about it, it could negate [HaluGen's] whole premise, he said. Theyre trying to tell you that the number of receptors that somebody has correlates with their subjective experience. Whereas that paper is saying its not the number of receptors that somebody has but it's the fraction of those receptors that are occupied by the drug that govern the subjective intensity of the experience.

Jacob Aday, an experimental psychologist at University of California San Francisco, agreed that the claim that higher density equals higher intensity doesnt have any solid research supporting it. In fact, it could be the complete opposite, Aday said. Those with a high density of serotonin receptors might need a higher dose to effectively stimulate all of the extra receptors. So theyre making an assumption that really hasn't been demonstrated anywhere.

My test results said that my psychedelics sensitivity should be "normal," since my variation of the gene for that serotonin receptor wasnt associated with increased or decreased receptor density. My colleagues results said that his variant meant his psychedelics sensitivity was increased. Yet if this test was supposed to be an indication of how the actual psychedelic experience might go, it wasnt predictive in our case. My colleague said that he has only had good psychedelic trips, and in my case, Ive only had challenging ones.

I found the most concerning part of the results to be the mental health risk assessment. HaluGens test looked at three genes, DISC1, NRG1, and how many copies of the C4A gene a person had, to determine risk of different psychiatric disorders. The results say that certain variations of DISC1 and NRG1 gene have been shown to increase the risk for psychosis, bipolar, and schizophrenia.

But DISC1 and NGR1 have been thoroughly ruled out as candidate genes for schizophrenia, bipolar, or psychosis, said Steven Hyman, director of the Stanley Center for Psychiatric Research at Broad Institute of MIT and Harvard. If you apply to the [National Institute of Mental Health] with an otherwise well-written grant purporting to study DISC1 or NRG1 in schizophrenia, the grant would be automatically rejected, he said. Its that straightforward.

In a 2017 paper titled No Evidence That Schizophrenia Candidate Genes Are More Associated With Schizophrenia Than Noncandidate Genes, the authors re-examined 25 candidate genes previously thought to be involved with schizophrenia, including DISC1 and NRG1. These commonly studied variants were no more associated with the disorder than would be expected by chance, the authors wrote.

My results for DISC1 and NRG1 were "normal," as were Marchman's and the twins', but it's worth explaining how such genes were once of interest and then lost their credibility. These genes were thought to be risk factors before scientists had the statistical power of Genome Wide Association Studies (GWAS) at their disposal, Hyman explained. In the past, researchers would pick candidate genes based on guesses about what genes might be at play in a given disorder, like genes that effective drugs targeted or neurobiological pathways that seemed important.

GWAS studies don't require such a priori guesses since they look at the entire genome indiscriminately. Advances in gene sequencing made it so that scientists could look at the whole genomes of large groups of people, with and without a disease, and see what genetic variations popped up in those with the condition compared to those without it. This process eliminated several candidate genes, including DISC1 and NRG1.

Entheon's spokesperson wrote that GWAS are "just one data point that looks at the influence of NRG1 and DISC1. There are other, equally valid peer-reviewed studies, that have shown there is a potential linkage between NRG1 and DISC1 and mental health risk."

In response, Hyman said, "'Equally valid' is not nearly correct," and directed me to a 2013 editorial written by, Patrick Sullivan, the chair of the Psychiatric Genomics Consortium, who wrote that, "The published genetic evidence for an association of DISC1 with schizophrenia does not meet a high standard."

"And since then there have been large unbiased GWAS and whole exome sequencing studies of schizophrenia and bipolar disorder and neither NRG1 nor DISC 1 show association to either disorder," Hyman said. "For that matter neither emerges in other GWAS, such as for major depression."

The other gene in HaluGen's test, C4, has more rigor behind it. In fact, the relationship between C4 and schizophrenia was discovered by GWAS done by researchers at the Broad Institute, where Hyman works. The graph that showed C4's prevalence was so dramatic that it was named the Manhattan plot, for the skyscraper-like bar that was C4.

The authors of the C4 study, published in Nature, used data from more than 100,000 DNA samples from around the world. They found 100 genetic risk factors, including one very strong signal on a specific location of the genome, the gene for complement component 4 (C4), which is typically an immune molecule that helps contain infections in the rest of the body.

The researchers found that people who had particular forms of C4 had higher expressions of the gene, and higher risks for developing schizophrenia. In animal models, Harvard neurobiologist Beth Stevens determined that the C4 gene plays a role in synaptic pruning, a process that occurs during brain development where some connections between brain cells are removed.

I knew about the significance of C4 already, so I was jarred to find that I have four copies of the C4A gene. The HaluGen test said this means I have an increased risk of psychosis, bipolar, and schizophrenia. When explaining why, the test summarizes the research finding: increased disorder synaptic pruning can be a contributing factor to a higher risk.

Entheon's spokesperson referred me to the Nature study, writing that C4 "has one of the strongest genetic risk-associations with mental health." But the legitimacy of the science behind the C4 finding doesnt mean that HaluGen testing me for copies of C4 is legitimate, said Hyman. C4 was an important discovery in the biology of schizophrenia, but Hyman said its taken out of context in this individual test result. The reason why researchers study these genes is to try to understand the underlying biology that gives rise to complex psychiatric illnesses, not for individual use.

All mental illnesses are polygenic, meaning there isnt one gene that can be implicated in its cause. Yet even polygenic predictions are not diagnostic. That doesnt mean theyre useless. They are a piece of a larger puzzle of mental illnessthe piece thats trying to understand mechanisms, while other pieces focus on treatment or knowledge that is more clinically useful.

From my results, Hyman said that my risk of schizophrenia has gone from a population base rate of 1% to 1.53%. And, he added, my risk of lupus may have slightly gone down. This reveals how its overly simplistic to pin complex illness on one or even a small handful of genes. Genes do many things, and they work in combination to produce phenotypesthe observable characteristics of a person in existence with their environment.

The results mean, basically, absolutely nothing, Hyman said.

Entheon responded: "While our test kits are not diagnostic in nature, results do not 'mean nothing.' They provide users with information, which within the proper context of set and setting, can be one point for discussion with a qualified medical professional about mental health."

Of the entire genetic test, Nichols said he thought the only partconceptuallythat had some promise was the ketamine metabolism section. There is a growing attempt to assess how people metabolize certain categories or types of drugs called personal pharmacogenomics.

My gene that encodes for the liver enzyme CYP2B6 has a variant that the test said means I metabolize ketamine very slowly. Slow metabolizers should be more cautious when being dosed with ketamine, as they will likely experience an increased duration and intensity of effect, the results said. It also said that I would metabolize intravenous or subcutaneous ketamine very slowly, compared to oral ketamine which was normal.

The gene HaluGen looked at was for a liver enzyme, and there are 40 or 50 different enzymes that are primarily responsible for metabolizing drugs, and different forms of the enzymes can be slow or fast metabolizers. Ketamine is known to be metabolized by a couple of major liver enzymes, and if you know which forms of enzymes you have, it could one day predict how fast or slow you metabolize, and perhaps one day inform dosage. But still, the HaluGen results fall short, Nichols said.

There are many different drugs, foods, or natural products metabolized by the enzyme they looked for, which is one of the more common ones. And theres more than one metabolic pathway to eliminate ketamine or to change it from an active compound to a metabolite thats not active anymore. This particular gene, could play just a minor effect to a major effect, depending upon what fraction of ketamine would normally be metabolized by this particular pathway, Nichols said.

In response, Entheon emphasized that, "There are a number of peer-reviewed studies that we cite that show a clear association with slow ketamine metabolism with the CYP2B6*6 genotype."

Another part of the test results was an ethnic comparison breakdown. For ketamine metabolism, for instance, it showed me how I compared to Caucasians, East Asians, and Africans. Some of the genes included different ethnic comparisons, like Indian.

These breakdowns are a reflection of what we know about the frequency of certain genetic variation in people of certain ancestries, and are often based on research that looked at specific parts of the world. "That's really the basis of tests like 23andMe," Nichols said. But since this test wasn't targeted at revealing my ancestry, it's hard to see how this summary is useful. The test kit did not ask for my background (I am biracial), so Nichols said that ancestral overviews wouldn't be predictive in most cases, and certainly not mine. Entheon wrote that "The ethnic breakdowns are for informational purposes only and are not designed to make a specific prediction."

How can we tell what a persons psychedelic experience be like? Will it be good or bad, healing or unsettling? Theres been quite the spectrum of reactions to psychedelics, everything from angelic to hell, Aday said. "And so a natural question is how can you predict if you're going to have the hellish experience or the angelic experience.

It's still a pressing question, especially when considering psychedelics in a therapeutic context. In a review from this year co-written by Aday and his colleagues, they summarized predictors for individual psychedelic experiences and concluded that were only starting to be able to name and verify what can actually forecast what kind of experience a person will have.

Notably, these predictors are dynamic, not fixed, as evidenced by the fact that the same person might have a bad trip at one point in their life and a good trip at another. (Also, calling a trip bad is subjective in and of itself; the word researchers and clinicians use today is challenging. While some psychedelic experiences can be challenging, and they certainly will be in the treatment of mental illness, if users are able to integrate the experience, they can often still find ways to make it meaningful.)

Aday and his colleagues went through all the literature published on predicting psychedelic trips in the last 20 years and found that, broadly, the most reliable predictors could be grouped into two categories: traits and states.

States are how someone is feeling in the moment before theyre about to take the drug. Traits are more stable variables, like personality. People who are more open to experiences, for example, or more willing to think in different ways before they took psychedelics have been shown to be more likely to have positive experiences. Those low in openness or with rigid thinking styles are more likely to have challenging experiences.

Traits are hard to alter, so thinking about how to modify peoples states and moods can be an approach to encouraging good experiences and outcomes, Aday said. Making sure people arent confused, that theyre focused on their intentions, and have a safe environment to take the drug in.

You can't control personality traits necessarily, but you can control the setting of the drug that is administered and the preparation that's done beforehand, Aday said. People who take psychedelics in research trials also have thorough interviews where theyre asked questions about their physical and mental health history.

This is all somewhat intuitive. But a trait like "openness" is mushier than a definitive-seeming genetic resultwhich is why a test like HaluGen's will have market appeal. (Entheon wrote to Motherboard that, "The presence of genetic risk factors is not a guarantee of developing a mental illness and is just one of many factors that can impact someones mental health, which HaluGen clearly states.The test kit is meant to provide users with additional information to help them make informed decisions about potential treatment, but only within the context of the very important set, setting, and subjective psychological predictors and other conversations that should be taking place with a medical professional or genetic counsellor.")

But since tests like these rely on genetic jargon, its results could unduly influence people, according to Woo-kyoung Ahn, a psychology professor at Yale University. Part of Ahns research is exploring how peoples expectations of their symptoms are influenced when they learn about genetic predispositions.

In an experiment, Ahn and her colleagues gave people a fake saliva test, which they were told could detect genetic susceptibility to depression. People who were told that they tested positive on the test felt there wasnt as much that could be done about their depression. That is, genetic attributions make them feel that they have less control, Ahn said.

Using the same saliva test framework, they measured peoples memory of their depression over the previous two weeks. People who were told they had elevated genetic risks for depression reported being more depressed.

Even those put into study groups that are told they arent genetically susceptible to a condition can experience negative consequences. People told that they werent genetically susceptible to obesity felt more invincible; they discounted the significance of a healthy diet and regular exercise, and when presented with a menu for a hypothetical lunch, they were also more likely to select unhealthy food, Ahn said. We call this the genetic invincibility effect.

While Entheon told Motherboard "We are fully transparent with the 55 peer-reviewed studies that we cite," and that "anyone that buys our psychedelics genetic test also has full access to these scientific references with our whitepaper and can review for themselves," that leaves it up to members of the public to interpret complicated genetic studies and apply them to their results.

When it comes to psychedelics, a sense of "invincibility" could have serious ramifications. Take the ketamine metabolism result: Nichols said that telling someone theyre a slow or fast metabolizer, and prompting them to modify their dose, might backfire if theyre metabolizing it through other routes. This is a potentially dangerous product, not only misinformative, Nichols said.

Many groups in the psychedelic field are working on optimizing the amount of a particular drug to give an individual, but it's not always intuitive. A recent study from Johns Hopkins University found that there was no significant difference in experience between groups that got psilocybin doses adjusted to their weight, for instancedespite this being common practice.

There are people putting millions of dollars into trying to develop these kinds of tests and assays, Nichols said. I think this kind of product is really taking advantage, and almost predatory, of people who want this kind of information but don't understand how complex the question is that they're trying to answer.

Telling a person that they have reduced, normal, or heightened sensitivity doesnt guarantee theyll avoid a challenging experience. Some people might become overly confident or think they can take the drug in a more dangerous location or more uncertain setting, Aday said. They might make riskier decisions because they've been told Im going to be fine beforehand.

In the future, there might be a more biological approach to customizing doses or predicting with more certainty the kinds of experiences people will have. "But even right now, I think thats kind of a big leap to make," Aday said. "I wouldnt spend my own money on this."

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At-Home Genetic Testing Cant Tell You If Youre Going to Have a Bad Trip - VICE

Daniel F. Kelly, M.D. 82 is director of Pacific Neuroscience Institute (PNI) at Providence Saint Johns Health Center and professor of neurosurgery at Saint Johns Cancer Institute in Santa Monica, California. He is internationally recognized for advancing techniques of minimally invasive keyhole and endoscopic brain tumor surgery. He has also overseen development of innovative programs at PNI including the launch of Pacific Brain Health Center in 2018 focused on cognitive, memory and mood disorders, and has been the creative force behind PNIs Treatment & Research in Psychedelics (TRIP) program.

Kelly is a 1982 graduate of Claremont McKenna College where he studied biology and chemistry. He attended Georgetown University School of Medicine and completed a neurosurgical residency training in 1993 at George Washington University Medical Center. He was professor of neurosurgery and vice-chief of clinical affairs for the UCLA Division of Neurosurgery until 2007 when he joined JWCI and Providence Saint Johns Health Center, where he currently serves on the Saint Johns Board of Directors and is chief of neurosurgery.

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Past, Present & Future of Psychedelic-Assisted Therapy: A New Dawn for Mental Health and Neuroscience - cmc.edu

Geoffrey Attardo first tried Prozac to treat his depression when he was doing postdoctoral research at Yale School of Public Health and was feeling the pressures of a new job in academia. Soon after he started, the colors around him seemed brighter, he had enough motivation to begin exercising more, and he felt hopeful for the first time in a long while. But about five months into the treatment, colors started dulling again and his energy waned. Increasing the dose didnt help.

He eventually switched to a similar antidepressant called Zoloft and has been on it for about 20 years, though it makes him emotionally numb and never completely got rid of the depression. It takes the edge off and keeps you from completely breaking down, he said, but its not really a great way to live.

Then this year, Attardo, who is 49, tried a new treatment for depression ketamine a drug long used as an anesthetic and that works through a different pathway in the brain than the traditional drugs hed taken. A few days after one of his first ketamine infusions, he found himself awake at 9 a.m., a time he usually slept long past, with much more energy than usual.

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Patient responses like Attardos, after years of unsuccessful treatment with standard drugs, are spurring a gradual and, some would say, overdue shift in psychiatry toward a new way of thinking about depression, its causes, and therapies. The professions long embrace of the monoamine hypothesis the idea that depression primarily results from abnormal levels of neurotransmitter chemicals in the brain and that drugs can restore the proper balance is giving way to a more complex understanding and alternative treatments, from ketamine to psychedelics to magnetic stimulation.

The stubbornly high, and steadily increasing, rate of suicides in the U.S.is one factor driving the shift. In April, the National Institute of Mental Health (NIMH) awarded eight grants to test new ways to reduce suicidal thoughts and behaviors in a fast-acting manner, including ketamine and using magnets to activate parts of the brain.

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Overall, an unofficial estimate shows the agencys funding for research involving novel antidepressants roughly doubled from $34.3 million in the 2007 fiscal year to $68.5 million in FY 2020, based on a search of the National Institutes of Health RePORTER database. A search for transcranial magnetic stimulation for depression reveals an estimated ninefold increase to $21.4 million over the same period.

Nolan Williams, a psychiatrist and neurologist at Stanford University, received one of the new grants as well as another from the NIMH to study magnetic stimulation in treatment-resistant depression. He said there is a push in the field to to think beyond the typical view of depression, and consider new treatments. Were enhancing [the monoamine] view to have a multilevel understanding of the problem, he said. Its about incorporating it into a deeper, more dynamic understanding [of depression].

NIMH Director Joshua Gordon told STAT the agency recognizes that new treatments for depression are needed and that it is funding research to explore the underlying biology beyond the monoamine hypothesis. When it comes to understanding depression, there are fewer and fewer questions of importance with regard to the monoamine systems, he said. He noted that in addition to federal funding, many startups and small companies are pursuing new treatments for depression.

Currently, almost all patients with depression are first treated with medications called selective serotonin reuptake inhibitors, a class of drugs that includes both Zoloft and Prozac. They increase the amount of the neurotransmitter serotonin in the brain, which controls mood, emotions, and cognition. Serotonin and two other neurotransmitters targeted by some antidepressants, norepinephrine and dopamine, are called monoamines because they contain one chemical group called an amine.

The entire thinking of the approach to treating depression is pretty much confined in that little box, said Lisa Harding, a psychiatrist at the Yale School of Medicine.

The monoamine hypothesis came about by serendipity. In the 1960s, doctors found that certain drugs, like iproniazid that was used to treat tuberculosis, had an unintended side effect: They messed with the levels of monoamine neurotransmitters and affected patients mood. The explanation for mental health disorders had previously eluded psychiatrists, so they were overjoyed to have a lead to follow.

The theories arose because of the actions of the drugs, said Phil Cowen, professor of psychopharmacology at University of Oxford who studies depression. In retrospect, its simplistic, but there wasnt really much else to go on.

Soon, clinicians realized that some observations didnt mesh with the hypothesis. Antidepressant drugs took weeks to improve the symptoms of depression, suggesting that the drugs may not be working through neurotransmitters exclusively. Then, psychiatrists found that many people, like Attardo, did not respond to monoamine antidepressants. About 1 out of every 3 patients with depression is diagnosed with treatment-resistant depression, meaning at least two antidepressants failed to improve their symptoms.

Even with these contradictions, doctors faithfully stuck by the hypothesis as the central dogma. The field got stuck in a cul-de-sac of just looking at [the same drugs], said Cowen.

Then a study done by researchers at Yale University in 2000 found that ketamine rapidly improved depression symptoms in seven patients. Although it was a small study, it opened the door for researchers to explore other potential treatments for depression.

Weve now got a completely different option for the treatment-resistant group, said Susannah Murphy, researcher at the University of Oxford who studies how to improve treatments for depression. The finding emboldened researchers to explore other drug targets and develop different therapies, she added: It put a lot more confidence back in new treatments.

Researchers are now exploring those new treatments and, in parallel, are seeking to advance the biological understanding of mental health disorders. In 2019, the FDA approved Spravato, a nasal spray of a version of ketamine called esketamine, for the treatment of adults with treatment-resistant depression. Studies have found that ketamine works through receptors for another neurotransmitter, glutamate, which is also dysregulated in depression. Glutamate and its receptors underlie a process called synaptic plasticity, in which brain connections strengthen or weaken. This supports the idea that changes in synaptic plasticity underlie depression and by targeting glutamate, ketamine could be reversing those changes.

Along with ketamine, other psychedelics, like psilocybin, have emerged as candidates for treatment-resistant depression. A small study published in the New England Journal of Medicine in April showed that psilocybin was as effective as a common antidepressant drug.

The psychedelic market is seen as so potentially lucrative that half a dozen companies in that space have gone public this year. Cybin, which has a psilocybin formulation in a Phase 2 clinical trial for major depression, started selling shares on the New York Stock Exchange last week, and five other psychedelics companies are already listed on the Nasdaq.

Psychedelics like psilocybin mostly activate receptors for serotonin, similar to the typical antidepressants. But studies show that psilocybin also can change levels of glutamate, suggesting it, too, involves synaptic plasticity.

Many clinicians and researchers say the field should move beyond a focus on neurotransmitters and look at activating entire neural circuits in the brain, networks of interconnected neurons that perform specific functions. Theres not one neurotransmitter, not one neural site where things go wrong, its some system-level dysfunction in the brain, said Cowen. A recent study analyzed patients with depression who underwent deep brain stimulation, in which electrodes are implanted to pass current through specific brain areas, or transcranial magnetic stimulation, which is a noninvasive form of stimulation. By looking at whether patients symptoms improved or worsened, researchers identified a brain circuit that includes the dorsolateral prefrontal cortex, an area that controls emotion processing and is impaired in patients with depression, that could be targeted to treat depression.

Understanding and treating depression could even go beyond the brain, as immune molecules such as cytokines that control inflammation could also be considered potential treatment targets. One analysis found that patients with depression had different levels of neuroinflammatory molecules in the blood. Other clues come from observing patients treated with medications that target inflammation for other conditions. Such studies found that patients treated with drugs that suppress immune activity, like those that target the molecule IL-6, had reduced depressive symptoms.

While the paradigms surrounding psychiatry seem to be shifting, new drugs and treatments still have a long road to approval and widespread use. The drug development pipeline has been particularly fruitless for psychiatry, which has a 6.2% likelihood of getting a drug from Phase 1 clinical trials to approval, as compared to infectious diseases treatments that have about 20% likelihood of approval.

Even if new treatments are approved, patients could encounter obstacles in accessing them, especially populations that already have poor access to mental health care due to high rates of poverty and lack of insurance, experts say. Many of the novel therapies are technically challenging to administer and require specialized facilities with trained professional staff. And many psychedelics are still classified as Schedule I drugs, as illegal as street drugs like heroin. Some, like ketamine, can be abused, and the long-term effects of chronic use of psychedelics are not clear, said Gerard Sanacora, psychiatrist and director of the Yale Depression Research Program.

A number of states have moved to relax laws governing use of psychedelics. In November 2020, Oregon became the first state to decriminalize possession and legalize therapeutic use of psilocybin, the active ingredient in magic mushrooms, and California may soon be next. In March of this year, a law decriminalizing magic mushrooms, ayahuasca, and mescaline went into effect in Washington, D.C. Recently, Rep. Alexandria Ocasio-Cortez (D-N.Y.) proposed an amendment to allow research into the therapeutic potential of Schedule I drugs like psilocybin and ecstasy.

The research and law changes are giving many patients a reason for optimism. Attardo is eager to try psilocybin, which data suggest could have a longer-lasting therapeutic effect than ketamine, whose benefits last just a few days for him. Just knowing that his depression can disappear, like when he is taking ketamine or during those first few months on Prozac, gives him hope: Im not trapped forever.

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Researchers breaking away from the central dogma of depression - STAT - STAT

Mexican soldiers destroy a marihuana plantation in Tecate.GUILLERMO ARIAS

Humans constantly alter the world. We fire fields, turn forests into farms and breed plants and animals. But humans dont just reshape our external world we engineer our internal worlds, and reshape our minds.

One way we do this is by upgrading our mental software, so to speak, with myths, religion, philosophy and psychology. The other is to change our mental hardware our brains. And we do that with chemistry.

Today, humans use thousands of psychoactive compounds to alter our experience of the world. Many derive from plants and fungi, others we manufacture. Some, like coffee and tea, increase alertness; others, like alcohol and opiates, decrease it. Psychiatric drugs affect mood, while psychedelics alter reality.

We alter brain chemistry for all kinds of reasons, using substances recreationally, socially, medicinally and ritually. Wild animals sometimes eat fermented fruit, but theres little evidence that they eat psychoactive plants. Were unusual animals in our enthusiasm for getting drunk and high. But when, where and why did it all start?

Given humanitys love of drugs and alcohol, you might assume getting high is an ancient, even prehistoric tradition. Some researchers have suggested prehistoric cave paintings were made by humans experiencing altered states of consciousness. Others, perhaps inspired more by hallucinogens than hard evidence, suggest that drugs triggered the evolution of human consciousness. Yet theres surprisingly little archaeological evidence for prehistoric drug use.

African hunter-gathers Bushmen, Pygmies and the Hadzabe people likely live their lives in ways similar to ancestral human cultures. The most compelling evidence for the use of drugs by such early humans is a potentially hallucinogenic plant !kaishe, used by Bushmen healers, which supposedly makes people go mad for a while. Yet how much Bushmen historically used drugs is debated, and otherwise, theres little evidence for drug use in hunter-gatherers.

The implication is that, despite Africas diverse plants and fungi, early humans used drugs rarely, maybe to induce trances during rituals, if at all. Perhaps their lifestyle meant they rarely felt the need for escape. Exercise, sunlight, nature, time with friends and family theyre powerful antidepressants. Drugs are also dangerous; just as you shouldnt drive drunk, its risky to get high when lions lurk in the bush or a hostile tribe waits one valley over.

Migrating out of Africa 100,000 years ago, humans explored new lands and encountered new substances. People discovered opium poppies in the Mediterranean, and cannabis and tea in Asia.

Archaeologists have found evidence of opium use in Europe by 5,700 BC. Cannabis seeds appear in archaeological digs at 8,100 BC in Asia, and the ancient Greek historian Herodotus reported Scythians getting high on weed in 450 BC. Tea was brewed in China by 100 BC.

Its possible our ancestors experimented with substances before the archaeological evidence suggests. Stones and pottery preserve well, but plants and chemicals decay quickly. For all we know, Neanderthals could have been the first to smoke pot. But archaeology suggests the discovery and intensive use of psychoactive substances mostly happened late, after the Neolithic Revolution in 10,000 BC, when we invented farming and civilization.

When hunters trekked across the Bering Land Bridge 30,000 years ago into Alaska and headed south, they found a chemical cornucopia. Here, the hunters discovered tobacco, coca and mat. But for some reason, indigenous Americans were especially fascinated with psychedelics.

American psychedelics included peyote cactus, San Pedro cactus, morning-glory, Datura, Salvia, Anadenanthera, Ayahuasca and over 20 species of psychoactive mushrooms. It was a pre-Columbian Burning Man. Indigenous Americans also invented the nasal administration of tobacco and hallucinogens. They were the first to snort drugs a practice Europeans later borrowed.

This American psychedelic culture is ancient. Peyote buttons have been carbon-dated to 4,000 BC, while Mexican mushroom statues hint at Psilocybe use in 500 BC. A 1,000-year-old stash found in Bolivia contained cocaine, Anadenanthera and ayahuasca and mustve been one hell of a trip.

A huge step in the evolution of debauchery was the invention of agriculture, because farming made booze possible. It created a surplus of sugars and starches which, mashed and left to ferment, magically transformed into potent brews.

Humans invented alcohol many times independently. The oldest booze dates to 7,000 BC, in China. Wine was fermented in the Caucasus in 6,000 BC; Sumerians brewed beer in 3,000 BC. In the Americas, Aztecs made pulque from the same agaves used today for tequila; Incas brewed chicha, a corn beer.

While in America psychedelics appear to have been particularly important, Eurasian and African civilizations seem to have preferred alcohol. Wine was central to ancient Greek and Roman cultures, was served at Platos Symposium and at the Last Supper, and remains incorporated in the Jewish Seder and Christian communion rituals.

Archaeology suggests alcohol and drugs date back millennia, to early agricultural societies. But theres little evidence early hunter-gatherers used them. That implies something about agricultural societies and the civilizations they gave rise to promoted substance use. But why?

Its possible large civilizations simply drive innovation of all kinds: in ceramics, textiles, metals and psychoactive substances. Perhaps alcohol and drugs also promoted civilization drinking can help people socialize, altered perspectives encourage creativity and caffeine makes us productive. And it may just be safer to get drunk or high in a city than the savannah.

A darker possibility is that psychoactive substance use developed in response to civilizations ills. Large societies create large problems wars, plagues, inequalities in wealth and power against which individuals are relatively powerless. Perhaps when people couldnt change their circumstances, they decided to change their minds.

Its a complex problem. Just thinking about it makes me want to grab a beer.

Nicholas R. Longrich is a senior lecturer in Evolutionary Biology and Paleontology, at the University of Bath.

This article was originally published in The Conversation.

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