04/16/24

Psychedelics as the Newest Psychiatric Craze, Part 2

On December 12, 2023 the MAPS Public Benefit Corporation announced it submitted a new drug application (NDA) to the FDA for MDMA-assisted therapy. MAPS PBC (now called Lykos Therapeutics) requested the FDA grant a priority review, given that MDMA received a Breakthrough Therapy designation in 2017. The FDA has 60 days to determine whether the NDA will be accepted for review and whether it will be a priority or standard review (six months or ten months, respectively). If approved by the FDA, the DEA will be required to reschedule MDMA making it available by prescription for medical use. The CEO of MAPS PBC said, “If approved, MDMA-assisted therapy would be the first psychedelic-assisted therapy, which we hope will drive additional investment into new research in mental health.”

Not everyone thinks FDA approval MDMA-assisted therapy is a good idea. The psychiatrist Allen Frances said the benefits in the active group were not much greater than the benefits in the placebo group. The cost of treatment would put it out of the reach of many potential patients, adding huge costs while providing only a small, benefit. Eric Turner, a former reviewer of psych drugs for the FDA, said he doubted the touted difference between MDMA and placebo groups was as big as it seems because the trials weren’t truly blinded. He didn’t think the MDMA trials met the FDA’s usual criteria for a well-controlled study.

The double-blind methodology in the Phase 3 Clinical trials was clearly ineffective and the dramatic results reported should be tempered with this in mind. The miniscule population size of participants for both trials also raised serious questions about an FDA approval. Phase 3 clinical trials are recommended to contain 300 to 3,000 participants by the FDA; the MAPS trials had 79 and 104 participants.

In Never Enough, Dr. Judith Grisel voiced her reservations with MDMA as a recreational or therapeutic drug. Grisel has a unique position as a neuroscientist and person in long-term addiction recovery. She said MDMA (ecstasy) is both a stimulant and a hallucinogen. Structurally, it fits better with the stimulants. “Amphetamine, methamphetamine and MDMA all acutely interact with monoamine transporters to block reuptake and cause release of dopamine, norepinephrine, and serotonin from nerve terminals.”

Ecstasy is not at all similar to LSD or psilocybin, though, and like that of other stimulants its ability to block reuptake of monoamines is what leads to enhanced energy, endurance, sociability, and sexual arousal, justifying its reputation as a perfect party drug.

It reaches peak concentration in the blood after two hours and has a half-life of about eight hours. Within an hour of taking MDMA, there is a huge increase in serotonin and other monoamines, followed by a reduction that develops over days as the drug is slowly metabolized. “As a result, people frequently experience aftereffects such as lethargy, depression, and memory or concentration problems” for a few days. Grisel acknowledged the acute effects make the short-term dip well worth it for some.

The drug greatly enhances a sense of wellbeing and produces extroversion and feelings of happiness and closeness to others, due in part to the fact that it impairs recognition of negative emotions, including sadness, anger, and fear. Affective neuroscience (the study of the brain’s role in moods and feelings) has demonstrated quite clearly that we can’t feel what we can’t recognize, so this pro-social bias seems perfectly engineered and helps explain why ecstasy is called the love drug and has been adopted for use by marriage counselors. In terms of unpleasant acute effects, the drug can cause overheating, teeth grinding, muscle stiffness, lack of appetite, and restless legs.

Grisel thought regular users were headed for a lifetime of depression and anxiety. Research in rats and primates suggests moderate to high doses of MDMA damages nerve terminals, perhaps permanently. “For example, primates given ecstasy twice a day for four days (eight total doses) show reductions in the number of serotonergic neurons seven years later.”

It seems MDMA causes non-repairable damage, especially to serotonergic neurons, leading to degeneration of axons and loss of connection between cells. These neurotoxic effects suggest that this drug is anything but innocuous. Though we’re not exactly sure how regular or semi-regular recreational use affects the human brain, because these studies would require autopsies (and control groups!), in my view it doesn’t look good. For instance, the extent of MDMA use in humans is positively correlated with the decrease in serotonergic function.

Grisel thought a study by Taurah, Chandler and Sanders published in Psychopharmacology should be read by everyone thinking of using the drug. The aim of their study was to see whether MDMA produced lasting effects on humans, as it did in animals. The loss of serotonin and norepinephrine function would be predicted to produce depression, impulsivity, and cognitive impairment “because serotonin transmission is so critically involved in mood, behavioral regulation, and thinking.” Their study included almost a thousand participants, about 20% who were drug naïve. The rest were equally divided among five groups of recreational drug users.

The researchers assessed a variety of measures including several associated with mood and cognition. There were two major findings. First, former and current ecstasy users were virtually identical, and second, these groups showed significantly more clinically relevant levels of depression, impulsiveness, poor sleep, and memory impairment. Again, these were recreational users, many had not had taken the drug for years, and still deficits were strikingly evident.

Grisel then related how her interactions with MDMA users matched the findings of Taurah, Chandler and Sanders. She described an encounter with a former undergraduate student, eager to gain research experience, who worked in her laboratory one summer. While he became less reliable as the weeks went on, she said he made up for it “by offering clever and insightful ideas about experimental design and interpretation, and when he was on, he was really very good.” She learned he worked as a DJ for local raves and told her that MDMA helped him “stay in the groove for the many hours of partying.”

The next summer he again applied to do research with her. While she wasn’t thrilled with the prospect, she remembered how undergraduate research experiences were significant in her own transition from a drug user to a drug researcher. “It didn’t go well. He was all over the place with his ideas, mads as many mistakes the first week as most newbies make in a semester, and couldn’t remember what we’d discussed from hour to hour, let alone day to day.” Grisel had to let him go, and when talking about the probable cause of his dramatic slip, he said it might be because he’d done “too much molly.”

I bumped into him a few years later while I was attending a scientific meeting in the same town which he worked as a bartender. More recently, I learned that a persistent state of chronic despair drove him to suicide.”

MAPS PBC changed its name to Lykos Therapeutics on January 5, 2024. This led to the FDA accepting Lykos Therapeutics’ New Drug Application (NDA) for MDMA-assisted therapy for PTSD on February 9, 2024. The FDA granted the application priority review and set a target action date of August 11, 2024 to make the review determination.

MAPS has been persistently and progressively chipping away at getting MDMA-assisted therapy approved to treat PTSD for many years. Let’s be careful to not release a so-called “treatment” that makes things worse for troubled people. For more on the concerns with FDA approval of MDMA-assisted therapy, see “Don’t Roll the Dice with MDMA.” For more information on concerns and reservations with psychedelics as the newest psychiatric craze, see Part 1 of this article.

02/6/24

Psychedelics as the Newest Psychiatric Craze, Part 1

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In October California Governor Gavin Newsom vetoed a bill that would have decriminalized the possession and personal use of several plant-based hallucinogens, including psilocybin, mescaline and dimethyltryptamine (DMT), saying more work needed to be done on treatment guidelines. The legislation would have decriminalized possession before setting up regulatory treatment guidelines, with the California Health and Human Services Agency supposed to make recommendations to lawmakers after the consequences of decriminalization. The bill would not have arrested or prosecuted individuals who possessed limited amounts of plant-based hallucinogens. Also, the bill did not legalize the sale of these psychedelics. They are still illegal under federal law.

Public opinion was said to have shifted on using psychedelics to treat trauma and other disorders such as depression, and alcohol use disorder. There has been a significant amount of interest in the potential of psychedelics for mental health that includes encouragement and discouragement of treating psychiatric conditions with them. Sandy Cohen opened her article “Do psychedelics have a role in psychiatric treatment?” for UCLA Health, with the provocative question, “What if there was a medication that could significantly reduce symptoms of treatment-resistant depression in a single dose?” A UCLA Health psychiatrist, Walter Dunn, described two studies where psilocybin was found to have a significant reduction in symptoms of treatment-resistant depression. He said these results were unprecedented: “We have nothing that works this well.”

Dunn said the coverage in mainstream media and books aimed at lay audiences (such as Michael Pollan’s book, How to Change Your Mind) have raised interest and curiosity in psychedelics. He said when he goes to dinner parties and people discover his work is with psychedelic drugs, “I’m talking about them for the rest of the evening.” According to a UC Berkeley Psychedelics Survey, 61% of registered American voters support legalizing regulated therapeutic access to psychedelics. Thirty-five percent of those supporters said they strongly support such action. But there were 35% who opposed it and 69% did not see it as something “for people like me.”

We are in a historic moment in the space for psychedelic science, research and also mental health in general. . . There hasn’t been any time in modern psychiatry where there has been so much interest, awareness and discussion around a potential mental health treatment.

Dunn acknowledged the drugs come with risks, which was one of the reasons the FDA has been cautious about the trials being run. “These are not benign medicines. Anything that can help you can harm you.” He discussed how the FDA was set to consider MDMA-assisted therapy for PTSD in 2024. It’s still unclear whether or not the FDA will want a Risk Evaluation and Mitigation Strategy (REMS), if these treatments are approved. A REMS could require psychedelic-assisted therapy to included two specially trained and certified clinicians during the psychedelic experience. If a REMS is required by the FDA for MDMA-assisted therapy, it would reduce the pool of therapists who could administer the treatment and decrease access even as it enhances safety.

Joanna Moncrieff, a British psychiatrist, noted in “Psychedelics—The New Psychiatric Craze” where they were viewed as an increasingly fashionable medical treatment. But she wondered if they had any objective health benefits and were they safe. She noted where psilocybin, LSD, MDMA and ketamine were some of the psychedelics being recommended for an ever-lengthening list of problems that include depression, anxiety, addiction, and PTSD. She acknowledged some people might learn important about themselves through the effects of psychedelic drugs.

But these benefits are not medical or health effects. They are akin to the personal development people achieve through other sorts of activities and life experiences. . . And although the concept of drug-assisted psychotherapy acknowledges that it is the way the psychoactive effects of the drugs are used to promote a process of personal learning that is relevant, why not employ other, safer and cheaper methods? Why not nature-assisted psychotherapy (a walk in the park), for example?

Yet, the use of these drugs is portrayed as if they work by targeting underlying dysfunctional brain processes. Moncrieff is concerned that when psychedelics get a medical license, psychotherapy will be dropped or minimized. “As with ketamine, the tendency of all psychedelic treatment will be towards the provision of the drug in the cheapest possible way, which means the minimum of supervision and therapy.” Presciently, Moncrieff wrote her article two years ago, before the accidental death of Matthew Perry from the acute effects of unsupervised ketamine use.

She said most psychedelic research ignores the way the immediate psychoactive effects of the drugs impact people’s feelings and behavior in a way that will influence mood symptom ratings and may produce the impression of improvement. She singled out the American Psychiatric Association’s report on ketamine treatment, which said there was compelling evidence the antidepressant effects of ketamine infusion are rapid and robust. While the APA acknowledged the antidepressant effects were transitory, they did not explain how they could be distinguished from the euphoria and other mental alterations associated with acute ketamine intoxication. “If ketamine’s effects are ‘antidepressant’ then so are the effects of all the other drugs that produce short-term euphoria including alcohol, cocaine, heroin, amphetamines, etc.”

Any powerful mind-altering drug will likely have ‘placebo’ effects. Drug-induced experience will lead people to expect they will improve or think they have improved. Psychedelic research also neglects the hours of medical supervision and professional attention associated with psychedelic treatment. Clinical contact improves people’s outcomes in depression, as was seen in esketamine trials, where a high level of professional contact seems to have exerted a powerful effect on some people.

The current craze for psychedelics also means the adverse effects are being minimised or overlooked. The ‘bad trip’ is a well-recognised phenomenon, and may not be that uncommon. Psychiatrist Rick Strassman, author of DMT: the Spirit Molecule, described how half of the 60 volunteers he injected with the powerful hallucinogen, DMT (N,N-dimethyltryptamine), experienced terrifying hallucinations and anxiety, and he discontinued his research, in part because of these effects. Science journalist John Horgan describes months of depression and flashbacks following a ‘bad trip’, and also reminds us that Albert Hofmann, who first synthesised LSD, also had doubts about it, calling his 1981 memoir LSD: My problem child.

Moncrieff ended her article by noting that while one or two doses of any drug is unlikely to do much harm, the tendency for treating mental health concerns is for long-term use. And repeated use of psychedelics is unlikely to be completely harmless. “As with so many other medical treatments, they have become popular through the potent mixture of financial interests and desperation.” There are many safer routes to promote personal development through an unusual experience. But we will be faced with a decision to legalize psychedelic-assisted treatment sooner rather than later, as MDMA-assisted therapy is expected to be submitted to the FDA for review for approval in early 2024. See Part 2 of this article for more information on the approval process for MDMA-assisted therapy.

11/14/23

Voyages on the Starship Ketamine

Image by ThankYouFantasyPictures from Pixabay

On October 10, 2023, the FDA issued a warning about the potential risks of compounded ketamine products for the treatment of psychiatric disorders such as depression, anxiety, OCD and PTSD. The concern seems to center on the at-home use of ketamine compounds from a multitude of online sources, dispensing oral formulations such as ketamine lozenges or tablets. Not only is ketamine not FDA approved for the treatment of any psychiatric disorder, it has known safety concerns such as abuse and misuse, increased blood pressure, slowed breathing and “psychiatric events.” The FDA said these compounds should only be used “under the care of a health care provider.”

Ketamine is a Schedule III controlled substance approved by the FDA as an intravenous or intramuscular injection to induce and maintain general anesthesia. It is not FDA-approved to treat any psychiatric disorder. It is a mixture of two-mirror-image molecules, R-ketamine and S-ketamine—arketamine and esketamine, respectively. The “S” form of ketamine (esketamine), known as Spravato, was approved by the FDA as a nasal spray for the treatment of major depression and adults with acute suicidal ideation or behavior in 2019. See “Red Flags with Spravato,” “Doublethink with Spravato?,” “Repeating Past Mistakes with Esketamine” and other articles on this website expressing concerns with esketamine/Spravato.

Spravato is also a Schedule III controlled substance and like ketamine, and has similar risks of adverse events. This led the FDA to require a Risk Evaluation and Mitigation Strategy (REMS) with esketamine, meaning that esketamine is required to be “dispensed and administered in medically supervised health care settings that are certified in the REMS and agree to monitor patients for a minimum of two hours following administration because of possible sedation and disassociation and the potential for misuse and abuse.” But ketamine and ketamine compounds can be legally prescribed off label to treat psychiatric disorders and do not have to have a FDA required REMS.

However, on February 16, 2022 the FDA published an alert describing the risks associated with the use of compounded ketamine nasal spray products. The FDA Adverse Event Reporting system (FAERS) and the medical literature identified five cases (reported between 2016 and 2021) of compounded ketamine nasal spray that resulted in psychiatric events “such as delusion, dissociation, visual hallucination, and panic attack as well as abuse and misuse.”

The reported concentrations of compounded ketamine nasal spray ranged from 125 – 200 mg/ml. Frequency of use varied from three sprays three times a day to six sprays eight times a day. The amount of medication administered to the patients with each spray is unknown. In most case reports, the patients self-administered the product at home, and it is unknown whether they were observed or monitored by a healthcare professional.

Because compounded ketamine nasal spray products are not FDA-approved, there is no FDA-approved dosing regimen for these products. There are also no data to support dosing conversion between Spravato (esketamine) nasal spray and compounded ketamine nasal spray.

The New York Times said the October 2023 alert sought to differentiate between the supervised use of ketamine as a therapy administered at clinics, and the “wellness centers” or online marketers that prescribe the drug via telemedicine so that buyers can take the drug at home. The alert included a caution that individuals receiving ketamine products from compounders and telemedicine platforms may not receive information about the potential risks associated with the product. “At-home administration of compounded ketamine presents additional risks because a health care provider is not available onsite to monitor for serious adverse outcomes resulting from sedation and dissociation.”

The pandemic-related boom in telehealth has given rise to a legion of online prescribers that dispense inexpensive ketamine lozenges, tablets or nasal sprays following a brief video interview. Some companies provide as many as 30 doses after one session, which experts say can lead to misuse.

Company executives in the compounding industry say they’d welcome government oversight. But they are concerned that a lack of flexibility in the FDA’s guidance could result in overly aggressive enforcement by state regulators. The manager of a compounding pharmacy in San Francisco said he is concerned these online sellers will ruin it for everyone. “Our fear is that regulators, if they perceive a threat to public health, will move to take this amazing medicine away and leave patients at risk.”

Psychiatric Times also expressed concerns with at-home ketamine therapy. They described a report by the All Points North Treatment Center in Edwards Colorado of 2,000 adults where 64% said they thought ketamine helped with their mental health symptoms. But 55% who tried at-home ketamine therapy also admitted accidentally or purposely using more than the recommended dose. The Editor in Chief of Psychiatric Times said, “Esketamine has to be administered in person by a trained health care provider. The use of at-home ketamine bypasses this safety net and puts individuals at risk, undermining the FDA’s REMS protocol to minimize risk and maximize safety and prevent diversion and abuse/misuse.”

There were reservations in 2019 with the approval process for esketamine, Spravato (see “Hype and Concern with Esketamine” and “Evaluating the Risks with Esketamine”). A NPR interview BEFORE the FDA approved esketamine predicted the problem the FDA is now attempting to address in its alert for “compounded ketamine products.” A doctor who prescribed ketamine to his patients said doctors would continue to offer a generic version of ketamine for depression because it would be cheaper than the cost of Spravato with its REMS. The generic form of ketamine was cheap, and could be taken at home with the assistance of a nasal spray, he said. “Any psychiatrist or physician can prescribe [it] without the restrictions that are going to be applied to esketamine.”

A Cunning Methodology

In a new study, Stanford researchers devised a cunning workaround to disguise the dissociative properties of ketamine. A major difficulty with doing clinical trials on psychedelic drugs like ketamine is the difficulty of providing a satisfactorily double blinded methodology. Participants can usually tell whether or not they were given ketamine or a placebo. The researchers “recruited 40 participants with moderate to severe depression who were scheduled for routine surgery, then administered a dose of ketamine or placebo when the participants were in surgery and under general anesthesia.”

They were surprised to find that both groups experienced the large improvement in depressive symptoms usually seen with ketamine. The senior author of the study he was surprised to see the result. He quoted some participants as saying their life was changed; they never felt like that before. “But they were in the placebo group.” Both the ketamine and placebo groups saw their depression rating scores drop by half and stayed roughly the same throughout the two-week follow-up of the study.

The researchers thought it was unlikely the surgeries and general anesthesia accounted for the improvement. They theorized the positive expectations of the participants played a key role in the effectiveness reported by them. “Those who had improved more in their depression scores were more likely to think they received ketamine, even when they didn’t, implying some preexisting positive expectations for ketamine.” The senior author said this was nothing new.

Placebo is probably the single most effective, consistent intervention in medicine, full stop. It’s seen in every trial, and we should probably be paying more attention to the factors that give rise to it.

However, he said the takeaway shouldn’t be that ketamine “is just a placebo.” He thought that was a disservice to placebos. He hypothesized there may be a physiological resonance between the placebo effect and how ketamine works. “There is most definitely a physiological mechanism, something that happens between your ears, when you instill hope.” He added that the results also suggest the psychedelic experience may not be crucial to the drug’s benefits, although it likely encourages more positive expectations.

Maybe with a non-hallucinogenic psychedelic analog you can get the same benefits without having to, you know, go to outer space.

01/17/23

The Eye of the Beholder with Psychedelic Therapy

Classical psychedelic drugs such as psilocybin, LSD, and mescaline were used and researched regularly in psychiatry before they were placed in Schedule I of the UN Convention in 1967 and in Schedule I of the US Controlled Substances Act in 1970. These actions legally defined these psychedelics as having no accepted medical use and a high potential for abuse. Without a clinical focus and the widespread use of LSD within the 1960s counterculture movement, research rapidly dwindled. But there has been a resurgence of clinical research interest in the use of psychedelics for psychiatric disorders such as major depression, PTSD, anxiety and addiction.

In “Psychiatry & the psychedelic drugs,” Rucker, Iliff and Nutt described clinical trials using psychedelics pre and post prohibition. They also discussed the methodological challenges of preforming good quality clinical trials, and suggested an approach to the existing legal and regulatory barriers to licensing psychedelics as a treatment in mainstream psychiatry.

Experimentation and clinical trials undertaken prior to legal sanction suggest that they are not helpful for those with established psychotic disorders and should be avoided in those liable to develop them. However, those with so-called ‘psychoneurotic’ disorders sometimes benefited considerably from their tendency to ‘loosen’ otherwise fixed, maladaptive patterns of cognition and behaviour, particularly when given in a supportive, therapeutic setting. Pre-prohibition studies in this area were sub-optimal, although a recent systematic review in unipolar mood disorder and a meta-analysis in alcoholism have both suggested efficacy. The incidence of serious adverse events appears to be low.

The term ‘psychedelic’ was coined by Humphry Osmond in a letter he wrote to Aldous Huxley in 1956. Osmond combined two ancient Greek words, psyché, meaning soul or mind; and delein, meaning to reveal. So psychedelic means ‘soul revealing.’ The earliest direct evidence for the use of psychotropic plants dates to around 3700 BC in the northeastern region of Mexico. Carbon-dated buttons of peyote and red beans containing mescaline were found in caves used by humans for habitation. Arthur Heffter isolated mescaline from the peyote cactus in 1897.

Albert Hofmann first synthesized LSD in 1938. Coming at a time before there were effective medicinal therapies, the discovery of LSD was of interest to psychiatry. Acute LSD intoxication appeared to mimic some of the symptoms of acute psychosis and drew the research interest of Humphry Osmond. There also seemed to be an increased awareness of repressed memories and other elements of the subconscious, which suggested it could be helpful in psychotherapy. Trials in depressive, anxious, obsessive and addictive disorders in conjunction with psychologically supportive contexts reinforced that view. “By the end of the 1960s, hundreds of papers described the use of mescaline, psilocybin and (most frequently) LSD in a wide variety of clinical populations with non-psychotic mental health problems.”

The widespread use of LSD outside of the carefully orchestrated clinical and research settings and the growing reports of adverse effects when under the influence of LSD and other psychedelics led to prohibition. Medical use stopped quickly when doctors could no longer prescribe it. The following graph taken from “Psychiatry & the psychedelic drugs” depicts how the annual number of publications listed in PubMed rapidly decreased after 1968.

Recently, there have been several studies and randomized controlled trials using psychedelics with various nonpsychotic disorders. In “LSD: can psychedelics treat mental illness?,” written by Anya Borrissova for the Mental Elf blog, Borissova reviewed the findings of Fuentes et al, “Therapeutic Use of LSD in Psychiatry.” This was a systematic review of randomized-controlled clinical trials with LSD. The authors identified 11 studies that met their inclusion criteria: randomized controlled trials of LSD that involved patients with a mental illness diagnosis. The qualities of the studies was scored with the Cochrane Collaboration Risk of Bias Assessment tool.

Seven of the 11 trials had recruited individuals diagnosed with what is now referred to as alcohol use disorder (AUD), 1 for AUD or neurotic diagnosis, 1 for heroin use disorder, 1 for anxiety associated with life-threatening diseases, and 1 with a neurotic diagnosis (depression, anxiety). The publication dates ranged from 1966 to 2014, which covered several changes in how mental disorders were labeled by the four different editions of the DSM, the 2^nd through the 5^th. The majority of the studies had a low risk of selection, attrition detection and reporting bias, as measured by the Cochrane Collaboration Risk of Bias Assessment tool. However, five of the studies had a high risk of bias due to blinding.

With the studies of alcohol use disorder, a significant effect of LSD was observed in four studies. “However, this effect was related to quality of life and general health in some of the studies, with no clear improvements in alcohol abstinence.” While there was a substantial improvement in total abstinence for the LSD group, there were not significant differences in the global adjustment scale. With regard to the two studies of neurotic symptoms, one study showed statistically significant improvement in symptoms at 6-8 weeks in most measurements. But it failed to reach statistical significance in six months, although all groups showed significant differences in a large number of variables. Fuentes et al concluded that LSD was a potential therapeutic agent in psychiatry; with the strongest evidence for its use in treating alcoholism.

Borissova said the heterogeneity of the studies did not allow for a meta-analysis, which made it difficult to draw firm conclusions. The earlier studies had different methodologies than what is used now, which limits the application of the results to modern research. The use of the gold standard of the double-blind methodology with psychedelics is extremely difficult, if not impossible to achieve, and five studies had a high risk of bias for blinding. The psychiatric diagnostic categories were also different in studies done over such a wide range of time. How the studies defined their ‘control group’ varied, with those that failed to use an active placebo having questionable validity.

When discussing the implications of Fuentes et al, she said LSD generally appears to be safe and potentially effective. The lack of consistency between the studies may have limited their ability to find an LSD effect. “On the basis of this review, we cannot conclude that there is strong evidence of positive effects.” She did think change in scheduling the drugs to allow for easier research into LSD was justified. Tellingly, she ended with this caution: “Psychedelic research inspires a lot of excitement; the danger is that this turns into hype.”

There has been a growing interest in psychedelics as an agent for reaching peak experiences, for self-care or wellness, and as an instrument of therapeutic change. Michael Pollan explored this psychedelic ‘renaissance’ in his 2018 best-selling book, How to Change Your Mind. In a New York Times article, he said now when you leave the airport in Quito, Ecuador, there are people with signs that say: ‘ayahuasca ceremony’ instead of ‘taxi.’ “These people became shamans, like last week. People are getting hurt.” He had positive things to say about his experiences with psilocybin, but cautioned against legalization: “Psilocybin has a lot of potential as medicine, but we don’t know enough about it yet to legalize it.”

The promise of pre-prohibition LSD and psychedelic studies and their potential as therapeutic agents has to be replicated within a modern, controlled context. A 2016 paper by Rucker with different researchers than those cited above, “Psychedelics In the Treatment of Unipolar Mood Disorders,” elaborated on some of the difficulties inherent in designing trials with psychedelics. Blinding is largely impossible. Therapeutic doses of psychedelics produce subjective and objective changes in thinking, feeling and behavior that are usually obvious to both the participant in the study and the observer. Because of this, placebo control is problematic because the absence of the psychedelic effect is obvious. The ‘set’ (psychological state) and ‘setting’ (the interpersonal and physical environment) within which the drug is experienced are inextricably linked to the therapeutic effect.

It appears that a particularly careful and well-considered balance between the needs of the participants and the needs of the trial will be required in studies using psychedelics. . . Trial designers will need, similarly, to be detailed and explicit about the environmental and psychotherapeutic milieu in which a study is to be performed. Clinical trials using psychedelics will need to be sufficiently methodologically detailed at the point of publication to allow genuine replication. Scientific mechanism studies will need, ideally, to be pursued alongside clinical trials if this is pragmatic and ethical. Within this multi-pronged approach to evidence gathering, and a sufficient degree of definition, replicable results and common threads of insight into the nature and applicability of psychedelics to medicine in general, and to psychiatry in particular, should emerge with time.

In “Psychedelics In the Treatment of Unipolar Mood Disorders,” Rucker et al referred to and quoted Rick Strassman’s 1984 literature review, “Adverse reactions to psychedelic drugs.” Strassman noted that the description and reporting of adverse reactions to psychedelics was subject to the investigators’ attitudes towards psychedelics.

With the available data, it appears that the incidence of adverse reactions to psychedelic drugs is low when individuals, both normal volunteers and patients, are carefully screened and prepared, supervised and followed up, and given judicious doses of pharmaceutical quality drug. The few prospective studies noting adverse reactions have fairly consistently described characteristics predicting poor response to these drugs. The majority of studies of adverse reactions, retrospective in nature, have described a constellation of premorbid characteristics in individuals seeking treatment for these reactions where drugs of unknown purity were taken in unsupervised settings.

The authors repeated an assessment of the perceived psychotherapeutic mechanism identified by Betty Eisner and Sidney Cohen in their 1958 article, “Psychotherapy with Lysergic Acid Diethylamide.” Eisner and Cohen said their review of the existing literature in 1958 suggested that 1) LSD lessened defensiveness; 2) there was a heightened capacity to relive early experiences with accompanying release of feelings; 3) therapist-patient relationships were enhanced; 4) there was an increased appearance of unconscious material. Eisner and Cohen went on to describe their exploration of the therapeutic possibilities of LSD with 22 patients with diagnoses ranging from neurotic depression, anxiety, character disorder, borderline personality and schizophrenia. Improvement was noted in 16 of 22 cases, where improvement was judged as continued success in behavioral adaptation.

Rucker et al concluded that psychedelic therapy may represent a kind of “catalyzed psychotherapy,” where the psychedelic drug hastens the breakdown of entrenched, maladaptive ways of thinking and behavior in supportive environments. While the evidence from pre-prohibition literature is unsystematic and methodologically inadequate, it suggests further research is worth doing. But there are limitations to the future research of psychedelic psychotherapy that researchers need to be aware.

As discussed above, it is essentially impossible to develop a double-blind methodology with psychedelics because of the unique characteristics of the drugs. This opens investigations into psychedelic therapy to the potential bias of the researchers—one that cannot be eliminated. Strassman raised this warning in Rucker et al, where he was quoted as saying it is important to use caution when discussing the idea of adverse reactions to psychedelic drugs. Whether the researcher views the drug-induced state as a pathological one, or as trying to reach a “higher” level of consciousness, “The description and/or reporting of adverse reactions to psychedelics is, therefore, subject to some degree of investigators’ perspective on the use of these drugs.”

Given the potential bias of researchers into psychedelic therapy and the current inability of medical research to neutralize it, caution when interpreting the conclusions of any research is necessary. As Anya Borissova said, although psychedelic research inspires a lot of excitement; “the danger is that this turns into hype.” This danger cuts both ways, whether a particular researcher sees the drug-induced state as a pathological one, or as an attempt to reach a “higher” level of consciousness. At the very least, it seems researchers should declare any personal bias with regard to psychedelics within any written or published research into psychedelic therapy.

As an illustration, does knowing that Betty Eisner and Sidney Cohen both personally used LSD at least once (and probably more than just once) alter your assessment of their endorsement of psychedelic therapy? It was 1958 and their failure to do so is not an ethical misstep, but that awareness added to the inability to adequately blind their research should lead to some reservations with their conclusions endorsing psychedelics. Michael Pollan acknowledged the concern of potential bias in psychedelic research:

Western science and modern drug testing depend on the ability to isolate a single variable, but it isn’t clear the effects of a psychedelic drug can ever be isolated, whether from the context in which it is administered, the presence of the therapists involved, or the volunteer’s expectations. Any of these factors can muddy the waters of causality. And how is Western medicine to evaluate a psychiatric drug that appears to work not by means of any strictly pharmacological effect but by administering a certain kind of experience in the minds of the people who take it?

It seems impossible for psychedelic psychotherapy to be separated from its set or setting; and for research into its effectiveness to be reliably evaluated by a double blinded research methodology. The effectiveness (or not) of psychedelic therapy will necessarily be in the eye of the researcher and beholder.

For more on Betty Eisner, Sidney Cohen and early LSD research look, see: “Bill W. and His LSD Experiences.”

Originally posted on October 13, 2020.

10/18/22

Back to the Future with Psychedelics

© Zhuxi1984 | Dreamstime.com – Back To The Future Photo

“I am 100 percent in favor of the intelligent use of drugs, and 1,000 percent against the thoughtless use of them, whether caffeine or LSD.” (Timothy Leary, in Chaos and Cyber Culture)

We’re going “back to the future” with recent research into the therapeutic benefits of hallucinogens for treating alcoholism and mood disorders. (See additional stories here and here; and a previous blog, “As Harmless as Aspirin?”) Classical hallucinogens such as LSD, mescaline or psilocybin, and dissociative anesthetics such as ketamine and PCP might be “useful” in the treatment of major depression, anxiety disorders and OCD. A recent study concluded: “There was evidence for a beneficial effect of LSD on alcohol misuse.” A single dose of LSD was found to be associated with a decrease in alcohol misuse. Another longitudinal study suggested that: “hallucinogens may promote alcohol and drug abstinence and prosocial behavior in a population with high rates of recidivism [with individuals on probation or parole].”

An issue of Current Drug Abuse Reviews (volume 6, number 1, 2013) was devoted to the investigation of psychedelics and their potential as therapeutic agents in the treatment of addiction. Several different articles suggested the therapeutic benefits of a variety of psychoactive substances—some classics and some newer ones.

Rick Doblin, in “Psychedelic-Assisted Psychotherapy for the Treatment of Addiction,” said: “There are multiple frameworks for understanding how psychedelic therapy can alleviate substance abuse.” He noted that the idea that psychedelics can be helpful in combating drug abuse conflicts with “the notion that psychedelic drug use is inherently wrong.”

Michael Bogenschutz of the University of New Mexico Health Sciences Center suggested that sacramental use of classic hallucinogens, like the Native American Church’s use of peyote, “is strongly associated with decreased alcohol and drug use.”

Lisa Jerome and others lobbied for studies that tested MDMA-assisted psychotherapy in people with an active substance use disorder. “It appears that MDMA, like classic psychedelics, may have a place in addressing substance abuse or dependence, which could be linked to its pharmacology or its psychological effects.”

Ayahuasca, a psychotropic brew prepared from an Amazonian vine and bush, may be associated with reduced substance use and “improvements in several cognitive and behavioral states.”

Thomas Kingsley Brown reported that ibogaine, a psychoactive alkaloid found in a rainforest shrub of West Central Africa, helps with withdrawal symptoms and reduces drug cravings.

A study of ayahuasca-assisted treatment for substance use problems by Gerald Thomas and others suggested that it was associated with significant improvements in several factors related to problematic substance use. While this particular study occurred in Canada, ayahuasca has been used as a remedy to help overcome drug addictions in Peru and Brazil. “Although these programs claim improved health outcomes for patients who complete them, neither has been evaluated with sufficient scientific rigor to provide definitive evidence of the success of their approaches.”

Ibogaine is not used in the US to treat addiction because of its severe side effects, which include hallucinations, bradycardia (slow heart rate), whole-body tremors and ataxia (lack of muscle control during voluntary movements). It also had cerebellar toxicity with high doses in rats. Nevertheless, it is a growing form of treatment outside the US. A subculture of ibogaine clinics has sprung up in Mexico. Read about a trip to one here.

A synthetic derivative of ibogaine, 18-MC, has been developed and is said to show promise. It resulted in “a long-lasting decrease in ethanol, morphine, cocaine, methamphetamine and nicotine self-administration [in rats], and attenuation [decrease] of opioid withdrawal symptoms.” Significantly, it is not expected to have hallucinogenic effects and does not have the negative side effects noted above with ibogaine.

In 2012 Savant HWP, a privately-owned pharmaceutical company in California, received a three-year grant from the National Institute on Drug Abuse (NIDA) for the pre-clinical development of 18-MC. Stanley Glick, the scientific founder of Savant and a long time researcher with ibogaine, said: “18-MC is likely to be the first of a new generation of agents effective against a broad spectrum of addictions—from hard drugs such as heroin and cocaine, to alcohol, nicotine and even sugary, high-fat foods, possibly reducing obesity rates.” On September 23rd of 2014 Savant announced they had begun human safety clinical trials on 18-MC. “Savant HWP plans to develop 18-MC as a treatment for many forms of addiction and compulsive behavior, with an initial focus on cocaine and opiate dependencies.”

The so-called “psychedelic treatment” approach, based on the original work of Humpry Osmond, uses pre and post therapeutic sessions and one large dose of your hallucinogen-of-choice (LSD, ayahuasca, psilocybin, mescaline). The spiritual, therapeutic goal is captured here by Aldous Huxley’s description of his experience with mescaline in The Doors of Perception:

The man who comes back through the Door in the Wall will never be quite the same as the man who went out. He will be wiser but less cocksure, happier but less self-satisfied, humbler in acknowledging his ignorance yet better equipped to understand the relationship of words to things, of systematic reasoning to the unfathomable Mystery which it tries, forever vainly, to comprehend.

But we should also remember the warnings of Albert Hofmann, the inventor of LSD, who cautioned not to underestimate the potential negative consequences of a deliberate provocation of mystical experiences with hallucinogens like LSD. “Wrong and inappropriate use has caused LSD to become my problem child.” In the “LSD state” the boundaries between the self and the outer world effectively disappear. “A portion of the self overflows into the outer world. . . . This can be perceived as a bless[ing], or as a demonic transformation imbued with terror.”

Originally posted on December 22, 2014.

04/12/22

The Psychedelic Pendulum and Psychiatry, Part 2

On October 12, 1955 psychiatrist Sidney Cohen took LSD for the first time. Expecting to feel catatonic or paranoid because LSD was then thought to produce a temporary psychosis, he instead felt an elevated peacefulness, as if the problems and worries of everyday life had vanished. “I seemed to have finally arrived at the contemplation of eternal truth.” He immediately began his own LSD experiments, even exploring whether it could be helpful in facilitating psychotherapy, curing alcoholism and enhancing creativity. But on July of 1962 in The Journal of The American Medical Association, he warned of the dangers of suicide, prolonged psychotic reactions, and said: “Misuse of the drug alone or in combination with other agents has been encountered.”

The history of psychedelics seems have followed this pendulum swing from hope and promise, to disappointment and warnings, and then back again to hope and promise. In Part 1 of this article, we looked at the current promise of psychedelic therapy and treatment and mentioned its use to supposedly enhance creativity. Here we’ll take a closer look at the present-day concerns and reservations with the proposed use of psychedelics as therapeutic tools. Tellingly, they haven’t change much since Cohen co-authored “Complications Associated with Lysergic Acid Diethylamide (LSD-25).”

In “Psychedelics—The New Psychiatric Craze,” Joanna Moncrieff acknowledged the “increasingly fashionable” interest in psychedelics as a medical treatment, but wondered if they weren’t just “a powerful form of snake oil.” She noted the ever-lengthening list of problems they were recommended to treat, which included PTSD, depression, anxiety, addiction, chronic pain and distress associated with having a terminal illness. The rationale behind the trend was said to be confusing and contradictory.

On the one hand, psychedelics are promoted as assisting the process of psychotherapy through the insights that the ‘trip’ or drug-induced experience can generate – on the other they are claimed to represent a targeted medical treatment for various disorders, through correcting underlying brain deficiencies.

Increasingly, the use of these drugs is portrayed as if they work by targeting underlying dysfunctional brain processes (i.e., resetting brain processes by acting on 5-HT2A receptors). Moncrieff said claims by David Nutt, a psychopharmacologist and psychedelic researcher that psychedelics “turn off parts of the brain that relate to depression” and reset the brain’s thinking processes by their actions on the 5-HT2A receptors were “pure speculation.” She made the same judgment on a John Hopkins website that said researchers hoped to “create precision medicine treatments tailored to the specific needs of individual patients.” The charity, Mind Medicine Australia’s claim that psychedelic treatments were curative and only required 2-3 dosed sessions, that they were “antibiotics for the mind”, Moncrieff thought was a sales pitch for an expensive therapy.

In reality, psychedelics do not produce the miracle cures people are led to expect, as experience with ketamine confirms. Some people may feel a little better after a treatment, and then the effect wears off and they come for another one and another one, and get established on long-term treatment just as people do on antidepressants.

Official research also over-plays the drug’s benefits. A study published in The New England Journal of Medicine, “Trial of Psilocybin versus Escitalopram for Depression,” found no significant difference between groups in their primary outcome. The study’s discussion then pointed out that secondary outcomes had small differences, but did not consider the placebo effect of participants having a drug-induced experience. The participants were also not typical of those with depression, consisting of mainly well-educated men, almost a third of whom had tried psychedelics before. The study’s researchers said:

The patients in the trial were not from diverse ethnic or socioeconomic backgrounds. Strategies to improve recruitment of more diverse study populations are needed in studies of psilocybin for depression. Also, average symptom severity scores at baseline were in the range for moderate depression, thus limiting extrapolations to patients with severe depressive symptoms or treatment-resistant depression.

The current craze for psychedelics means adverse effects are being minimized, according to Moncrieff. Whether or not people find the effects of psychedelics enlightening or not depends on how the drug-induced experience is interpreted. This highlights the importance of staff as support people while clients are under the influence. Yet she worried that when, and if, psychedelics obtain a medical license, psychotherapy would be dropped or minimized. “The tendency of all psychedelic treatment will be towards the provisions of the drug in the cheapest possible way, which means the minimum of supervision and therapy.”

In “When Drugs of Abuse Become Psychiatric Medications,” Sara and Jack Gorman noted that some commentators have been suggesting we’re on the cusp of a new era in psychopharmacology with the potential of ketamine, MDMA and psilocybin as psychiatric treatments for depression, PTSD and other disorders. They noted how we have information about the biological mechanisms of action for all three of them. Ketamine works mainly through interaction with the brain’s glutamate neurotransmission system. MDMD and psilocybin enhance the brain’s serotonin receptors—the same system affected by SSRI antidepressants.

Unfortunately, however, we still have no firm idea if derangements in any of these neurotransmitter systems are actually the cause of any mood or anxiety disorder. There are many theories linking abnormal glutamate neurotransmission to depression, for example, and some solid data from animal studies suggesting such a link, but no definitive proof that any abnormality in glutamate neurotransmission is part of depression yet exists. We cannot say that any of these drugs work by remediating a known abnormality in the brains of people with psychiatric illnesses any more than we can say that about any of the traditional psychiatric medications.

One final issue is that regardless of the fact that currently approved medications for depression and PTSD are only partially effective for many patients, they are not usually abused or addictive. Yet ketamine, psilocybin and MDMA have long histories as recreational street drugs that can be addictive for some people. In the clinical trials done to date adverse side effects have been minimal, and with the doses and manner in which they are given, addiction is unlikely. Moreover, there are widely used, FDA-approved, psychiatric drugs with known histories of misuse—benzodiazepines and ADHD medications.

Then the Gormans asked a telling question: Is psychiatry following solid science, or going in the direction of approving the use of mind-altering street drugs as medications—and I’d add—because they have no other potential medications on the horizon?

In the journal, JAMA Psychiatry, Joshua Phelps and two others expressed concerns with the growth of industry-sponsored drug development and the assessment of psychedelic drug effectiveness. They noted the market for psychedelic substances was projected to grow from $2 billion in 2020 to $10.75 billion by 2027, “a growth rate that may even outpace the legal US cannabis market.” They said the interest in psychedelic medicine seems to hope that psychedelics will be the next blockbuster class of medicines and has led to efforts to decriminalize psychedelics at the local level, as with Oregon (see Part 1) and other locations. Their concern is that these regulatory changes will adversely affect the quality and rigor of biomedical research with psychedelics.

Although popular excitement, policy momentum, and financial investment in psychedelics continue to increase, it is imperative that research maintains scientific rigor and dispassion to outcomes in the pursuit of improved therapeutics and new insights into the mind, brain, and consciousness that this class of molecules may well afford in the coming years. The presence of large-scale, newly established public companies as an unprecedented category of stakeholder may help to further understanding of these molecules and their possible clinical applications, but these firms also have a unique set of self-interests that must be understood and considered. Research enabled by these firms must still meet the same rigorous standards that are expected elsewhere, even if breakthrough status is warranted.

Then there is another concern described by Will Hall on “Ending the Silence Around Psychedelic Therapy Abuse.” He made his decision to write about therapy abuse when he read Michael Pollan’s best-selling book on psychedelics, How to Change Your Mind. Hill thought Pollan was overly enthusiastic and largely uncritical. “All the new hype about miracle psychiatric treatments and the next wave of cures for mental disorders leaves out the risk of therapy abuse.”

He said from his perspective, as far as drugs go, psychedelics were relatively safe—safer than benzodiazepines or SSRIs. He even acknowledged that reported healings from emotional pain with psychedelics did happen. By raising an alarm about therapy abuse he said he wasn’t exaggerating the dangers of psychedelics, rather: “I’m calling for more honesty about the implications of putting psychedelics in the hands of therapists.”

He noted the inherently imbalanced power relationship of therapist and client, where there is already the potential danger of authority being misused. The therapist has too much influence over a client, and the consequences for clients are too severe to see each side as equal, according to Hall. “And so we protect clients from therapists in the same way we protect children from adults, especially from the most exploitive and extreme violation of therapist trust, sex with clients.” The risks are magnified when you add psychedelics.

Drugs affect judgment, drugs can enhance idealization, drugs can promote risk taking, drugs can lower defenses, drugs can amplify suggestibility, drugs can lead to dissociation… all drugs. Imagine if you heard therapists were giving their clients alcohol to get them talkative, lines of cocaine to get them confident, or cannabis to get them relaxed? You would easily recognize that even if some clients do benefit, the client is also put into a heightened and more easily exploited state. Despite their many unique and often positive qualities, this is still true of psychedelics. And the influence is magnified when the therapist is supplier of and expert about the drug, when the drug has a taboo cultural aura of esoteric healing powers, the media are hyping miracle cures, and scientific experts are waving their hands and calling it “medical treatment.” Add that psychedelic therapists are typically also themselves users of and true believers in these substances. The dangers are obvious.

Psychedelics present some of the same risks as any drugs. Hall said we need to name those risks, and be especially vigilant about them. Otherwise, even though some people will be helped, others will be harmed. “And as the history of psychedelic therapy abuse shows, they already have.” Hall then gave specific historical examples and details from past abuse as well as his own personal experiences.

He wasn’t alone in pointing to this safety concern with psychedelic therapy. In her article on Oregon’s experiment with legalizing psychedelics for STAT, Olivia Goldhill noted that sexual abuse has historically been a problem with psychedelic therapy. “All the usual power imbalances of patients and therapists are exacerbated in a setting where drugs can create feelings of sexual arousal.”

Hall also pointed out that with psychedelics or any other drug, “it’s called getting high for a reason—we lose our feet on the ground.” Gaining a new perspective can be illuminating, but avoidance could come instead of insight. Psychedelics also increase suggestibility, a tendency to accept the beliefs of others illustrated in hypnotic trance states and situations where there is social pressure for conformity. Psychedelics can make some people more dependent on outside influence and more reluctant to consider they may have misjudged their safety when using the drugs.

There is more Will Hall has to say about the potential for therapy abuse with psychedelics, but what we’ve reviewed lays out the concerns. I don’t agree entirely with what seems to me to be a “laissez faire” approach to people who want to use psychedelics for healing or illumination. I’d say there is as much of concern with their use as with benzodiazepines or SSRIs. And given the pendulum swing evident in the history of psychedelics as therapeutic agents, there is a swing back to disappointments and concerns ahead. As Hall astutely said,

All medical treatment outcomes are driven in part by expectation and placebo: eventually the hype around new psychiatric products wears off, and then we are on to the next marketing wave—with iatrogenic harm to patients left in the wake.

STAT said that Washington, New York, Colorado and California are all considering some form of legalizing psychedelics. Other states are enacting decriminalization measures. If Oregon-style legislation spreads to other states, the potential market for legalization will get bigger. Field Trip, a company with a series of clinics used for ketamine therapy plans to set up clinics in Oregon. “Oregon is just the first step. But there’s a big wave coming almost certainly.”

04/5/22

The Psychedelic Pendulum and Psychiatry, Part 1

In November of 2020, Oregon became the first state to legalize the use of psilocybin in therapeutic settings. Measure 109 created a two-year time period during which regulatory details were to be worked out by the Oregon Psilocybin Advisory Board (OPAB). These details would include issues like what qualifications would be required of therapists overseeing those who chose to use psilocybin. Significantly, psilocybin treatment will not be limited to individuals struggling with mental health issues. Anyone 21 or older who passes a screening will be able to access these psychedelic services for “personal development.”

The first draft of rules recommended by the OPAB were made public in February of 2022. Manufacturers will only be permitted to cultivate one of about 200 different types of mushrooms containing psilocybin, Psilocybin cubensis. Some people were concerned with this recommendation, believing the board was also limiting potential benefits. “It is believed that different species promote different types of experiences.”

Psilocybe cubensis was chosen because it’s one of the most popular mushrooms consumed and one of the most studied. Advisory board members also thought that it would be best to start simple, with one mushroom. Other species might be introduced later.

The OPAB also recommended a ban on growing Psilocybe cubensis in wood chips. This is to prevent a rare condition known as wood lover’s paralysis that produces muscle weakness a few hours after hallucinogenic mushrooms grown in wood chips are consumed. Scientists don’t know why this condition occurs. “But it isn’t believed to happen with Psilocybe cubensis.”

The rules also prohibit the chemical synthesis of psilocybin. Measure 109 also requires the state to only license people to set up grow operations who have been Oregon residents for at least two years. Well, at least until 2025. These recommendations are attempting to allow small farmers to set up grow operations and limit the ability of large pharmaceutical companies to move in and potentially dominate the market.

There are other reasons for banning synthesized psilocybin. The synthesis requires using toxic chemicals that have to be extracted before sale so there’s no residue in the final product. Mason Marks, a member of the OPAB, said synthesizing psilocybin is a huge undertaking. “There was some sentiment that that might be maybe unrealistic or overly burdensome, at least initially to expect people to have that level of expertise or equipment in order to do that.”

Manufacturers will have to use clean, food-grade equipment in an area that can be locked. They won’t be permitted to make psilocybin products that may appeal to minors, like in the shape of cartoon characters. Psilocybin is only permitted to be used orally—not with an inhaler, a suppository or an injection. Students will have the opportunity to observe “non-ordinary states of consciousness.”

Facilitators (not therapists?) will have to take at least 120 hours of instruction, covering everything from the history of psilocybin use to safety concerns. They will have to have sufficient experience to teach classes for individuals interested in trying psilocybin. But what about ethical expectations and boundaries with clients under the influence?

Therapeutic facilitators of individuals doing psychedelic therapy from the time of its origins in the 1950s recommended two therapists, one male and one female. This was to minimize the possibility of sexual exploitation of the clients when they are under the influence of psychedelics. More about this in part 2 of the article.

These draft rules need to be discussed and adopted by the Oregon Health Authority. Other rules are still pending, such as how research with psilocybin should be conducted, and the conditions (i.e., schizophrenia) that would prohibit people from trying psilocybin treatment. There are more complicated issues that need to be decided as well. There’s a desire to permit microdosing psilocybin (taking one-tenth or one-twentieth of a normal dose), over a few days. This practice is thought to boost creativity and focus, as well as alleviate depression.

Oregon’s psilocybin system is scheduled to begin in 2023. The Oregon Health Authority will begin taking applications for licenses to manufacture, transport, deliver, sell and purchase psilocybin products on January 2, 2023.

Psychology Today has a page that introduces the reader to “Psychedelic-Assisted Therapy,” giving information on the most common psychedelic substances, their general effects and properties, as well as potential harms and proposed therapeutic uses. It also has a section on “Understanding Microdosing.” The most common psychedelic substances listed on the page were: psilocybin, LSD, ayahuasca, mescaline and MDMA. All but MDMA listed psychosis as a potential harm. Therapeutic uses being investigated include: PTSD, addiction to alcohol, tobacco and cocaine; anxiety associated with terminal illness; depression and general anxiety.

Dependence or substance misuse is not listed as a potential harm for any of the psychedelics, which do have a low risk for addiction. But the repeated therapeutic use of psychedelics increases the ritualized, long-term use of these drugs, and raises the possibility of misuse or dependence problems developing in users over time.

Information on microdosing said there was some evidence of positive effects performance and creativity, but it was mostly anecdotal. One 2018 study published in the journal Psychopharmacology, “Exploring the effect of microdosing psychedelics on creativity,” found support for its cognitive enhancing properties, but fluid intelligence was unaffected. The researchers concluded that while large doses of psychedelics can introduce several undesirable side effects, microdoses might be an alternative that could eliminate the risks of these side effects, while maintaining the benefits on emotion and thinking.

A 2016 study by Roland Griffiths et al, also published in the journal Psychopharmacology, found that when a high dose of psilocybin was administered to patients with a life-threatening cancer diagnosis under supportive conditions, there were “substantial and enduring” decreases in depressed mood and anxiety. It also resulted in increases in measures of quality of life, life meaning, the acceptance of death, and optimism. The effects were sustained for six months.

There has been a veritable flood of articles and research on the supposed benefits of psychedelics, particularly psilocybin and MDMA, over the last several years besides these two Psychopharmacology studies. In 2019, the FDA designated psilocybin therapy as a breakthrough therapy for Usona Institute, the second pharmaceutical company to gain such an approval in that year. The first company, Compass Pathways, is looking at how psilocybin may help with treatment-resistant depression, that is patients who have not improved after trying two different antidepressants. The significance of the second FDA breakthrough approval is related to how it expands the potential market from the relatively small population of individuals struggling with treatment resistant depression to the estimated 17 million with major depressive disorder, according to a statement by Usona:

This is a significant milestone for the over 17 million people in the US who suffer from MDD. Although there are several existing MDD treatments, Breakthrough Therapy Designation recognizes that psilocybin may offer a clinically significant improvement over these therapies. Psilocybin potentially offers a novel paradigm in which a short-acting compound imparts profound alterations in consciousness and could enable long-term remission of depressive symptoms.

Dr. Samoon Ahmad provided a helpful description of how psilocybin affects the brain in a Psychology Today article, “Understanding the Buzz About Magic Mushrooms.” He said psilocin, not psilocybin, seems to be the substance responsible for the psychoactive effects of “magic mushrooms.” Psilocybin and other psychedelics like LSD and mescaline activate the 5-HT1A and 5-HT2A receptors in the prefrontal cortex, which in turn has downstream effects on serotonin and dopamine. “The increase in dopamine is believed to be part of the reason for some of the psilocybin’s effects on mood, such as euphoria, and the commonly reported phenomenon of depersonalization.”

He said the probability of serious adverse events and abuse of psilocybin was low when compared to other classes of abused drugs. The association of the lifetime use of psychedelics and an increased likelihood of mental illness or suicidality “simply does not exist,” according to Ahmad. By associating “lifetime use of psychedelics” and an “increased likelihood of mental illness or suicidality,” Ahmad’s sidesteps how psychedelics can be destabilizing for some individuals who have a past history of psychotic disorders like schizophrenia. See Part 2 for more information on concerns with psychedelic psychotherapy.

Psilocybin can also produce side effects like hypertension, nausea, vomiting, anxiety, confusion and more. Ahmad also pointed out the importance of “set and setting,” the individual’s mindset and their environment.

A positive experience may inspire life-changing epiphanies and grant individuals a greater perspective on life. A negative experience may result in disturbing thoughts or hallucinations, which may lead to anxiety, disorientation, delirium, and, in extreme circumstances, temporary psychosis. Researchers have found that they can significantly diminish the likelihood of negative experiences by providing patients with more preparation and interpersonal support during the period of drug action.

There is still a risk if the interpersonal support is inadequate or inappropriate—not respecting clear, therapeutic boundaries between the support person and the client. And the preparation may not get the person ready for the actual psychedelic experience. Careful attention to the “set and setting,” the inner and outer environments of the drug event, is crucial for a positive experience.

Ahmad said research has shown that psychedelics hold a great deal of promise, “as long as they are administered in a controlled and clinical environment or under the guidance of individuals who are experienced in the use of psychedelics.” But stigma surrounds the use and research into these drugs. His hope is that there will be a loosening of restrictions and regulations in the U.S. as there is more research published, “and the case for the use of psychedelics becomes stronger.”

Dr. Ahmad and researchers like Roland Griffiths (see this Google scholar link for “Roland Griffths psilocybin”) are representative of those who see the potential for psychedelic therapy, particularly with psilocybin. Rick Doblin and his organization MAPS (Multidisciplinary Association for Psychedelic Studies) are attempting to bring MDMA to market as a treatment for PTSD see this Google scholar link for “Rick Doblin MDMA”). British researchers including Robin Carhart-Harris and David Nutt want to treat depression with psilocybin. Michael Pollan, author of a best-selling book on psychedelics, How to Change Your Mind, thought there has been a sea change in attitudes towards psychedelics. In “The Psychedelic Revolution Is Coming,” he said, “Given the mental health crisis in this country, there’s great curiosity and hope about psychedelics and a recognition that we need new therapeutic tools.”

But what are the risks in turning to psychedelics like psilocybin and MDMA as the next great hope in psychiatric drug treatment? As Andrew Jacobs noted in his NYT article, “The Psychedelic Revolution Is Coming,”

The question for many is how far — and how fast — the pendulum should swing. Even researchers who champion psychedelic-assisted therapy say the drive to commercialize the drugs, combined with a growing movement to liberalize existing prohibitions, could prove risky, especially for those with severe psychiatric disorders, and derail the field’s slow, methodical return to mainstream acceptance.

We’ll look at some of the concerns others see with the growing move towards psychedelics as the newest fad in the pursuit of therapeutic tools in Part 2 of this article. For more information on psychedelics as therapy, see the following articles on this website: “Psychedelics Are Not a Magic Bullet,” “The Long, Strange Trip of Psychedelic Psychiatry,” “Give MDMA a Chance?,” and “Psychedelic Renaissance?”

08/3/21

Psychedelics Are Not a Magic Bullet

The Society for Cultural Anthropology published a series of articles, “The Psychedelic Revival,” which noted that psychedelics were making a comeback in modern science, public discourse, and cultural significance. Popular books and mainstream media have highlighted seemingly promising research with drugs such as MDMA, psilocybin and ayahuasca. The medicalization of psychedelics has stimulated the expansion of institutional research and private investment as these new treatments move towards the market. The New York Times published, “How MDMA and Psilocybin Became Hot Investments.” There is even a webpage for Psychedelic Investors, where you can “find financial backing for your psychedelic-driven idea.”

The NYT noted how the nation’s top universities are setting up psychedelic research centers. Investors are giving millions of dollars to an ever-increasing group of start-ups with psychedelic-driven ideas. Michael Pollan, the author of the best selling How to Change your Mind, said there has been a sea change in receptiveness about what had been considered fringe science. “Given the mental health crisis in this country, there’s great curiosity and hope about psychedelics and a recognition that we need new therapeutic tools.”

The two leading psychedelic candidates being developed as therapeutic tools are MDMA and psilocybin. The journal Nature Medicine published the results of the ongoing quest of Rick Doblin and his organization MAPS (Multidisciplinary Association for Psychedelic Studies) to bring MDMA to market as an FDA treatment for PTSD. The New England Medical Journal just published the findings of a British group of researchers, most notably Robin Carhart-Harris and David Nutt, and their desire to treat depression with psilocybin. Scientists, psychotherapists and entrepreneurs in the rapidly growing field of psychedelic medicine believe it is only a matter of time before the FDA gives approval for these drugs to be used therapeutically.

The question for many is how far — and how fast — the pendulum should swing. Even researchers who champion psychedelic-assisted therapy say the drive to commercialize the drugs, combined with a growing movement to liberalize existing prohibitions, could prove risky, especially for those with severe psychiatric disorders, and derail the field’s slow, methodical return to mainstream acceptance.

Psychedelic research is now swimming in money. Rick Doblin can remember when research money was scarce. But MAPS has raised $44 million over the past two years. “I spend a lot of my time saying no to investors,” said Doblin. John Hopkins, The University of California Berkley, and Mount Sinai Hospital in New York have or soon will have psychedelic research programs funded by private donors.

There are over a dozen psychedelic start-ups and a handful of companies that have gone public. Compass Pathways is a Nasdaq-listed health care company that has raised $240 million and is conducting 22 clinical trials across 10 countries of psilocybin therapy for treatment-resistant depression. Field Trip Health is a two-year old Canadian company trading on the Canadian stock Exchange that raised $150 million to finance dozens of ketamine clinics in North American cities like Chicago, Los Angeles and Houston. Oregon became the first state to legalize the therapeutic use of psilocybin last year. So far, the Justice Department has taken a hand-off approach to enforcing the fact that psychedelics are still illegal under federal law.

Field Trip got its start opening cannabis clinics across Canada. This summer the company plans to test psilocybin therapy in Amsterdam, where psilocybin mushrooms are legal. They are also developing a new psychedelic with the same therapeutic effects of psilocybin, but it works in half the time—about two or three hours. This would reduce the staffing costs of supervised sessions. More importantly, it would give the company propriety control of the new drug. Other biotech companies are doing the same.

Ronan Levy, Field Trip’s executive chairman said, “We are riding the forefront of what I think is going to be a significant cultural and business wave.” This corporate interest is both thrilling and troubling. Potential missteps could undo the progress of recent years. Veteran psychedelic scientists like Charles Grob of UCLA worry that commercialization and the rush toward the recreational use of psychedelics will trigger a public backlash again, “especially if increased availability of the drugs leads to a wave of troubling psychotic reactions.”

Rigorous protocols and a system to train and credential psychedelic medicine professional is needed, according to Grob. They have to be meticulously attentive to safety conditions. If these conditions are not maintained, there is a risk that some people will become psychologically unstable. “And if the primary motivator is extracting profit, I feel the field is more vulnerable to mishaps.” Rick Doblin shares some of those concerns. “I realize we could screw things up at the last minute so I’m not planning to celebrate any time soon.”

The Pollan Effect

Since the publication of How to Change Your Mind the expectations of participants in the research trials of what’s going to occur have skyrocketed. In “The Pollan Effect,” a psychedelic trial researcher said it was a big problem, but there’s not much they can do about it. The promising results are published and describe an 80 percent success rate and mystical experiences. Then a participant has a session where they don’t feel anything and are hugely disappointed; and sometimes feel like failures. “You want people coming into this with some openness, and typically once you have all these preconceived ideas, they think they know what they want. That doesn’t always work out well.”

For my part I definitely think this issue is a big problem, and my guess is that it will only be getting worse in the near-term. I actually just drew up a slide for a talk at APA [American Psychological Association] next month with the title in bold, PSYCHEDELICS ARE NOT A MAGIC BULLET. I’ll also be talking about . . . this mythology that with psychedelics they can take this brief trip to a faraway place (like Disneyland) and come back magically transformed/cured, whereas the reality is much more complex.

But these warnings don’t seem to discourage the so-called “psychonauts” (someone who explores altered states of consciousness, particularly through hallucinatory drugs). On the maps.org home page is the statement: “Together, we can cross the finish line and make MDMA a medicine.” It adds that if successful, the treatment could transform the lives of millions of people living with complex trauma. Rick Doblin is quoted as saying, “Psychedelics, when used wisely, have the potential to heal us, help inspire us, and perhaps even save us.” And this appears to be the goal behind what MAPS is presenting as MDMA-assisted therapy for PTSD—MDMA-assisted therapy for everyone.

On May 11, 2021, MAPS won an appeal to do a phase 1 trial of MDMA-assisted therapy with healthy volunteer therapists to measure the “development of self-compassion, professional quality of life, and professional burnout among clinicians.” The FDA had placed a clinical hold on the proposed study in 2019 due to concerns regarding the scientific merit of the study, the risk-to-benefit ratio for healthy participants, and the credentials of the clinical investigators. “Personal experience is widely considered to be an important element in preparation and training to deliver psychedelic-assisted therapies.” If the appeal had not been granted, the Lead Facilitator in each two-person facilitator team would be required to hold an M.D., Ph.D. or equivalent degree and be on-site instead of on-call during treatment sessions.

The hoped-for process would seem to be something like this once there is FDA approval for MDMA-assisted therapy for PTSD. Once allowed by the FDA, MDMA-assisted therapy for PTSD would be linked with FDA approval of MDMA-assisted therapy for healthy volunteer therapists; and then followed by FDA approval of MDMA-assisted therapy for any interested, healthy party. Rick Doblin implied as much when he said:

For three decades, we have sought to educate the FDA in our novel approach rather than simply accept FDA requirements that are unjustified by the evidence. The dedicated work and incisive strategy of our Clinical Development team continues to improve the regulatory landscape for all future patients of psychedelic-assisted medicines.

Since 2010, MAPS has organized a series of Psychedelic Science conferences. In 2013, it was a three-day conference with over 1,900 international attendees. The 2017 conference was a six-day global gathering with three days of conference programming. In 2019, the conference became a Psychedelic Science Summit. The 2023 Psychedelic Science Conference expects an estimated 10,000 attendees, “At the world’s largest psychonaut gathering.”

In 2014, Scientific American republished a brief article on the resurgence of in psychedelics as therapeutic agents, which said: “Psychedelic drugs are poised to be the next major breakthrough in mental health care.” The hype is accelerating and the enthusiasm is growing for psychedelic-assisted therapies. But let’s wait and see what the open science and total transparency of MAPS shows us with MDMA. Remember psychedelics are not a magic bullet, whether they are used to heal or inspire us. They certainly won’t save us and may not be as efficacious as claimed.

In “Trial of Psilocybin versus Escitalopram for Depression,” researchers sought to compare psilocybin-assisted therapy with escitalopram assisted therapy in a randomized, blinded study. The Mental Elf website reviewed and commented on the study. There were no statistically different differences in the primary outcome measure between the psilocybin and escitalopram groups at six weeks, but no conclusions could be drawn from the data. “In both trial groups, the scores on the depression scales at week 6 were numerically lower than the baseline scores, but the absence of a placebo group in the trial limits conclusions about the effect of either agent alone.”

Writing for The Mental Elf, James Rucker and Sameer Jauhar commented how the lack of a placebo control condition made it difficult to differentiate between the two drug treatments and the psychological therapy that went along with these. They noted the six week follow up may not have been long enough to effectively evaluate the escitalopram condition. “Positive and negative expectancy effects are likely to have affected the results in this trial and are liable to bias results in favour of psilocybin.” Given that participants likely received extensive psychological support, “The results of this trial may reflect more the therapeutic efficacy of attentive psychological therapy than to psilocybin or escitalopram.” (emphasis in the original)

07/13/21

The Long, Strange Trip of Psychedelic Psychiatry

There seems to be a full court press of articles on the renaissance of clinical research into psychedelic substances. NPR had a segment on their program Short Wave. Salon published an article on how researchers are studying psychedelics all wrong. The New York Times published an article describing a new study that showed where MDMA-assisted therapy resulted in 67% of the participants no longer qualified for a diagnosis of PTSD. You can even find receptive discussions of psychedelics by H. Steven Moffic and Tiago Merques on Psychiatric Times and an article on a presentation of this research at the 2021 APA Annual Meeting. Welcome to psychedelic psychiatry.

The takeaway from the NPR broadcast, “The Resurgence of Psychedelic Psychiatry” was that we are “at the beginning of a new era.” Dr. Moffic presented a breezy history of research with psychedelics in “The Trip Resumes for Psychedelics, Psychiatry, and Society” and said the topic required more careful study. Merques noted the trial was testing the drug plus assisted psychotherapy. He acknowledged this was very different from normal FDA studies.

The NYT article, “Looking to the Future of MDMA-Assisted Psychotherapy,” highlighted the work of Rick Doblin and MAPS, the Multidisciplinary Association for Psychedelic Studies, in bringing MDMA-assisted therapy through the FDA approval process. Doblin was the senior author of “MDMA-assisted therapy for severe PTSD,” recently published in the prestigious journal, Nature Medicine. The presentation at the 2021 APA Annual Meeting, “Looking to the Future of MDMA-Assisted Psychotherapy,” reviewed the results described in the Rick Doblin article and quoted one of the presenters as saying, “The future is here.”

The MAPS efforts with MDMA-assisted therapy to treat PTSD is getting the most press and interest at this time. Jennifer Mitchell, who was the lead author of “MDMA-assisted therapy for severe PTSD,” said in the NYT article, “This is a wonderful, fruitful time for discovery, because people are suddenly willing to consider these substances as therapeutics again, which hasn’t happened in 50 years.” Doblin added that it wasn’t the MDMA that produced the therapeutic effect, “it’s the therapy enhanced by the drug.” MDMA combined with therapy was thought to allow the brain to process painful memories and heal itself.

For this process to work, a person must be primed to engage with their trauma. Participants first undertook preparatory sessions with two trained therapists. Then in three sessions of eight-hours each, spaced a month apart, they received either an inactive placebo or MDMA. Neither the participants nor the therapists knew which. While most participants correctly guessed whether they received a placebo or MDMA, this did not undermine the study’s results or its methodology, which was agreed to in advance by the F.D.A.

“MDMA-assisted therapy for severe PTSD,” concluded from their results that MDMA-assisted therapy could be a potential breakthrough therapy. The authors speculated that the pharmacological properties of MDMA, when combined with therapy, could produce a ‘window of tolerance,’ where participants could revisit and then process traumatic events without becoming overwhelmed. The acute prosocial and interpersonal effects of MDMA seem to support the quality of the therapeutic alliance, “a potentially important factor relating to PTSD treatment adherence and outcome.” They even found it effective with comorbid issues such as childhood trauma, depression and dissociation.

PTSD is a particularly persistent and incapacitating condition when expressed in conjunction with other disorders of mood and affect. In the present study, perhaps most compelling are the data indicating efficacy in participants with chronic and severe PTSD, and the associated comorbidities including childhood trauma, depression, suicidality, history of alcohol and substance use disorders, and dissociation, because these groups are all typically considered treatment resistant. Given that more than 80% of those assigned a PTSD diagnosis have at least one comorbid disorder, the identification of a therapy that is effective in those with complicated PTSD and dual diagnoses could greatly improve PTSD treatment. Additional studies should therefore be conducted to evaluate the safety and efficacy of MDMA-assisted therapy for PTSD in those with specific comorbidities.

The Salon article, “Why mental health researchers are studying psychedelics all wrong,” was written by two psychedelic advocates who said they have worked for decades with thousands of people. They questioned whether the current mental health industry was the place for psychedelic drugs. There is a history of supposed breakthrough modalities that would bring psychiatry into the realm of medical science. “Yet none of these claims have demonstrated a high benchmark of legitimate authority, and many have even been harmful.” The authors thought there would be a substantial loss when psychedelics were medicalized.

The model for introducing psychedelics into a medical framework is being defined by the Multidisciplinary Association for Psychedelic Studies (MAPS), the most visible and politically connected psychedelic organization. Their flagship research project is using MDMA, a psychostimulant, to treat Post Traumatic Stress Disorder (PTSD), a diagnosis that has become increasingly common. Its public association with war vets and sexual abuse survivors makes PTSD the perfect public relations focus for psychedelics as the next medical breakthrough.

If psychedelics hold promise, the authors said, it may be a result of the drugs not working in a linear fashion or providing overnight results. They can lead people on paths of self-inquiry and growth that don’t become evident until years later. As Robert Whitaker pointed out, this doesn’t fit with a medical model that gets FDA approval. The reductive research of the FDA process requires a strict protocol that leads to replicable changes for anyone with a given diagnosis. “Why do you need a doctor for that? Why do you go to medical school for that?”

There is a need for research into psychedelics as they present an opportunity to recontextualize how we think about and experience suffering. However, drowned in the media hype of psychedelic advocacy organizations and the mental health industry, there is little public discourse about the potential implications of moving psychedelics into a system with such a problematic history.

The medicalization of psychedelics raises several questions about psychopharmacology and psychiatry. With psychedelics, their sensitivity to set and setting—the psychological and physical environments of their consumption—has been known for a long time. This compels researchers to consider the context as a variable when measuring the effectiveness of psychedelic substances. Does this mean that the FDA is moving away from its essentialist methodology for drug approval? A double-blind methodology can’t be implemented, effectively neutralizing this “gold standard” of scientific investigation embedded in the FDA’s methodology. Rick Doblin acknowledged this above when he admitted that most participants correctly guessed whether or not they received a placebo or MDMA.

If MDMA-assisted therapy ever achieves FDA approval to treat PTSD, it will challenge the scientific foundation upon which Western drug testing has depended for decades. Assuming the FDA ultimately approves MDMA-assisted therapy, does this signal the agency’s willingness to modify its clinical trial protocols for other potential “breakthrough” therapies? Will we be able to trust that the findings of a flexible methodology are truly scientific? In its pursuit of the next breakthrough therapy, is psychiatry moving away from a consistently scientific evaluation of its effectiveness? Michael Pollan, in his best-selling book, How to Change Your Mind, made similar observations:

Western science and modern drug testing depend on the ability to isolate a single variable, but it isn’t clear that the effects of a psychedelic drug can ever be isolated, whether from the context in which it is administered, the presence of the therapists involved, or the volunteer’s expectations. Any of these factors can muddy the waters of causality. And how is Western medicine to evaluate a psychiatric drug that appears to work not by means of any strictly pharmacological effect but by administering a certain kind of experience in the minds of people who take it?

For one future psychiatrist, his youthful LSD trip led to an insight that focused his attention on psychopharmacology. Jeffrey Lieberman is the Chairman of the Department of Psychiatry at Columbia University, and a former president of the American Psychiatric Association. In his book Shrinks: The Untold Story of Psychiatry, he described how an LSD trip played a role in his professional development. In 1968, as a junior at Miami University in Oxford Ohio, Lieberman decided to try LSD.

He jotted down notes on his insights while tripping, expecting to revisit “these profound pearls of wisdom” once the drug wore off. Afterwards, he found his notes either “boringly mundane” or “ludicrously nonsensical.” He learned that “Just because a person believes he is having a cosmic encounter—whether because of drug or mental illness—it doesn’t mean he is.” However, there was one lasting insight for which he is still grateful.

Though my LSD-fueled reverie dissipated with the light of the morning, I marveled at the fact that such an incredibly minute amount of a chemical—50 to 100 micrograms, a fraction of a grain of salt—could so profoundly affect my perceptions and emotions. It struck me that if LSD could so dramatically alter my cognition, the chemistry of the brain must be susceptible to pharmacologic manipulation in other ways, including ways that could be therapeutic.

Lieberman’s LSD experience led him to become a biological psychiatrist and not a surgeon or neurologist. Yet, his generation of psychiatrists has failed to discover the underlying causes of mental illnesses. And now it seems psychiatrists are turning back to see if psychedelics can be used as medicine. What a long, strange trip it has been for psychedelic psychiatry.

06/11/19

Vine of the Spirits

The Hollywood Reporter described a trend emerging over the past few years in Hollywood—ayahuasca ceremonies. It appeared as part of the plot in the 2014 movie, While We Were Young, with Jennifer Aniston, Naomi Watts and Ben Stiller. The website Ranker, in “Celebrities Who have Tried Ayahuasca,” said stars like Paul Simon, Chelsea Handler, Jim Carrey, Tori Amos, Lindsay Lohan, Sting and others have taken the “yage” plunge. Described as a muddy tea, the active ingredient in ayahuasca is one of the world’s most potent psychedelics. Derived from a vine harvested in Peru and Brazil, it has been used for spiritual ceremonies for centuries and apparently it wants to be more widely used. A Hollywood psychiatrist that hosted a yage ceremony said: “The plants told them [shamans leading the ceremonies] Hollywood’s a good place to get the word out.”

Despite its faddish use today, it was originally described by 16^th century Christian missionaries from Spain and Portugal who encountered South Americans using ayahuasca. The missionaries described it as “the work of the devil.” It was also sought out by William Burroughs in the early 1950s. Burroughs had hoped ayahuasca would relieve or cure his opiate addiction. His experience became the basis of a 1963 novel he co-wrote with Allen Ginsburg called The Yage Letters. Traditional use by shamans led to native religions forming around ayahuasca rituals in the 1930s. In Brazil ayahuasca has had a legal status for ritual use since 1987.

Ayahuasca is a combination of chacruna leaves and the bark of the Banisteriopsis caapi vine, or caapi. “Aya” contains DMT (dimethyltrytamine), a powerful psychedelic. It is illegal in the U.S. and classified as a Schedule 1 drug. Its acute effects last about four hours and include intense perceptual, cognitive, emotional and affective experiences. After about forty minutes the visions begin, but they are not always “Go Ask Alice-White Rabbit” experiences. An Emmy-winning television producer said:

The first thing you see is often your worst fear come to life. . . . Mine was Holocaust horror. Another time I saw a 50-foot black widow spider — my fear of death manifesting. It illuminates the dark of your subconscious, and like a horror movie, once you see it, it no longer scares you.

Other visions were less intense. One person saw what looked like a Star Wars set: “dragonflies, sparks of light, plants, stars — everything moving. You go into it asking Mother Ayahuasca a question, then she shows you what you need to know.” Another person said: “I saw a spaceship the first time, then a machine with little gears and fobs. ‘This is how the universe works,’ a woman’s voice told me. The more you do it, the less anxiety you have. It lifts us out of the isolation everyone feels, particularly in Los Angeles.” But a Hollywood internist named Gary Cohen wasn’t convinced:

Ayahuasca contains chemicals found in SSRI antidepressants like Prozac and dangerous, older MAO-inhibitor antidepressants like Parnate. There are potential serious side effects, both with other drugs and food. Foods that contain tyramine — alcohol, cheese, meat, chocolate — can theoretically interact with ayahuasca to cause severely elevated blood pressure, resulting in strokes and extremely high body temperatures, which can cause death. I strongly advise my patients against using it recreationally or ‘spiritually.’

A handful of deaths have been reported, particularly those with heart ailments and high blood pressure. An 18-year old California teen seeking spiritual rebirth in 2012 was buried at the center in the Amazon jungle where he took the drug. “His shaman was convicted of homicide and sentenced to five years in prison.” The stories of transformation tend to hook interested individuals into trying it. “The rise of festival culture, Burning Man, plus technology — it’s all making everyone desire a deeper place.”

There has been some research into the effects of Ayahuasca. A paper was published in Psychological Medicine. The researchers conducted a double-blind randomized placebo-controlled trial of 29 (14 received ayahuasca; 15 received the placebo} patients with treatment-resistant depression. They found a rapid antidepressant effect after a single dosing session with ayahuasca when compared to placebo. The authors concluded: “This study brings new evidence supporting the safety and therapeutic value of ayahuasca, dosed within an appropriate setting, to help treat depression.” The study was registered at http://clinicaltrials.gov (NCT02914769).

We found evidence of rapid antidepressant effect after a single dosing session with ayahuasca when compared with placebo. Depression severity changed significantly but differently for the ayahuasca and placebo groups. Improvements in the psychiatric scales in the ayahuasca group were significantly higher than those of the placebo group at all time points after dosing, with increasing between-group effect sizes from D1 to D7. Response rates were high for both groups at D1 [day 1] and D2 and were significantly higher in the ayahuasca group at D7. Between-groups remission rate showed a trend toward significance at D7.

I would suggest there are several issues with the study. First is the washout period of 2 weeks, meaning any patients using antidepressants were rapidly tapered off them two weeks before the study. This was to ensure antidepressant medication was no longer present in the patient’s body. However, because of the rapidness of the taper the patients will likely have experienced antidepressant discontinuation syndrome (withdrawal) and a rebound of their negative mood, confounding the assessment of depression.

This short maximum time—seven days—for assessing the antidepressant effects is another limitation of the study. Ketamine, another medication with rapid antidepressant effects and psychedelic effects, has been shown to fade rapidly and require frequent, repeated treatments. The positive effects (or evidence of fading effects) ayahuasca may have on the patients beyond seven days is not known since antidepressant treatment is resumed at that point. Then there is the context of the ceremony itself.

Neuroskeptic reviewed the study on his blog, stating it revived some long-standing questions. He did think it was a promising, well-designed study, however. One of the qualities he pointed out was how the placebo brew looked, tasted and smelt like the real thing. He noted where Palhano-Fontes et al. concluded that while no serious side effects occurred, “the ayahuasca session was not necessarily a pleasant experience.” He thought the antidepressant effects were themselves a kind of placebo response—”the ayahuasca caused powerful psychedelic effects, such as ‘altered perception’ and ‘transcendence.’”

Such potent subjective experiences could lead patients to have confidence in the treatment and thus drive placebo effects, if combined with expectations that ayahuasca will be beneficial. A profound experience could trigger improvement in other ways, as well, such as by giving patients a new perspective on their own mental state.Now, in the case of ayahuasca, this ‘psychological’ interpretation of the antidepressant effect is not necessarily a problem. I think most people (including the traditional ayahuasca users) already assume that the psychedelic experience is part of the therapeutic process.

But it does raise the possibility the positive effects are not due to the ayahuasca itself. As the researchers themselves said, ayahuasca is not a panacea.

Three of the study’s authors described their study on The Conversation. They said it was the first randomized, placebo-controlled clinical trial of ayahuasca, which means “the vine of the spirits” in the Quechua language. They began by recruiting 218 patients with depression. The twenty-nine selected for the study had treatment-resistant depression and no history of psychiatric disorders like schizophrenia, “which ayahuasca may aggravate.” Although the sessions took place in a hospital, the space used was designed like a quiet and comfortable living room.

One day afterwards, 50% of all patients were significantly improved, including reduced anxiety and improved mood. After a week, 64% of the patients who just received ayahuasca felt their depression had eased. They also noted that because ayahuasca is illegal in many countries, its therapeutic value is difficult to test. Even in Brazil, using ayahuasca to treat depression remains a fringe, informal endeavor. They cautioned that ayahuasca was not a panacea or cure for depression.

Such experiences may prove too physically and emotionally challenging for some people to use it regularly as treatment. We have also observed regular ayahuasca users who still suffer from depression.

Another of the study’s authors pointed out the media interest given to ayahuasca as a potential “cure” for addiction and depression and said maybe it is, but “it’s too soon to tell.” He cautioned against such a conclusion. Acknowledging the power of the placebo effect, he said, “It is not currently possible to conclude that the observed effects were really caused by ayahuasca, or that ayahuasca can ‘cure’ depression.” He also seemed to agree with Neuroskeptic, that the powerful psychedelic effects were a kind of placebo effect: “By helping us find the sacred within us, its psychoactive power seems to hold therapeutic potential as an alternative way to address common disorders that modern medicine has thus far found difficult to treat.” He concluded by saying we’ll have to wait and see what the science says.

For more on ayahuasca, go to: “Ayahuasca Anonymous,” Part 1 and Part 2.

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag Archives: psychedelics