Tag: MDMA

08/20/24

The Long Strange Trip of MDMA-Assisted Therapy

ID 220296694 | Mdma © Yee Xin Tan | Dreamstime.com

The FDA accepted a new drug application (NDA) by Lykos Therapeutics for MDMA-assisted therapy in February 2024. Lykos was formerly known as MAPS PBC (Multidisciplinary Association for Psychedelic Studies, Public Benefit Corporation) and MAPS had been doing research and collecting clinical trial data on MDMA-assisted therapy for over two decades. The founder and President of MAPS, Rick Doblin, optimistically said one of his primary motivations for founding MAPS was to bring psychedelic-assisted therapies to market as FDA-approved treatments. He hoped the potential approval of MDMA-assisted therapy for PTSD would only be the first of many psychedelic-assisted therapies that become available. But in August of 2024, the FDA officially rejected the Lykos request to approve MDMA-assisted therapy.

NPR reported the FDA asked Lykos to further study the safety and efficacy of the treatment. An FDA spokesperson said there were “significant limitations to the data contained in the application that prevented the agency from concluding the drug is safe and effective for the proposed indication.” Lykos’ CEO Amy Emerson said the request for another Phase 3 trail was “deeply disappointing” and “would take several years.” She thought many of the requests from the FDA could be addressed with existing data, post-approval requirements “or through reference to the scientific literature.” Lykos said it planned to request a meeting with the FDA to reconsider the decision.

An article on Nature about the FDA rejection said many researchers were surprised by the decision. But I don’t think it wasn’t an entirely unanticipated decision. In June, an independent advisory committee overwhelming voted against approving MDMA, citing problems with the clinical trial design that made it difficult to determine the drug’s safety and efficacy. One concern was that around 90% of the participants in Lykos’ trials guessed correctly whether they had received the drug or placebo.

Another problem was the Lykos approach of giving the drug alongside psychotherapy. Rick Doblin had previously stated in an interview on Fox Business that he thought the drug’s effects was inseparable from guided therapy which was the main change agent: “It’s not the drug itself; it’s the therapy that is the primary act of treatment.” He thinks MDMA makes the therapy more effective. The Nature article said:

MDMA is thought to help people with PTSD be more receptive and open to revisiting traumatic events with a therapist. But because the FDA doesn’t regulate psychotherapy, the agency and advisory panel struggled to evaluate this claim.

One expert said it was like trying to fit a square peg into a round hole. But even he was “a little surprised” by the agency’s decision. The FDA’s decision could affect future applications for other psychedelics—such as psilocybin and LSD—that are currently in late-stage trials for treating psychiatric disorders. An anaesthesiologist at Stanford who studies psychedelics doubted that other companies developing these drugs will include a psychotherapy component in their application submission to the FDA. The respective effects of the interventions are difficult to untangle from the drug.

Data Integrity Problems

Medscape reported in June that the FDA’s Psychopharmacologic Drugs Advisory Committee found the benefits of MDMA-assisted therapy did not outweigh the risks. Only two of 11 members thought Lykos had proved the treatment’s effectiveness. “In a second vote, only one panelist agreed the benefits outweighed the risks.” The committee’s chairperson was not convinced MDMA was effective. He said he and others on the panel thought the “functional unblinding” in Lykos’ two pivotal trails was concerning.

The FDA advised Lykos in 2016 to consider using an active comparator instead of placebo to minimize bias and functional unblinding, but the company rejected the FDA’s suggestions, said David Millis, MD, the lead reviewer from the FDA’s Division of Psychiatry.

Some members of the committee said it was difficult to differentiate from the trial design whether therapy had any impact over and above MDMA. One person said: “The way it’s presented in the application makes it impossible to untangle the two.” Another commented how the therapy element was “a bit of a black box.” They were also concerned about financial and other conflicts if Lykos were solely responsible for training therapists. In STATS News, Thomas Insel, the former director of the NIMH,  commented:

Administration of MDMA within the context of psychotherapy might constitute best practice, and might confer effectiveness and safety that is profoundly different from taking the same drug at a rave or outside of a therapeutic environment. But the FDA approval process — optimized for drugs used in other areas of medicine — is not really adapted for psychiatric medications in which “the world does its bit.” Indeed, a regulatory approach that looks at psychiatric medications without attention to such powerful psychological interventions as exposure and cognitive therapy is not aligned with the research showing that the combination of medication and psychotherapy is preferable to either intervention alone.

During the public hearing on the MDMA-assisted therapy proposed by Lykos, a psychology PhD candidate noted the core idea of the therapy was that humans have “an inner healing intelligence” that is accessed through MDMA and other non-ordinary states of consciousness. She observed the Lykos therapy manual “is based on New Age psychospiritual theory.”

Some companies, such as Compass Pathways in London, which is conducting a Phase III trial of psilocybin for depression, do not have psychotherapy as a component of the trial. Atai Life Sciences in Berlin is excluding anyone who recently started psychotherapy from participating in its trial of the psychedelic DMT (dimethyltryptamine) for depression. However, studying the effects of psychedelics independent of the psychotherapy goes against the traditional method of guided trips dating back to 1950s experiments of LSD to “treat” alcoholism. See “Bill W. and his LSD Experiences,” Part 1 and Part 2.

Nature also reported that the Institute for Clinical and Economic Review alleged that Lykos therapists pressured study participants to report only positive results. The Institute said Lykos employees’ advocacy for the drug affected the participants’ judgement. Oh, and then there was a report that an unlicensed therapist working for MAPS at a trial site in Canada was sued for sexually assaulting a participant who was under MDMA’s influence.

MDMA Papers Retracted and Lykos Reorganizes

These issues were known by the researchers who published three papers, but they turned a blind eye to them and published research papers touting the positive effects of MDMA-assisted therapy without mentioning the concerns. One of the researchers even admitted there were potential problems with the proposed treatment process, including the expense and time needed; and the potential for addiction. Psychologist James Coyne thought there had been a well-orchestrated publicity campaign on the research done by MAPS. See “Don’t Roll the Dice with MDMA,” Part 1 and Part 2.

One day after the FDA’s rejection of Lykos’ NDA for MDMA, the journal Psychopharmacology retracted three papers about MDMA-assisted therapy. Many of the authors of the three studies, including Rick Doblin and Lykos CEO Amy Emerson, are affiliated with MAPS and Lykos. According to the retraction notice for the one of the retracted papers,

The Editors have retracted this article after they were informed of protocol violations amounting to unethical conduct at the MP4 study site by researchers associated with this project. The authors have subsequently confirmed that they were aware of these violations at the time of submission of this article, but did not disclose this information to the journal or remove data generated by this site from their analysis. Additionally, the authors also did not fully declare a potential competing interest. Several of the authors are affiliated with either the Multidisciplinary Association for Psychedelic Studies (MAPS) or MAPS Public Benefit Corporation (MAPS PBC), a subsidiary that is wholly owned by MAPS. As is stated in the Funding declaration, MAPS fully funded and provided the MDMA that was used in this trial, and MAPS PBC organised the trial.

Then on August 15th, Lykos announced it was laying off 75% of its workforce and Rick Doblin also resigned his position on Lykos’ board. In a news release from Lykos, he said: “After 38 plus years of work, I’m profoundly saddened by the FDA decision around this critically needed therapy, but am heartened that Lykos will still move forward continuing clinical research that addresses the FDA’s questions.” He added the FDA delays made it more important than ever that he work at MAPS to develop global access to MDMA and other psychedelics.

Lykos will continue to pursue its goal of FDA approval of MDMA-assisted therapy. While Lykos was announcing its restructuring plans, the company also announced that David Hough has been appointed to oversee Lykos’ resubmission of MDMA treatment to the FDA. When Hough was with Janssen, he led the development team that brought Spravato (esketamine) to market to treat major depression and treatment-resistant depression. See “Red Flags with Spravato” and “Doublethink with Spravato?” for more information on esketamine.

Conclusions

Let’s hope that if there is a meeting between Lykos and the FDA, that Lykos won’t attempt to present research or data they know is tainted by protocol violations again. And look for the FDA to re-examine the “existing data” from Lykos for MDMA-assisted therapy for any additional undetected or undisclosed problems. Amy Emerson may be disappointed in the FDA rejection, but MAPS and Lykos should have been less slipshod in their research. If it takes years before the credible research can be done, we’ll just have to wait.

04/16/24

Psychedelics as the Newest Psychiatric Craze, Part 2

Image by Gordon Johnson from Pixabay

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.

09/26/23

Don’t Roll the Dice with MDMA, Part 2

Photo by Guillermo Velarde on Unsplash

The psychedelics industry is booming, as companies plan out their patent strategies in order to stake out their future share of the market. In the early days of the industry, nonprofits like MAPS and smalltime startups dominated the psychedelics space. Then the FDA granted breakthrough status to MAPS for MDMA-assisted therapy to treat PTSD in 2017. And in 2018 psilocybin-assisted therapy was approved as a breakthrough therapy for treatment-resistant depression. According to Insider, venture capitalists have now invested $139.8 million into startup psychedelic companies in a few short years.

The Hill noted California was on its way to be the third state to decriminalize psychedelics after its Assembly passed Senate Bill 58 by a 42-11 vote. In addition to decriminalizing personal possession and cultivation, the bill would allow “community-based healing” practices to promote the therapeutic use of psychedelics. Interestingly, the specified substances included psilocybin, psilocin, dimethyltryptamine (DMT) and mescaline, but did not mention MDMA. However, ecstasy or MDMA has been progressively moving through the FDA’s clinical trial gauntlet for approval in MDMA-assisted therapy and MAPS recently published the results of its second Phase 3 clinical trial.

MAPS, the Multidisciplinary Association for Psychedelic Studies, has been advocating for MDMA-assisted therapy to treat PTSD since 1986. In 1985 the DEA classified MDMA as a Schedule I drug, meaning the agency thought it to have no medical use and a high potential for abuse. Rick Doblin, the founder of MAPS said, “The big tragedy to point out is that it was pretty clear in the late 1970s and early 1980s that MDMA had incredible therapeutic potential.” But there is more to know about the history of MDMA and Rick Doblin, who chose PTSD as the disorder to target in his quest to end the government ban on psychedelics.

Doblin said MAPS wanted to help a population that would automatically win public sympathy. “No one’s going to argue against the need to help them [veterans].” When the DEA moved to criminalize MDMA in 1984, Doblin created MAPS and sued the agency, but failed to stop the DEA from permanently classifying it as a Schedule I controlled substance. He realized then psychedelics were seen as too fringe to win public support and decided that both he and the issue needed to go mainstream. So, he applied to the public policy program at Harvard, shaved off his mustache, cut his hair and began to dress more conventionally.

“I used to laugh about how simple it was,” he said. “You put on a suit, and suddenly everyone thinks you’re fine.” Doblin’s dream is to see psychedelic treatment centers in every city, but not simply to treat PTSD. These centers would be where people could go for spiritual experiences, enhanced couples therapy and personal growth. He believes psychedelics can even help homelessness, global warming and world peace: “These drugs are a tool that can make people more compassionate, tolerant, more connected with other humans and the planet itself.”

But this kind of rhetoric makes others nervous. A psychology professor at Swansea University in Wales thinks MDMA’s a dangerous substance. He’s worried FDA approval for the treatment of PTSD will lead many in the public to believe MDMA is safe for recreational use, despite its problematic side effects. See “Give MDMA a Chance?” and “MDMA-Not!” for more information on the history of MAPS and concerns with adverse side effects with MDMA.

Nevertheless, MAPS plans to submit a new drug application (NDA) for MDMA-assisted therapy to the FDA by the end of the year, which brings us to the question posed towards the end of Part 1 of this article: Should the FDA approve MDMA-assisted therapy?

The New York Times described the second Phase 3 clinical trial for MDMA-assisted therapy in “MDMA Therapy [was] Inches Closer to Approval” and said it seemed to be effective in reducing symptoms of PTSD. After giving a brief history of MAPS and Doblin’s efforts towards FDA approval of MDMA-assisted therapy, they gave a summary of MAPP2, the second Phase 3 clinical trial: “MDMA-assisted therapy for moderate to severe PTSD,” published in Nature Medicine. The findings were similar to the results of MAPP1, the first Phase 3 study of MDMA-assisted therapy for PTSD. See Part 1 for a discussion of those findings.

As in previous studies of MDMA-assisted therapy, the treatment was generally well-tolerated, according to the data presented about adverse events. Common side effects, primarily for those in the MDMA group, included muscle tightness, nausea, decreased appetite and sweating.

Two participants in the MDMA group and one in the placebo group experienced serious suicidal ideation during the study, but no suicide attempts were reported.

Allen Frances, a professor emeritus of psychiatry at Duke University and the chair of the DSM-IV, didn’t think the study’s results would meet the FDA’s criteria. He said the benefits in the active group were not much greater than the benefits in the placebo group. The cost of the treatment process would also put it out of the reach of many, if not most, potential patients. “MDMA treatment would add huge costs to the treatment system while providing only a small, specific benefit — and thus result in a massive misallocation of already very scarce resources.”

There is the cost of training therapists for psychedelic-assisted therapy as part of that expense. MAPS already oversees its own therapist education program. But the standards and requirements from the FDA are still not specified for MDMA-assisted therapy. “Drug-assisted therapy hasn’t been approved before, so there’s not a lot of precedent.” Then there is the variability of the price for assisted therapy. MAPS “will not manage how much the therapy component will cost.”

In a Nature news article, “Psychedelic drug MDMA moves closer to US approval,” Eric Turner, a psychiatrist at Oregon Health & Science University (and a former reviewer of psych drugs for the FDA), said while the reported difference between the MDMA and placebo groups was impressive, he doubted it was as big as it seems because it wasn’t a blinded study. “Around 94% of people who received the drug and 75% of those who didn’t correctly guessed which group they were in.” He added that even if MDMA was a safe substance, the study didn’t meet the FDA’s usual criteria for a well-controlled study. Jennifer Mitchell, the lead author for “MDMA-assisted therapy for moderate to severe PTSD,” worried about people trying MDMA on their own, where it could be harmful for those with heart conditions or with a family history of schizophrenia, which could be triggered by the drug.

I’ve been following the MAPS progress with MDMA-assisted therapy since 2016. And I’ve also wondered about the associated proliferation of psychedelic start-ups in “Psychedelics Are Not a Magic Bullet.” With the examination of the rhetoric and published spin on the two studies of the clinical trials for MDMA-assisted therapy, I think it almost appears to be a “con job” of rhetoric instead of the steady, progressive march towards the approval of a novel treatment for PTSD. And it seems I am not alone.

Psychologist James C. Coyne was critical of what he saw as a well-orchestrated publicity campaign by the funders of the MDMA research done by MAPS in “The MDMA-Assisted Therapy for PTSD Study: What You’ll Get Wrong.” He focused his critique initially on an older New York Times article, which he accused of “shilling for the promoters of psychedelics.” He likened the clinics dispensing psychedelics for mental health treatment to “expensive spas where customers can go without a diagnosis of mental disorder and have a guided psychedelic experience.” He said:

Readers, including even experts, are falling for a hard sell job by venture capitalists who launder their funding of the study through a nonprofit foundation [i.e., MAPS] and seek not legalization of psychedelics and related illegal drugs but lucrative control over their use for therapeutic and recreational use.

The potential dangers with MDMA are real and even acknowledged by researchers like Jennifer Mitchell, the lead author of “MDMA-assisted therapy for severe PTSD.” She conceded the expense and time intensity of MDMA-assisted therapy and the concern of addiction. In Psychiatrist.com, she said: “Just like all the other amphetamines, you want to be very careful with them, to not over-administer, and to make sure that somebody doesn’t have an addictive tendency to the amphetamine.” You wouldn’t send it home with people to do in their own living room. “You do it in a good, trained treatment facility and that way, you don’t have to worry as much.”

But people will try it at home in their own living room unless its only dispensed in a treatment setting with trained therapists. But this adds to the expense and time intensity of MDMA-assisted therapy. And also leads to Coyne’s expectation of expensive, spa-like treatment centers.

Mitchell thinks younger generations and the prevalence of psychostimulant use among millennials and Gen Zers with ADHD will make them more accepting of psychedelic, MDMA therapies. She also looks to how MDMA has completely transformed some patients. “That’s typically the kind of change that takes years to occur in psychotherapy.”

But this does not change the fact that there is a lack of research on the impact of MDMA on the entire brain and its long-term effects Psychedelic researchers, including MAPS, don’t allow participants in their studies who suffer with comorbidities. The participants are PTSD without co-occurring like the ones noted previously—substance use disorder, eating disorders, depression, autism, compulsive disorders, schizophrenia and anxiety. Mitchell herself said, “We don’t yet know what these compounds in general—but MDMA in particular—do to those people who have these other disorders.” Could it make the depression worse, increase anxiety, or compound the substance use diagnosis in some participants?

Let’s not roll the dice with MDMA and PTSD. And let’s be sure the research studies are done in a way that clearly demonstrates its potential to heal an individual and not just give them a substance use problem or an intensified mental health disorder. Let’s insist that Phase 3 clinical trials for MDM and other psychedelics have at least the recommended 300 participants and a more credibly double-blinded methodology.

09/19/23

Don’t Roll the Dice with MDMA, Part 1

Photo by lil artsy: pexels.com

Rick Doblin, the founder and Executive Director of MAPS, the Multidisciplinary Association for Psychedelic Studies, was interviewed on Fox Business in January of 2023. He announced that the MAPP2 clinical trial study was completed in November of 2022 and had achieved its objectives. With two confirmatory Phase 3 Trials now completed, Doblin thought it “quite likely” the FDA will approve MDMA-assisted therapy by May of 2024. He predicted the significance FDA approval of MDMA-assisted therapy would be for the “whole field of psychedelic-assisted therapy” (i.e., for psilocybin, ibogaine, ayahuasca, mescaline and others). He added that MDMA was a therapy drug in the 1970s before it became the party and “rave” drug, ecstasy.

In the interview, Doblin emphasized that it was therapy that was main change agent. “It’s not the drug itself; it’s the therapy that is the primary act of treatment. And the MDMA, the medicine, makes the therapy more effective.” Don’t miss what he is saying—the therapeutic process is the primary treatment and the MDMA facilitated the therapy. Nevertheless, the results reported in the MAPS studies were dramatic.

In Mapp1, 67% of the participants in the MDMA-assisted group “no longer qualified for a PTSD diagnosis” after three treatment sessions. Another 21% had a clinically meaningful response, adding up to 88% of participants in the MDMA-assisted therapy group experienced a clinically meaningful reduction in symptoms. These participants also had statistically significant reductions in functional impairment relative to the placebo group with therapy. However, 32% of the placebo with therapy group also no longer met the criteria for PTSD. This percentage of change in the placebo group underscores the importance of the therapy as the primary change agent emphasized by Doblin. See the following graphic.

The results of the MAPP1 clinical trial were published in Nature Medicine, “MDMA-assisted therapy for severe PTSD” and provide a more detailed examination of the data underlying the Phase 3 trail results reported in the above graphic.

The study abstract reported the standard methodology used in the study as “randomized, double-blind, placebo-controlled” and that the placebo itself was inactive. The small number of participants in the study groups was also noted. There were 42 individuals in the MDMA-assisted group and 37 individuals in the placebo group. Turning to the celebrated primary endpoint of the study being met by 67% of the study participants, there were only 28 participants who no longer met the diagnostic criteria for PTSD. The researchers acknowledged that the participant population was smaller than originally planned, which they attributed to the pandemic. They then pointed to the results, saying “given the power noted in the study, it is unlikely that population size was an impediment.” Really?

The FDA described how researchers should design clinical trials to answer specific research questions for a medical product here, saying “Clinical trials follow a typical series from early, small-scale, Phase 1 studies to late-stage, large scale, Phase 3 studies.” Phase 3 clinical studies, like MAPP1 And MAPP2 were recommended to contain 300 to 3,000 participants who have the condition; and the length of study to be 1 to 4 years. The MAPP1 study only had 79 participants; and the length of the study was only 18 weeks. The Procedural timeline in “MDMA-assisted therapy for severe PTSD” said: “Following the screening procedures and medication taper, participants attended a total of three preparatory sessions, three experimental sessions, nine integration sessions and four endpoint assessments (T1–4) over 18 weeks, concluding with a final study-termination visit.”

The double-blindedness of the study was also neutralized by using an inactive placebo, given the psychoactive properties of MDMA. Participants as well as the researchers and others who assisted in the study (i.e., the trained therapy team) would know in which study group the “blinded” participants were in by observing participant’s behavior after they ingested the supposedly unknown substance. This limitation was acknowledged by the researchers:

Given the subjective effects of MDMA, the blinding of participants was also challenging and possibly led to expectation effects. However, although blinding was not formally assessed during the study, when participants were contacted to be informed of their treatment assignment at the time of study unblinding it became apparent that at least 10% had inaccurately guessed their treatment arm. Although anecdotal, at least 7 of 44 participants in the placebo group (15.9%) inaccurately believed that they had received MDMA, and at least 2 of 46 participants in the MDMA group (4.3%) inaccurately believed that they had received placebo.

Anecdotally then, 95% of the MDMA-assisted group (44 of 46) and 84% of the placebo group (37 of 44) were able to accurately state which research group they were in. The double-blind methodology was clearly ineffective and the dramatic results reported by the study should be understood with this in mind. Emphasizing the differences between the MDMA-assisted group and the placebo group for the lost PTSD diagnosis and a clinically meaningful response draws the readers attention away from these damning limitations for a Phase 3 clinical trial study: the miniscule population size and the failure to use a legitimately double-blinded study methodology.

The MAPP2 Clinical trial was completed on November 2, 2022, and MAPS announced the results on November 17, 2022. The primary and secondary endpoints for the MAPP1 and MAPP2 studies were the same. However, MAPP2 enrolled participants with moderate and severe PTSD, where MAPP1 only enrolled participants with severe PTSD. It had 104 participants.

The results for MAPP2 are expected to be in a peer-reviewed journal sometime in 2023: “The full data from MAPP2, expected to be published in a peer-reviewed journal later this year [2023], will support MAPS PBC’s new drug application to be filed with the U.S. Food and Drug Administration (FDA).” MAPP2 treated its 104 participants “living with PTSD with either MDMA-assisted therapy or placebo with therapy.” The results were said to confirm the findings from MAPP1, with no serious adverse events observed among the participants. Rick Doblin was quoted as saying:

When I first articulated a plan to legitimize a psychedelic-assisted therapy through FDA approval, many people said it was impossible. Thirty-seven years later, we are on the precipice of bringing a novel therapy to the millions of Americans living with PTSD who haven’t found relief through current treatments. The impossible became possible through the bravery of clinical trial participants, the compassion of mental health practitioners, and the generosity of thousands of donors. Today, we can imagine that MDMA-assisted therapy for PTSD may soon be available and accessible to all who could benefit.

MAPS went on to give a brief history of where MDMA had been legally used in therapy for a decade before it was “criminalized” (i.e., classified as a Schedule 1 Controlled Substance) in 1985. MAPS was founded the next year “to fund and facilitate research into the potential of psychedelic-assisted therapies; educate the public about psychedelics for medicine, social, and spiritual use; and advocate for drug policy reform.” The publication of the MAPP1 clinical trial was said to be a major milestone. MDMA-assisted therapies are being planned or conducted to evaluate “conditions closely related to PTSD” such as substance use disorder and eating disorders. Trials of other therapies with couples and group therapy among Veterans are also being planned or conducted.

“These additional Phase 2 trials will determine if MDMA-assisted therapies may be effective for other conditions or with other treatment modalities commonly used to address PTSD.”

Psychiatrist.com echoed these expectations if the FDA approves MDMA-assisted therapy, adding that approval would enable the exploration of the drug’s benefit for depression, anxiety, substance-use disorders, autism spectrum disorder, and compulsive disorders. The lead author of “MDMA-assisted therapy for severe PTSD” described for Psychiatrist.com how MDMA acts on the amygdala, the part of the brain that processes fear-related memories and facilitates memory retrieval. When used in a clinical setting (i.e., with therapy), “they say it helps untangle, consolidate, and release deeply-ingrained memories that may have been suppressed.” MDMA also facilitates the release of oxytocin, a hormone that makes you feel self-compassion and connected to others. The end result is MDMA helps create an environment in which “participants take comfort in their therapy team, approach their memories from a different lens, and ultimately begin to heal.”

This description of MDMA and oxytocin needs to be nuanced, as it glosses over some of the not-so positive connections made with the release of oxytocin. In “The two faces of oxytocin,” the American Psychological Association said recent research has shown that oxytocin is part of a response to social separation and related stress. When it operates during times of low stress, oxytocin physiologically rewards people with good social bonds with feelings of well-being. However, it may “lead people to seek out more and better social contacts” during times of high social stress or pain. This two-faced context for MDMA facilitating the release of oxytocin again underscores the importance of the therapeutic aspect of MDMA-assisted therapy.

Should the FDA approve MDMA-assisted therapy? Should we roll the dice and see what happens? A recent survey noted Americans have mixed feelings. According to the 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.

And yet, there were 35% who opposed it, with 61% also saying they do not see psychedelics as “good for society” and 69% who don’t think psychedelics are something they would personally use. “The data suggested voters are open to policy change but also have significant reservations.”

A reliable answer to whether the FDA should approve MDMA-assisted therapy is hampered by the Schedule I classification of psychedelics, which creates multiple hurdles that researchers have to get over in order to investigate their therapeutic value. And further, it seems supporters of psychedelic-assisted therapies are following a strategy taken from the playbook of legalizing recreational marijuana—focus on the legalization of psychedelics one state at a time. More on this in Part 2.

10/18/22

Back to the Future with Psychedelics

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

04/5/22

The Psychedelic Pendulum and Psychiatry, Part 1

© rolffimages | 123rf.com. Opened door to another dimension.

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

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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

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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.

05/7/19

Psychedelic Renaissance?

© Jozef Klopacka | 123rf.com

Spravato (esketamine), a chemical cousin of ketamine (Special K), was recently approved by the FDA as a fast-acting antidepressant. MDMA is now in a Phase 3 clinical trial for PTSD. Psilocybin has received a breakthrough therapy designation for treatment-resistant depression by the FDA. Clinical research into the therapeutic effects of psychedelics has resumed for a variety of conditions, including depression, substance abuse and individuals living with serious medical conditions like cancer. This has led to calls for increasing the availability of psychedelics by loosening the regulatory restrictions that currently limit the drugs’ use for research.

In his book, How to Change Your Mind, Michael Pollan said beginning in the 1990s, a small group of scientists, psychotherapists and so-called “psychonauts,” have sought to resurrect what they saw as a wrongful termination of research into the therapeutic value of psychedelics. “A new generation of scientists, many of them inspired by their own personal experience of the compounds, are testing their potential to heal mental illnesses such as depression, anxiety, trauma and addiction.” Others are using psychedelics in conjunction with brain-imaging technology to explore the links between brain and mind. “The hoary 1960s platitude that psychedelics offered a key to understanding—and ‘expanding’—consciousness no longer looks quite so preposterous.”

Psychedelics are currently classified as Schedule I controlled substances, meaning they have a high abuse potential; no accepted medical use; and have safety concerns, even under medical supervision. Some advocates are calling the DEA to place them into Schedule III, along with ketamine, anabolic steroids and buprenorphine. Writing for Scientific American, Rick Strassman described his own research with DMT in the 1990s. One of the most difficult impediments he faced was DMT being Schedule I.

After nearly two years of close work with FDA and DEA, an effective system developed allowing our studies to proceed. My subsequent applications to use psilocybin and LSD were much more quickly and easily approved. The New Mexico project’s success established the current American regulatory framework that has allowed for the current burgeoning of human studies with psychedelics.

Psychedelics have unique characteristics that make it difficult to fit them into the criteria used to define schedule placement. “Their safety and efficacy exist only within highly structured specialized treatment settings.” Outside of that structure, psychedelics retain their ability for abuse and are capable of debilitating, psychological damage. “How one understands the psychedelic drug state determines the assessment of risks and benefits, and thus drives recommendations for rescheduling.” William Richards, the clinical director for the John Hopkins University psychedelics research program, publicly advocates for the increased availability of the drugs, referring to their ‘inherent spirituality’ in lectures and talks.

Glorifying psychedelics’ benefits and rendering innocuous their adverse effects therefore may explain the Hopkins group’s recent publication of a paper suggesting rescheduling psychedelics into Schedule IV—the most liberal recommendation yet to appear.

Strassman suggested a new category—IA—that would acknowledge psychedelics’ abuse potential, while allowing for their use. “The security requirements established by the DEA for possession of psychedelics for clinical research—background checks of those handling the drugs, secure storage, regular inventory, etc.—would be the same as for Schedule I substances.” Significantly, only those with specialized training would be permitted to administer psychedelics to humans. With such a regulatory structure in place, He thought the clinical promise of psychedelic drugs could be realized without exposing patients to unnecessary risk. “It would also ensure that we maintain scientific rigor, intellectual honesty and high ethical standards as we continue investigating how these drugs produce their fascinating effects.”

One study published in the Journal of Psychopharmacology did produce some interesting effects with psilocybin. Two randomized controlled trials with late-stage cancer patients suggested that a single, high dose of psilocybin had “clinically significant and long-lasting effects on mood and anxiety.” There were no serious adverse events; no participants abused psilocybin; no cases of prolonged psychosis or hallucination. “No participants required hospitalization.”

Single moderate-dose psilocybin, in conjunction with psychotherapy, produced rapid, robust, and sustained clinical benefits in terms of reduction of anxiety and depression in patients with life-threatening cancer. This pharmacological finding is novel in psychiatry in terms of a single dose of a medication leading to immediate anti-depressant and anxiolytic effects with enduring (e.g. weeks to months) clinical benefits. Even though it is not possible to attribute causality of the experimental drug (in terms of sustained clinical benefit) after the crossover, the post-crossover data analyses of the two dosing sequences suggest that the clinical benefits, in terms of reduction of cancer-related anxiety and depression, of single-dose psilocybin (in conjunction with psychotherapy) may be sustained for longer than 7 weeks post-dosing, and that they may endure for as long as 8 months post-psilocybin dosing. The acute and sustained anti-depressant effects of psilocybin in this trial are consistent with a recently published open-label study of oral psilocybin treatment in patients with treatment-resistant depression (TRD) in which psilocybin (25 mg) was associated with 1 week and 3 months post-psilocybin anti-depressant effects.

Reflecting on the results of the study, Stephen Ross, MD, the director of Substance Abuse Services at the Langone Medical Center, said it possibly provides a new model in psychiatry. “This is potentially earth shattering and a big paradigm shift within psychiatry.” David Nutt, MD, PhD, of the Imperial College London said the studies were the “most rigorous controlled studies to date” using psilocybin. Others urged caution applying and interpreting the results. Jeffrey Lieberman, MD, from Columbia University said:

[W]e cannot tell if the anxiolytic and antidepressant effects of the drugs are direct results of their serotonergic effects or secondary to the mystical altered state of consciousness that they produce. Since other serotonergic agonists (eg, lisuride) do not produce this psychedelic experience it has been suggested that psychedelic drugs must bind to the 5-HT2A receptors in a special way or exhibit functional selectivity or receptor bias.”

A study of the abuse potential for psilocybin confirmed low abuse and no physical dependence potential. The study used all 8 factors required to guide the FDA and DEA recommendations for the Controlled Substance Act (CSA). They suggested placement as a Schedule IV Controlled substance. There was “no clear evidence of physical dependence and withdrawal in preclinical or clinical studies, or among those who chronically used illicit products.” The authors said the lack of therapeutic and mechanistic studies of psilocybin and other psychedelics stems from the lack of federal funding for the research and the barriers imposed by a Schedule I classification, not a lack of interest among researchers.

While some psychedelics like psilocybin may be viable therapeutic options, there simply isn’t enough modern controlled trials. James Rucker, MD, MRCPsych, PhD, of the King’s College London Institute of Psychiatry, said: “Psychedelics deserve to be investigated in modern, controlled trials if we are to know whether they are useful treatments in psychiatry, or not . . .  At the moment there isn’t enough high-quality evidence to make that judgment.”

The biggest barrier to their wider use likely stems from the lack of research. Buy there are additional obstacles in doing the research. Most pharmaceutical companies aren’t interested because of the legal obstacles with Schedule I substances and because it’s not profitable to develop treatments with these drugs. The FDA approval of esketamine as a new molecular entity (NME) is the exception. Another problem is the impossibility of using a placebo control or blinding because of the identifiable effects from psychedelics. Finally, there is the challenge of obtaining sources of psilocybin that meet the standards required for the clinical trials. Rucker said:

I think everyone in this field is interested in one thing — that psychedelics get a fair hearing by Western medicine by undergoing well-funded, well-designed controlled trials . . . Then we will know whether they have any benefit, and we can judge whether this benefit is suitably balanced against any harm they might do. Until then we won’t know, and that is a worse state of affairs than knowing.

Benjamin Bell, from John Hopkins University, wrote “The psychedelic renaissance is here.” He is a proponent of psychedelic medicine, and gave a clearly biased history of how research into psychedelics was “turned off,” after Timothy Leary made the phrase “turn on, tune in, drop out” famous. “Researchers in the field are posed at the precipice of progressing forward with revolutionary studies and may conscientiously move our culture forward with them. But moving the culture will require awareness and action from scientists and citizens.” Researchers believing that psychedelics are important and useful need to recognize how that faith is a double-edged sword “and we must remain truly willing to reconsider beliefs in light of new evidence, or it will be impossible to convince the broader public to do the same.”

Researchers have the opportunity and responsibility to properly communicate their findings and recommendations to the public. He thought this was vital if psychedelics were to be integrated into medical use within the wider culture. Meaningfully, he then said: “It is important to remember psychedelics are not the ultimate panacea for treating mental health concerns.” With time and reams of further research, they may become invaluable components of the medical and mental health toolkit. If the research is carefully and systematically done, I’d cautiously agree.

Let’s not repeat the mistake made with marijuana—failing to reschedule it so research into its risks and benefits is easier to do. The science—not the rhetoric—should be the deciding factor in the medicalization and the legalization of psychedelic substances. Rescheduling psychedelics as suggested by Rick Strassman seems reasonable and would permit the researchers holding back from doing psychedelic research to forge ahead. Some psychedelics, like psilocybin, appear to have potential while ketamine and the ketamine knockoff Spravato increasingly ring alarm bells for me because of their abuse potential and the quickness with which their effects seem to fade. For more information on ketamine and esketamine, see: “Hype and Concern with Esketamine” and “Is Ketamine Really Safe & Non-Toxic?”

01/29/19

Turn On, Tune In, Drop Out

Credit: YouTube

At the end of the Second World War in 1946 the Army wanted to show how new “experimental” treatments at the time, hypnosis and injections of sodium pentothal, were helping psychiatric casualties of war. These cases of “battle neurosis,” what we now call PTSD, were highlighted in a documentary called “Let There Be Light.” John Houston spent two months filming the documentary at Mason General Hospital. We see a paralyzed man (with no physical injury to explain it) walk; a soldier with amnesia regained his memories; and a man with a severe stutter cured. Then the Army prohibited Houston from releasing the film; it wasn’t until 1980 that it was released to the public.

Houston thought the reason it was sidelined was the film contradicted how the government portrayed the returning soldier. The film opened with this quote: “About 20% of all battle casualties in the American Army during World War II were of a neuropsychiatric nature.” In his autobiography he said: “I think it boils down to the fact that they wanted to maintain the ‘warrior’ myth, which said that our Americans went to war and came back all the stronger for the experience, standing tall and proud for having served their country well.” The official, flimsy, reason given was it was a violation of the soldiers’ privacy. Yet “the soldiers themselves were knowingly and consensually filmed.” It seems that Houston was too realistic.

None of the scenes were staged. “The cameras merely recorded what took place in an Army Hospital.” Writing for ZeroHedge, Tyler Durden said although the film intended to optimistically show the new treatments unavailable to soldiers of previous wars, but the audience takeaways were not positive. Instead of showing the potential for healing, audiences remembered “the psychosomatically paralyzed soldier being carried into a room, the trembling amnesiac, and the incommunicable stuttering of a psychologically damaged man.”

The soldier’s joy at the successful treatment did not explain, for audiences unfamiliar with such psychological phenomena, how such a problem could manifest. In all three cases of treatment, Huston believed he was showing the world the tremendous breakthroughs of psychiatric medicine, but instead, he showcased the horrors of war, without even having to visit a battlefield.

“Battle neurosis” was known as “shell shock” in World War I. Within the first edition of the Diagnostic and Statistical Manual (DSM) it was “gross stress reaction,” which would become posttraumatic stress disorder in the third edition. By then we had the Korean War, the Vietnam War and their portrayals on television and in the movies with the Deer Hunter, Apocalypse Now, MASH and others.

I wonder if another reason the Army decided to suppress Let There Be Light was a 1946 movie with Dana Andrews, Myrna Loy and Fredric March called “The Best Years of Our Lives.” It told of the difficult and traumatic adjustments of three servicemen returning home after WWII. We see problems with alcoholism, unemployment and adultery. Samuel Goldwyn was inspired to make the movie after reading an article in Time about the problems experienced by men returning to civilian life. It won seven Academy Awards, including Best Picture. And it was the highest grossing and most attended film in the US and UK since Gone with the Wind.

These days ecstasy or MDMA is seen as a promising treatment for PTSD. The British medical journal The Lancet published a study of 26 individuals with chronic PTSD who were not helped by traditional methods. The New York Times reported “The improvements were so dramatic that 68 percent of the patients no longer met the clinical criteria for PTSD.” There were also improvements with sleep and becoming more conscientious.

The results, which mirror those of similar, small-scale studies of the illegal drug in recent years, come as MDMA is about to enter larger, Phase 3 trials this summer. Based on previous results, the Food and Drug Administration has given MDMA breakthrough therapy status, which could speed approval. If large-scale trials can replicate safety and efficacy results, the drug could be approved for legal use by 2021.

If approved by the FDA, MDMA would only be administered after three sessions of therapy by a licensed psychotherapist. During the fourth session, the patient takes the MDMA, and two therapists—one male and one female—are at the patient’s side as guides. Dr. Michael Mithoefer, lead author of The Lancet study said: “We encourage them to set aside all expectation and agenda and be open. Experiences tend to be very individual.” The drug releases hormones and neurotransmitters facilitating feelings of trust and wellbeing, allegedly allowing patients to re-examine traumatic memories.

The large-scale trials, which began in the summer of 2018, included up to 300 participants at 14 sites. Phase 3 trials are expected to cost $27 million. The funding comes from donations, not Pharma. David Bonner, of Dr. Bonner’s Magic Soaps, gave $5 million, as did an anonymous donor only known as Pine.

There is a possibility they will not be able to replicate the success of the previous trials. Yet there is a current lack of effective therapy for PTSD. “Only about one in three combat veterans with PTSD are effectively treated.”

The study was sponsored by the Multidisciplinary Association for Psychedelic Studies (MAPS). According to a MAPS press release, the study replicated previous research with an acceptable risk profile for MDMA. The most frequently reported adverse reactions were anxiety, headache, fatigue, and muscle tension.

MDMA was originally patented by Merck in 1912, but never marketed and the patent lapsed. The FDA would grant temporary data exclusivity to MAPS, giving it a five-year monopoly in the U.S. MAPS plans to funnel sales to a for-profit corporation, which would then return the money for more clinical research into the use of MDMA with other disorders. Rick Doblin, the founder of MAPS, has a vision for legalizing MDMA. See “Give MDMA a Chance?” for more on MAPS and Doblin.

But there are risks, despite the potential of MDMA. It can cause anxiety and increase stress. Chronic use may cause memory impairment. At high doses, it can cause your body to overheat. Chronic use may cause memory impairment. The National Institute on Drug Abuse (NIDA) said MDMA affects the brain by increasing the activity of at least three neurotransmitters: serotonin, dopamine, and norepinephrine. “Like other amphetamines, MDMA enhances release of these neurotransmittersand/or blocks their reuptake, resulting in increased neurotransmitter levels within the synaptic cleft (the space between the neurons at a synapse).” Releasing large amounts of serotonin causes the brain to become depleted of this neurotransmitter, contributing to the negative psychological aftereffects some people experience for several days after taking MDMA.

Low serotonin is associated with poor memory and depressed mood, thus these findings are consistent with studies in humans that have shown that some people who use MDMA regularly experience confusion, depression, anxiety, paranoia, and impairment of memory and attention processes. In addition, studies have found that the extent of MDMA use in humans correlates with a decrease in serotonin metabolites and other markers of serotonin function and the degree of memory impairment. In addition, MDMA’s effects on norepinephrine contribute to the cognitive impairment, emotional excitation, and euphoria that accompanies MDMA use.

Rick Doblin has been trying to achieve a legal justification for MDMA use for decades. Unlike Timothy Leary, he sought to embrace the dominant culture instead of turning on, tuning in, and dropping out. And he just may achieve his goal, with MDMA therapy for PTSD now in Phase 3 clinical trials. I suspect Doblin is not just trying to help facilitate more effective treatment for PTSD. Rather, it is a means to an end—an end parallel to that of Timothy Leary.

Leary first used the phrase “turn on, tune in, drop out” in a speech he gave on September 19,1966. His purpose was to encourage people to detach themselves from existing conventions in society by embracing the use of psychedelics. “Like every great religion of the past we seek to find the divinity within and to express this revelation in a life of glorification and the worship of God. These ancient goals we define in the metaphor of the present—turn on, tune in, drop out.” In his 1983 autobiography he explained what he had meant by the use of this metaphor:

“Turn on,” meant go within to activate your neural and genetic equipment. Become sensitive to the many and various levels of consciousness and the specific triggers that engage them. Drugs were one way to accomplish this end. “Tune in,” meant interact harmoniously with the world around you—externalize, materialize, express your new internal perspectives. “Drop out,” suggested an active, selective, graceful process of detachment from involuntary or unconscious commitments. “Drop Out” meant self-reliance, a discovery of one’s singularity, a commitment to mobility, choice, and change. Unhappily my explanations of this sequence of personal development were often misinterpreted to mean: “Get stoned and abandon all constructive activity.”

I suspect we will see more of the same if MDMA is approved for the treatment of PTSD.