Tag: MAPS

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.

06/4/24

Don’t Legalize Psychedelics Until the Guardrails Are In Place

Image by Ratfink1973 from Pixabay

Starting in the Summer of 2023, there was a flurry of announcements about psychedelics being used to treat psychiatric disorders. Australia became the first country to permit psychiatrists to prescribe psychedelics for depression or post-traumatic stress disorder (PTSD). MAPS formally submitted a New Drug Application to the FDA for the approval of MDMA-assisted therapy for PTSD. California passed Senate Bill 58, which would decriminalize psychedelics and make several naturally occurring psychedelic substances like psilocybin, and mescaline legal within the state. But then, Governor Newsom vetoed the bill, saying more needed to be done before decriminalizing hallucinogens.

The legislation would have required the California Health and Human Services Agency to make recommendations to lawmakers on the therapeutic use of psychedelics after their decriminalization. Newsom vetoed Senate Bill 58 because there were no existing regulated treatment guidelines; no dosing information or therapeutic guidelines. There wasn’t a medical clearance attesting there were no underlying psychoses; or rules against exploitation during guided treatments. He said: “Unfortunately, this bill would decriminalize possession prior to these guidelines going into place, and I cannot sign it.”

The Associated Press noted how public opinion has shifted to support the therapeutic use of psychedelics. Psilocybin was designated as a “breakthrough therapy” for depression in 2019 and the FDA published guidelines on clinical trials with psychedelic drugs. MAPS anticipates an FDA decision on MDMA-assisted therapy very soon. The FDA acknowledged this growing interest in the therapeutic potential of psychedelic drugs and noted a need for applicants to attend to various conditions in order to facilitate its review process of psychedelics. “Designing clinical studies to evaluate the safety and effectiveness of these compounds presents a number of unique challenges that require careful consideration.”

The document describes basic considerations throughout the drug development process including trial conduct, data collection, subject safety and new drug application requirements. For example, psychedelic drugs may produce psychoactive effects such as mood and cognitive changes, as well as hallucinations. As a result, there is the potential for abuse of these drugs, which is a drug safety issue that requires careful consideration and putting sufficient safety measures in place for preventing misuse throughout clinical development. For psychedelics that are currently Schedule I controlled substances, the draft guidance notes that activities associated with investigations under an Investigational New Drug Application must comply with applicable Drug Enforcement Administration regulatory requirements.

The California Coalition for Psychedelic Safety and Education, which opposed Senate Bill 58 thought more safeguards were necessary before decriminalization of psychedelics in California. “We’re grateful that Governor Newsom listened to some of the top medical experts, psychedelic researchers and psychiatrists in the country who all warned that legalization without guardrails was at best premature for both personal and therapeutic use.” They thought there should be public education campaigns, safety protocols and emergency response procedures “to keep Californians safe.”

The Australian announcement noted above surprised some scientists in that country when it was made. The Australian & New Zealand Journal of Psychiatry published an editorial by psychiatrist Steve Kisley, “The down-scheduling of MDMA and psilocyin(e): Too fast and too soon.” Australia’s Therapeutic Goods Administration (TGA) had rejected a petition to down-schedule both substances as recently as 2020. As a result of criticism, the TGA commissioned an independent report into the risks and benefits of MDMA and psilocybin.

The report concluded while the substances showed promise in highly selected populations in closely supervised settings, the trial quality was variable “with only small proportions of potential participants included in randomised comparisons.” The certainty of evidence was rated low or very low using the Cochrane Collaboration’s GRADE framework.  The TGA confirmed its decision, but inexplicably approved the down-scheduling of MDMA for PTSD and psilocybin for treatment-resistant depression. Dr. Kisley said:

In the view of this author of the independent report to the TGA, the decision to down-schedule is ahead of the available scientific evidence especially as unresolved issues remain surrounding relapse, long-term safety and the challenges of conducting randomised controlled trials in this area.

The wisdom of a slower, more cautious approach to decriminalizing psychedelics or approving their use to treat mental health disorders was illustrated in the May 2024 edition of the journal Addiction, where a study of hallucinogen-associated emergency department visits and hospitalizations in California from 2016 to 2022 showed increases by 54 and 55% respectively. The researchers thought this was a concerning trend, especially given that public opinion is that hallucinogens are low-risk. “There is a pressing need for broader and more rigorous tracking of the harms associated with these emerging substances on the individual and population level, especially as policy changes increase access.”

Science Alert described a recent study done at Imperial College London that highlighted the potential risks of psychedelic use and therapy for individuals with personality disorders. The study collected self-reported data from 807 people who used psychedelics in various settings, including recreational and therapeutic use. The Warwick-Edinburgh mental wellbeing scale was given before and after participants used psychedelics. Only 16% of all participants reported an overall negative response. “But a significant portion of these negative experiences (31%) [5 cases of 16] were reported by people with a history of personality disorders.”

There were several limitations to the study, including the reliance on self-reported data, a 56% dropout rate, and the small number of participants with a history of personality disorders. There were also variations in the types and doses of psychedelics used. The study’s method of participant selection may also lead to biased results. Yet, the potential benefits of psychedelics for mental health were acknowledged, “stressing the need for careful screening for personality disorders.”

Using psychedelics safely and effectively requires a personalised approach. This is especially true for vulnerable people. This highlights the importance of refining psychedelic therapy to make it safe and effective for all.

As we explore the expanding territory of psychedelic therapy, it’s vital to understand how these substances interact with mental health conditions – including personality disorders.

In a study published May 8, 2024 in Nature, Warren et al highlighted how psychedelics interacting with serotonin receptors could produce potential therapeutic benefits with depression and anxiety. In “Psychedelics Activate Serotonin to Produce Antidepressant Effect,” Audrey Warren said: “Our study highlights, for the first time, how serotonin receptors like 5-HT1A likely modulate the subjective effects of the psychedelic experience and also play a potentially pivotal role in their clinically observed therapeutic outcome.” The researchers believed their study will lead to a better understanding of the pharmacology of psychedelics involved with many receptor types. “We’ve demonstrated that psychedelics have complex physiological effects that span many different receptor types … and are now ready to build on that finding to develop improved therapeutics for a range of mental health disorders.”

But before this happens, rigorous, replicated studies of the therapeutic use of psychedelics should occur before they are decriminalized or made available to treat mental health disorders. A medical clearance procedure that screens for underlying psychoses needs to be put in place. Dosing information and regulated treatment guidelines needs to be established. In other words, don’t legalize psychedelics until the guardrails are in place to ensure the safe and effective use of these compounds.

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.

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.

03/10/20

The Unique Scientific Value of Ibogaine, Part 1

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Investigating the potential of psychedelic drugs to treat addiction has been around since the 1950s, when a British psychiatrist named Humphry Osmond first wondered in 1953 if a controlled LSD-produced delirium would help alcoholics stay sober. He would treat over 700 patients in the following ten years and Bill W., a co-founder of A.A., was one of them. Currently, there are a variety of psychedelics being investigated as treatments for conditions ranging from addictions with various drugs to PTSD. One of those is ibogaine, a psychoactive compound extracted from the West African Tabernanthe iboga plant.

Erowid said the first report of Tabernanthe iboga use as a stimulant and aphrodisiac in Gabon and the Congo was in 1864 by Griffon du Bellay, a doctor in the French Navy. A syncretic Christian church called “Bwiti,” who used Tabernanthe iboga in their initiation rites, was founded among the Fang people of Gabon in the late 19th century. In 1903 was the first report of iboga being used as a visionary plant in the Congo. By 1939 an extract of the Tabernanthe iboga plant was sold in tablet form under the name Lambarene for treating fatigue and depression. “It was popular among athletes who used it as a stimulant and to accelerate red blood cell production.”

In 1962 Howard Lotsof inadvertently discovered the anti-addictive properties of ibogaine when he realized after a several-hour trip on ibogaine, he had no withdrawal symptoms even though he had not used any heroin. He administered the drug to several of his addicted friends with similar results. He would later acquire patents for ibogaine as a treatment for acute addiction in 1985 and 1992. In 2009 he founded The Global Ibogaine Therapy Alliance (GITA), a non-profit corporation dedicated to supporting the sacramental and therapeutic uses of iboga. He has authored or coauthored several scientific papers on ibogaine and produced a web portal for scientific studies and lay information on ibogaine, the “Ibogaine Dossier.”

Ibogaine was completely synthesized in 1966, classified as a hallucinogen and made an illegal substance in the USA in 1967. It was classified then as a Schedule I substance, meaning it was considered to have a high potential for abuse and no acceptable medical use. Because of this action, most of the research into ibogaine’s use in addiction treatment has occurred outside of conventional clinical and medical settings and outside of the US.

The Ibogaine Dossier said there were two general types of ibogaine treatment. The first type is sometimes referred to as “initiatory,” and involves a dosage around 8 to 12 mg/kg; it’s used to orient users towards psychotherapeutic or spiritual insight. The other type of ibogaine treatment, which is used for addiction, involves a dosage of 15 to 25 mg/kg, twice as much as an initiatory dose. Lotsof’s early “research” reported that he gave up to 19 mg/kg to a total of 20 individuals.

A subset (n= 7) of Lotsof’s individuals were heroin addicts who reported the alleviation of physical dependence and cravings. Five of the seven individuals reportedly remained free of heroin for 6 months or more following their treatment with ibogaine. “The activity of the group eventually ceased in 1963 when FDA and law-enforcement agencies eliminated the ability of S&L Laboratories, as Lotsof put it, ‘to procure drugs and administer them to interested persons.’” The pharmaceutical industry was not interested at the time in developing ibogaine, viewing addiction as an economically unattractive area for medication development.

But Lotsof and others persisted in their efforts to do research and provide treatment with ibogaine. Lotsof organized a company, NDA International, which provided research funding to Dr. Stanley Glick at Albany Medical College, who demonstrated ibogaine decreased the intake of morphine in rats. See here and here for Glick’s 1991 articles on his research. Glick would continue his research on “iboga” for the next ten years and generate a body of work with over 60 peer-reviewed articles on ibogaine and related compounds. His work has been supported by the National Institutes of Health (NIH).

NDA International recruited and treated patients in the Netherlands because ibogaine treatment could not be legally provided in the US. A total of 40 to 45 individuals were treated between 1989 and 1993 in the Netherlands. “The data from these treatments, together with the 20 subjects treated in the United States by Lotsof between 1962 and 1963, provide the principal source of the case study evidence that has been presented to the National Institute on Drug Abuse (NIDA) and the FDA.” But the death of a female patient in the Netherlands in June of 1993 ended the treatments there by NDA International. Although the official Dutch inquiry into the woman’s death was not conclusive, it nevertheless decreased the enthusiasm to do further investigations with ibogaine.

Kenneth Alper said in “Ibogaine: A review” that while the death of the 24-year-old woman during a heroin detoxification treatment was a significant factor in the NIDA decision not to fund a clinical trial in 1995, “Forensic pathological examination revealed no definitive conclusion regarding the probable cause of death.” There was some evidence that suggested the possibility she had secretively used opioids, presenting another element of uncertainty for her death. He then added: “There is evidence suggesting that the interaction of opioids and ibogaine potentiates opioid toxicity.”

However, in 1991 there was some interest in ibogaine research sparked with Deborah Mash, a faculty member in the Department of Neurology of the University of Miami. In a 1996 radio interview, she said she became interested in ibogaine after hearing a presentation by Dr. Glick on his research with ibogaine and rats. Dr. Mash organized a clinical trial of ibogaine and received approval of an Investigational New Drug Application from the FDA. The study began in December of 1993, but was eventually suspended as result of the unavailability of grant support. She said the ibogaine molecule was unique, doing something to human consciousness, “something to the brain, something to craving and withdrawal signs that’s very different than anything we know about right now.”

Ibogaine has a very unique structure, it’s almost as if that plant has created a magical structure that has a very rigid backbone, that is somewhat seratonin-like. Seratonin is a neurotransmitter that is associated with drugs like Prozac and with depression and changes in the brain that are normal with aging. Ibogaine also has another alkaloydal piece that hangs off the side of this rigid backbone that seems to resemble cocaine. It’s a molecule that seems to have affinity for the opiate side, and has some affinity for the cocaine side and as a pharmacologist that really grabbed my attention. There’s something real fundamental about this molecule that maybe explains its efficacy, and if these anecdotal reports that were out there in the addict self-help movement were true and could be validated, then together with our knowledge of the structural chemistry of the molecule, we might get some fundamental insight into the process of addiction itself.

This was not the end of Dr. Mash’s research and treatment efforts with ibogaine. In 1998 she coauthored a study into the safety, pharmacokinetics and dose effects of ibogaine and its metabolite, noribogaine in cocaine-dependent patients. In 2001 she coauthored a chapter in The Alkaloids: Chemistry and Biology, “Ibogaine in the treatment of heroin withdrawal.” Along with her coauthors, Dr. Mash found ibogaine to be effective in blocking opiate withdrawal. However, it has complex pharmacokinetics and an uncertain mechanism of action with regards to treating opiate dependency. The authors suggested “Identifying noribogaine’s mechanism of action may explain the way ibogaine promotes rapid detoxification from opiates after only a single dose.”

In a 2016 a study of noribogaine, Mash and others investigated the effects it had on substance-related disorders. Their findings suggested the metabolite noribogaine rather than ibogaine mediated the effects of ibogaine blocking withdrawal. “Noribogaine may hold promise as a non-addicting alternative to standard opiate replacement therapies to transition patients to opiate abstinence.” Then in 2018 Mash and others published a study whose results “Confirms the original claims made by Howard Lotsof.” It demonstrated that medically assisted ibogaine detoxification was a safe and effective method to discontinue substance dependence or misuse. Dr Mash has published additional studies with ibogaine besides those mentioned here.

MAPS, the Multidisciplinary Association for Psychedelics, has been supportive of research into the use of ibogaine to treat addiction and has an extensive listing of research updates, news and event announcements on a variety psychedelic drugs, including ibogaine. It also funded two observational studies of the long-term effects of ibogaine treatment in Mexico and New Zealand. The Mexican study reported on outcomes up to one year following opioid detoxification with ibogaine of 30 individuals with OUD (opioid use disorder). Participants were followed up at intervals of 1, 3, 6, 9 and 12 months. The results indicated that ibogaine had a substantial treatment effect in opioid detoxification and appeared to reduce drug use at one month, which was sustained up to 12 months in a subgroup of subjects. “No clinically significant cardiovascular or other medical events occurred in this study.”

The New Zealand study was a prospective observational case series of 14 participants seeking ibogaine treatment for opioid dependence and who were committed to regular contact for 12 months post-treatment follow up. “Consistent with preceding studies, evidence showed significant attenuation of withdrawal, sustained reduction in drug craving/use, and cessation of use in some cases.” This sustained reduction occurred in 12 of 14 participants. One patient died during treatment before they were formally enrolled. Two investigations suggested the participant’s death was due to a failed duty of care by the treatment provider. The death was likely “related to ibogaine ingestion and most probably related to a cardiac arrhythmia.”  There will be more discussion of this potential adverse event with ibogaine treatment in part 2 of this article. In conclusion, the author noted that despite the limitations, which included its reliance on a small (n= 14) convenience sample already intending treatment,

This study has demonstrated that for some opioid-dependent individuals, ibogaine treatment can be effective in significantly reducing opioid withdrawal, craving and depressed mood, and reducing or ceasing opioid use. Given the modest success of existing treatments, some of which involve extensive, repeated administration and considerable risk, and the significant increase in opioid dependence globally, it seems prudent to more seriously examine the place of ibogaine in the context of treating this intractable problem.

Despite the apparent promise of the research reported above, the ghost of adverse events, particularly fatalities, haunts serious research into ibogaine for opioid treatment. It was what stopped the clinical trial in the Netherlands in June of 1993, and raised its head again in the New Zealand study described above. Yet, there seems to be a growing body of research interest into its use for opioid treatment. For example, there are two clinical trials registered for ibogaine in the treatment of alcoholism and methadone detoxification. Neither study is recruiting yet and neither study is to be done in the US.

The fact that ibogaine is largely unregulated as a treatment for addiction and used to promote spiritual and healing experiences—sometimes by the same provider—should give someone seeking it for addiction treatment pause. But addicts are often desperate individuals, willing to take the risk. We will look at some of the risks and concerns in Part 2.

For more information on Bill W. and LSD, see “As Harmless as Aspirin?”

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.

12/26/17

Give MDMA a Chance?

© lightwise | 123rf.com

In August of 2017 the FDA designated MDMA-assisted psychotherapy as a breakthrough treatment for PTSD. Bringing MDMA to market as a legal, legitimate therapeutic agent has been the goal of Rick Doblin, the Executive Director of MAPS (Multidisciplinary Association for Psychedelic Studies), since he founded the nonprofit in 1986. That was one year after the DEA classified MDMA, better known as the street drug ecstasy, as a Schedule I controlled substance. Doblin said: “For the first time ever, psychedelic-assisted psychotherapy will be evaluated in Phase 3 trials for possible prescription use, with MDMA-assisted psychotherapy for PTSD leading the way.”

The MAPS press release said the Phase 3 trials will assess the efficacy and safety of MDMA-assisted therapy in 200-300 participants with PTSD in the U.S., Canada and Israel. Two Phase III clinical trial studies will begin enrolling participants in the spring of 2018. Randomized participants will receive three day-long sessions of either MDMA or placebo in conjunction with psychotherapy over a 12-week treatment period. There will also be 12 associated 90-minute nondrug preparatory and integration sessions. Now that the FDA is onboard, Doblin said MAPS plans to start negotiations with the European Medicines Agency.

Speaking for MAPS, Amy Emerson, said the Phase 2 data was extremely promising. Out of 107 participants, 61% no longer qualified for PTSD after three sessions of MDMA-assisted psychotherapy two months after treatment. Then at the 12-month follow up, 68% no longer had PTSD. “All Phase 2 participants had chronic, treatment-resistant PTSD, and had suffered from PTSD for an average of 17.8 years.” The Phase 2 trials are being prepared for publication.

The willingness of MAPS to use the existing clinical trial process to scientifically validate the potential therapeutic benefits of MDMA is encouraging. Running the FDA gauntlet for drug approval, for better or worse, is the most effective process we currently have to prevent a return to the days of patent medicines, when anything and everything was promoted as “cures” and “treatments” to an unsuspecting public. Those were the days when cocaine was in tonics (Coca Cola); heroin was in cough suppressants and teething medication; and the typical heroin addict was a middle class woman in her forties.

At least one individual at John Hopkins has referred to the recent interest of MAPS and others into the therapeutic effects of psychedelic substances as a “psychedelic renaissance.”  Writing for Massive, Benjamin Bell said: “Astounding preliminary research suggests psychedelics may yet revolutionize mental health care.” His historical gloss painted the history of the medical use of psychedelics as going from a potential revolution in psychotherapy during the 1950s to drug-addled lunacy by 1968. The culprits responsible for this change, according to Bell, were Timothy Leary and Richard Alport. “Although the pair began as respected researchers at Harvard, their firing coincided with their choice to promote hallucinogens in unique, and distinctly non-academic, ways.”

Unwittingly, when Harvard psychologist Timothy Leary signaled springtime for the “Summer of Love,” promoting LSD as a means to achieve cosmic connection, he also drew closed the curtain on academic research into a class of substances which held massive promise.

Richard Nixon labeled Leary as “The most dangerous man in America.” Alport went to India and a spiritual quest and changed his name to Ram Dass. In 1968, the US government outlawed all hallucinogens, universally restricting research on the substances. In the early 1980s, there was a brief time of psychotherapeutic research with MDMA. “But recreational use quickly captured the spotlight, and MDMA was classified as a Schedule 1 drug” in 1985. This was what motivated Rick Doblin to found MAPS.

According to The Washington Post, Doblin used LSD “as a rebellious, long-haired college freshman in the 1970s.” He believes it helped him see the world and himself in new ways. He wanted to become a therapist and use psychedelics to help others achieve similar insights, but he couldn’t because LSD was banned. When MDMA was criminalized, he realized psychedelics were too much on the fringe of culture to win public support. “The flaw of the early psychedelic movement was that they made it countercultural, a revolution. . . . Culture is dominant. Culture is always going to win.” He decided he had to bring psychedelics as therapeutic agents into the mainstream.

Doblin was admitted to the public policy PhD program at Harvard, shaved off his moustache, cut his hair and “learned to navigate the federal bureaucracy.” He laughed about how simple it was. “You put on a suit, and suddenly everyone thinks you’re fine.” Instead of fighting government officials, he sought to use science to win them over. So MAPS was born. And it was no accident the organization chose PTSD as its initial foray into its quest to end the government ban on psychedelics. Dobin said: “We wanted to help a population that would automatically win public sympathy. . . . No one’s going to argue against the need to help them.”  He added that if you were going to design a drug to be used as an adjunct in psychotherapy to treat PTSD, “MDMA would be it.”

But his dream extends beyond just developing a treatment for PTSD. Rick Doblin dreams of a time when psychedelic treatment centers are in every city. People could go there for enhanced couples therapy, spiritual experiences and personal growth. “These drugs are a tool that can make people more compassionate, tolerant, more connected with other humans and the planet itself.” He thinks they can help address homelessness, war and even global warming. Needless to say, this kind of talk makes others nervous.

Despite its promise, there are risks. What’s sold on the street as “molly” is often not MDMA See “MDMA—Not!” for more on this topic. At high doses, it can cause the body to over heat.  It can cause anxiety and increase stress. Chronic use can cause memory impairment. But there are additional concerns with MDMA not mentioned in The Washington Post.

The National Institute on Drug Abuse (NIDA) related the following in its article on MDMA (Ecstasy) Abuse. MDMA was said to affect the brain by increasing the activity of at least three neurotransmitters: serotonin, dopamine, and norepinephrine. “Like other amphetamines, MDMA enhances release of these neurotransmitters and/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.

So despite the optimism of individuals like Rick Doblin and Benjamin Bell, there are clear dangers with a renaissance of psychedelic psychotherapeutics. Attributing objections and concerns to over fifty years “of drug prohibition and abstinence-only education,” as well as “a culture that has shaped the negative stigma of all psychedelics,” is disingenuous and dismissive of the legitimate concerns. Should there be further research into the potential for MDMA-assisted psychotherapy as a breakthrough treatment for PTSD? If all they are saying, is give MDA a chance, then absolutely. See the photo in Bell’s article of Timothy Leary singing, “Give Peace a Chance” with John Lennon and Yoko Ono.

But let’s not run ahead of the science to treat other emotional or psychiatric problems; or apply psychedelics to resolve the problems of world peace, homelessness and global warming just yet.

04/26/16

MDMA—Not!

Ecstasy tablets © portokalis | 123rf.com
Ecstasy tablets © portokalis | 123rf.com

There are a handful of names for 3,4-methylenedioxymethamphetamine (MDMA), including: E, X, XTC, Rolls, Adam, Molly and Ecstasy. The pro-drug website Erowid noted it is one of the most popular recreational psychoactives, known for its euphoric, stimulant and empathogenic (feelings of oneness, emotional openness, empathy or sympathy) effects. This last effect indicates it has a past and current history of use in psychotherapy. But when you see a warning that, “Ecstasy tablets are notoriously impure, often containing chemicals other than MDMA,” be forewarned you may not be actually using MDMA.

The MDMA timeline on Erowid indicated MDMA was first synthesized and patented by Merck Pharmaceuticals in 1912. And the first animal testing of MDMA occurred at Merck in 1927. An article titled, ‘The Origin of MDMA (“Ecstasy”)’ indicated the 1912 Merck patent was a procedural patent, meaning MDMA was a precursor compound for another therapeutic and was not isolated as a drug in its own right. “Obviously, it was never intended for sale. MDMA was not tested pharmacologically in 1912.” The 1927 experiments were only aimed at exploring the potential pharmacological actions of MDMA. You can also read about MDMA and it history here on Wikipedia.

The first scientific paper on MDMA wasn’t published until 1960—in Polish. Alexander Shulgin resynthesized MDMA in 1965 while working at Dole Pharmaceuticals, but did not try it on himself at this time. Between 1967 and 1975 there were reports of small underground batches of MDMA being used recreationally, but Erowid said it had no clear documentation of its use before the mid 1970s. It didn’t become widely available as a street drug until around 1977.

Schulgin first heard of the psychoactive effects of MDMA from a student, and he tried it himself in September of 1976. He then reported on MDMA at a conference in December of 1976. Along with David Nichols, Schulgin wrote and published a report on the drug’s psychoactive effects in 1978. They described MDMA as inducing “’an easily controlled altered state of consciousness with emotional and sensual overtones”’ comparable ‘to marijuana, to psilocybin devoid of the hallucinatory component, or to low levels of MDA.’” Schugin referred to MDMA as “window”, because it allowed users to strip away habits and perceive the world clearly.

Because of its disinhibiting effects, Schulgin thought it could be useful in psychotherapy, so in 1977 he gave some to Leo Zeff, a psychotherapist. Zeff was so impressed with the effects, he came out of semi-retirement to promote its therapeutic use. Reportedly, he eventually trained an estimated four thousand therapists in the therapeutic use of MDMA. Zeff referred to MDMA as “Adam”, as he saw it putting users into a state of “primordial innocence.” It is believed that MDMA eliminates fear and increases communication in therapeutic users.

Concerned that MDMA would become an illegal substance like LSD and mescaline, early advocates tried unsuccessfully to restrict the available information and use of MDMA while they conducted informal research on its properties. By the late 1970s, there was a small recreational market for MDMA. By the early 1980s, it began to take hold as a “club drug” in places like Studio 54.

In 1984, Michael Clegg put together some financial backing, coined the term “Ecstasy” for MDMA, and mass-produced it in a Texas lab. “Ecstasy parties” were advertised at bars and discos. MDMA use quickly became a common sight on college campuses. “By May 1985, MDMA use was widespread in California, Texas, southern Florida, and the northeastern United States.”

Concern over the recreational use of MDMA resulted in its temporary placement as a Schedule I controlled substance on July 1, 1985. As a result of a hearing challenging the placement of MDMA as a Schedule I controlled substance, it was removed from its Schedule I status because of an improper procedure when it was originally scheduled on December 22, 1987. Within a short period of time, the DEA administrator reclassified MDMA as Schedule I, and it was permanently placed as a Schedule I controlled substance on March 23, 1988.

Ecstasy has remained a common recreational substance, particularly at dance clubs and raves. But it also persisted as a potential psychotherapeutic agent. The non-profit organization MAPS—Multidisciplinary Association for Psychedelic Studies—is currently funding clinical trials of MDMA as a “tool to assist psychotherapy” in the treatment of PTSD. Rick Doblin, the executive director of MAPS, founded it in 1986. His pre-MAPS organization, Earth Metabolic Design, held a conference on MDMA in March of 1985, in the midst of the fight over whether MDMA should become an illicit controlled substance.

MAPS is undertaking a roughly $20 million plan to make MDMA into a Food and Drug Administration (FDA)-approved prescription medicine by 2021, and is currently the only organization in the world funding clinical trials of MDMA-assisted psychotherapy. For-profit pharmaceutical companies are not interested in developing MDMA into a medicine because the patent for MDMA has expired. The idea of using MDMA to assist psychotherapy of any kind for any specific clinical indication has long been in the public domain.

The development of psychoactive substances like MDMA, LSD, Ibogaine and Ayahusca as psychotherapeutic “tools” has gained momentum in recent years. In part, this is because of the growth of concerns over the adverse effects and long-term use of FDA approved medications like antidepressants and antipsychotics. MAPS supports research into the therapeutic use of each of the above-named psychoactive substances. The following quote illustrates how MAPS presents the therapeutic benefits of MDMA-assisted psychotherapy: “MDMA is only administered a few times, unlike most medications for mental illnesses which are often taken daily for years, and sometimes forever.”

Along with Erowid, MAPS cautions that substances sold as “Ecstasy” or “molly” may not be pure MDMA. “Substances sold on the street under these names may contain MDMA, but frequently also contain unknown and/or dangerous adulterants.” The rise of novel or new psychoactive substances (NPS) such as “bath salts” has meant that many partygoers who think they are using MDMA aren’t. Media outlets such as Newsweek and The Fix have reported on a recently published study in the journal Drug and Alcohol Dependence that tested hair samples from ecstasy users for the presence of NPS. The lead author of the study, Joseph Palmer, said in an NYU press release on his research that:

Given the sharp rise in poisonings and recent deaths at dance festivals related to ecstasy use, research was needed to examine whether nightclub/festival attendees who use ecstasy or Molly have been unintentionally or unknowingly using “bath salts.”

The researchers surveyed young adults outside of nightclubs and dance festivals in the summer of 2015 about their use of ecstasy and other drugs.  The participants were asked if they had knowingly used any of a list of more than 35 NPS; and whether or not they had knowingly used ecstasy, MDMA or “molly.” Then they were asked if they would submit a lock of their hair for the researchers to test for NPS. “We collected hair samples from about a quarter of the survey sample to be tested for novel drugs.”

A lot of people laughed when they gave us their hair saying things like “I don’t use bath salts; I’m not a zombie who eats people’s faces.”

However, the researchers found that among individuals who reported they had not knowingly used bath salts or some unknown substance, 40% tested positive for “bath salts” and other NPS. Among participants reporting they had used ecstasy, half the samples tested positive for MDMA and half tested positive for bath salts and other NPS. One sample tested positive for alpha-PVP, flakka.

Ecstasy wasn’t always such a dangerous drug, but it is becoming increasingly risky because it has become so adulterated with new drugs that users and the scientific community alike know very little about. . . .   Users need to be aware that what they are taking may not be MDMA.