Tag: ecstasy

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.

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.

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.

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.

09/29/14

Psychoactive Science or Sideshow

© Randomshots | Dreamstime.com - Medicine Wagon Photo
© Randomshots | Dreamstime.com – Medicine Wagon Photo

There is a growing call to permit research into the therapeutic benefits of a variety of psychoactive drugs currently classified by the DEA as Schedule 1 controlled substances. The editors of Scientific American called for the U.S. government to move LSD, ecstasy, marijuana and others into Schedule 2, with cocaine, methamphetamine, fentanyl and Ritalin. They point out that such a move would not lead to decriminalization, “but it would make it much easier for clinical researchers to study their effects.”

Schedule 1 controlled substances are “drugs with no currently accepted medical use and a high potential for abuse.” They are seen as the most dangerous drugs, “with potentially severe psychological or physical dependence.” Schedule 2 controlled substances are “drugs with a high potential for abuse, less abuse potential than Schedule 1 drugs, with use potentially leading to severe psychological or physical dependence.”

British researchers have also called for greater access to “classical hallucinogens” such as psilocybin (magic mushrooms, another Schedule 1 drug) and LSD for research into treating depression.

Classical hallucinogens alter the functioning of this system [serotonergic], but not in the same way current medications do: whilst there are identified receptors and neurotransmitter pathways through which hallucinogens could therein produce therapeutic effects, the neurobiology of this remains speculative at this time.

These drugs are all caught in a catch-22, de facto ban on their use in medical research because of their Schedule 1 placement. “These drugs are banned because they have no accepted medical use, but researchers cannot explore their therapeutic potential because they are banned.” Three United Nations treaties extend similar prohibitions to rest of the globe, further complicating their reclassification as Schedule 2 drugs.

British psychiatrist David Nutt has argued that the U.N. charters are outdated and restrict doctors and scientists from studying hundreds of drugs.  He likened this “research censorship” to the Catholic Church banning Galileo from teaching or defending heliocentric ideas in the 1600s. Nutt suggested the Catholic Church banned the telescope, but the ban was actually on books that taught Copernican beliefs.

Nevertheless, he called the laws, which do not discriminate between research and recreational drug use relics of another age. “These laws serve no safety value. . . . The licenses and bureaucracy surrounding them can increase the costs of research tenfold, further limiting what is done.”  Dr. Nutt commented on how LSD and other hallucinogens like psilocybin had potential to explore and treat the brain. “Other therapeutic targets for psychedelics are cluster headaches, OCD and addiction.”

The argument for reclassifying psychoactive substances like marijuana, LSD, ecstasy and psilocybin from Schedule 1 to Schedule 2 has its pros and cons for me. The above discussion presents the case for reclassification, permitting future research into these substances. IF the ideal of rigorous, methodical research into the therapeutic potential of these drugs is followed, all is well.

But we are now in the midst of an epidemic of prescription drug abuse that came through the very same gauntlet of review and approval that these known recreational drugs would pass through to become medicinal agents once they were reclassified. And while there are potential therapeutic applications for marijuana, the current state of medical marijuana looks more like the older sideshow of patent medicines, where you could get cocaine toothache drops, heroin for cough relief, and Mrs. Winslow’s Soothing Syrup (which contained morphine) for teething discomfort.

UntitledIf special interest groups can be held off from bringing about a new age of snake oil salesmanship, then reclassifying these substances and permitting legitimate scientific research makes sense. Done correctly, it might even demonstrate that some of the existing curative claims for medical marijuana and other substances were false. But if these psychoactive substancess achieve FDA approval for any reason, they could be prescribed “off label” as is currently the case with other FDA approved drugs.