Tapering off antidepressants before psilocybin treatment; New concerns about MAPS’s MDMA trials; University of Maryland Baltimore joins patent lawsuit against Compass
Plus: The link between psychedelics and psychotic or manic symptoms; Utah passes psychedelic prescription bill, Connecticut lowers punishments for psilocybin possession
Happy Friday and welcome back to The Microdose, an independent journalism newsletter brought to you by the U.C. Berkeley Center for the Science of Psychedelics.
How tapering off antidepressants before psilocybin treatment affects outcomes
Classic psychedelics act on the body’s serotonin system — and so do many common antidepressant medications. As a result, participants in psychedelic clinical trials are sometimes asked to discontinue use of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) before receiving psychedelic treatment, but it’s not yet known how taking SSRIs and SNRIs could affect participants’ response to psychedelic-assisted therapy.
A paper recently published in the British Association for Psychopharmacology reanalyzed results from a clinical trial comparing the efficacy of psilocybin-assisted therapy to that of the SSRI escitalopram in treating moderate to severe major depressive disorder. Some participants in that study were on SSRIs or SNRIs prior to the trial’s start, while others were not. In this new analysis, researchers found that “unmedicated” participants who were not taking an SSRI or SNRI before the study showed greater improvement in their depression scores for six weeks after psilocybin therapy than “discontinuers,” the participants who had to taper off their SSRI or SNRI before the study.
While these results could indicate that SSRI or SNRI use directly affects participants’ responses to psilocybin therapy, the researchers investigated an alternate explanation: that the results were due at least in part to direct effects of discontinuing antidepressants, which can worsen depressive symptoms. Though discontinuers didn’t respond as well to psilocybin treatment as unmedicated participants, discontinuers given escitalopram in the study showed better outcomes than discontinuers given psilocybin. On X, co-lead author Tommaso Barba wrote that the analyses “shed light on the complex dynamics of antidepressant discontinuation effects in psychedelic research,” and warrant further investigation.
Healthcare non-profit raises concerns around MAPS’s MDMA trial validity
The Institute for Clinical and Economic Review (ICER) released a draft report assessing MAPS’s clinical trials using MDMA-assisted therapy to treat PTSD, a key component of Lykos Therapeutics’ pending application to the U.S. Food and Drug Administration. The non-profit research institute conducts assessments of medical treatments’ cost-effectiveness, which are often used by states and private industry to make decisions about healthcare and health policy; this draft report was written in collaboration with researchers at the University of Colorado and University of Kansas. According to the report, the results of MDMA-assisted therapy, as reported by researchers, “would be an important addition to treatment options for PTSD” but, the organization says it has “substantial concerns about the validity of the results.”
ICER’s concerns include a range of methodological and ethical issues. Though studies included “blinding” protocols to prevent participants and researchers from knowing whether participants received MDMA or placebo, ICER writes that “functional unblinding is a particular concern,” since patients and researchers were likely to be able to guess whether they’d received MDMA — a recurring concern raised about other psychedelic research on human subjects as well. They also interviewed trial participants who say they experienced negative outcomes and were told by researchers that those outcomes were “evidence they were responding appropriately and would eventually improve.” ICER also included mention of one participant experiencing sexual abuse, a case that is also detailed in the podcast “Cover Story: Power Trip” from New York Magazine.
Overall, ICER characterized the evidence for the effectiveness of MDMA-assisted psychotherapy for PTSD as “insufficient” due to their concerns about the validity of MAPS’s clinical trials. The Microdose requested comment from MAPS for-profit arm Lykos Therapeutics about ICER’s report, but did not receive a reply. ICER is accepting public comment on the draft report through April 22.
Edited 4/1/24: Lykos Therapeutics tells The Microdose that their clinical trials "were designed in partnership with the FDA" and that those designs "mitigate the risk of functional unblinding and ensure the reliability and validity of efficacy endpoints."
"We stand behind the design of the clinical trials, the integrity of the investigators, and are grateful to the patients who participated in the clinical trials," they say.
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University of Maryland Baltimore joins patent lawsuit against Compass
Last week, the University of Maryland, Baltimore joined psychedelics company Terran Biosciences in their lawsuit against Compass Pathways. The lawsuit was initially filed in 2022, a few months after Terran entered into an exclusive licensing deal with UMB to commercialize the university’s patents. Terran alleged that Compass stole psilocybin trade secrets from UMB professor Scott Thompson and that at least six of Compass’s patents include trade secrets from Thompson’s work. Thompson is now a professor at the University of Colorado School of Medicine.
Adding UMB to the suit gives the claimants a stronger jurisdictional claim to the state of Maryland. That could be critical to the case, which was filed in Maryland: last year, Compass filed a motion to dismiss the case on jurisdictional grounds, arguing that the company had no business in Maryland. The most recent court documents, filed jointly by Terran, UMB, and Thompson, point out that Compass not only reached out to Maryland-based researchers like Thompson but also had clinical trial sites in the state. The parties have requested that the judge deny Compass’s motion to dismiss, and the case awaits the judge’s ruling.
The link between use of psychedelics and psychotic or manic symptoms
In clinical trials of psychedelics, it’s common for researchers to exclude would-be participants with a family or personal history of psychosis, schizophrenia, or bipolar disorder. But not much is known yet about the link between psychotic or manic episodes and psychedelics. A new study published in JAMA Psychiatry attempts to better understand the link between psychiatric issues and psychedelic use by studying twins. Researchers often turn to twin studies to probe the relative contributions of genetic predisposition versus life experiences.
The study was led by Swedish researchers who analyzed data from the Swedish Twin Registry, a national dataset that includes self-reported drug use and psychotic and manic symptom occurrence. There were 119 twin pairs that responded to the survey saying they had taken psychedelics; the study was administered to twins when they were 15 years old. The researchers’ analyses found no significant association between psychedelic use and psychotic symptoms, but in comparing identical twin pairs in which one had taken psychedelics while the other had not, the twin who’d tried psychedelics was more likely to report experiencing manic symptoms. In the twin data researchers reviewed, mania was also strongly correlated with a genetic predisposition to schizophrenia and to bipolar I disorder. In other words, those who experienced manic symptoms after psychedelic use may have been more genetically prone to mental illnesses.
State of Psychedelics: Utah passes psychedelic prescription bill, Connecticut lowers punishments for psilocybin possession
In mid-March, the Utah legislature passed Senate Bill 266, which would create a pilot program allowing healthcare systems in the state to prescribe psilocybin and MDMA treatments. Last Thursday, Utah governor Spencer Cox (R) penned a letter to the state’s senate president and house speaker detailing his vetoes on various bills and explaining that he will allow two bills to go into effect without his signature due to “overwhelming legislative support.” SB 266, the psilocybin and MDMA treatments bill, was one of those. Cox said that while he is “generally supportive” of the efforts, he was disappointed that the legislature passed the bill when the state had previously established a task force to advise the legislature on studying psilocybin. As it’s written, SB 266 would take effect on May 1, 2024 and the pilot program would sunset in 2027.
Connecticut legislators passed House Bill 5297, which would change state statutes around psilocybin possession. The bill changes possession of less than a half-ounce of psilocybin from a misdemeanor to an infraction subject to a $150 fine for the first offense. Subsequent offenses would net a fine between $250 and $500.
It’s worth noting there’s an important difference between psilocybin and psychedelic mushrooms. Psilocybin is the psychoactive compound that occurs naturally in mushrooms; while a half-ounce of mushrooms would amount to a handful of moderate trips, a half-ounce of pure psilocybin would be hundreds of doses. (For reference, most psychedelic clinical trials use around 25 milligram doses of psilocybin for a session; a half-ounce of psilocybin would include more than 500 25mg doses.)
A spokesperson for Governor Ned Lamont (D) told the Hartford Courant in January that “the governor has concerns about broad decriminalization of mushrooms,” so it remains to be seen whether Lamont will veto or pass the bill.
In Greeley, Colorado, an overdue library book about psychedelics was finally returned — 36 years late.
At this year’s SXSW conference, MAPS founder Rick Doblin told the audience that MDMA-assisted therapy might make soldiers “less reactive” and help them stay in the military, reports journalist Russell Hausfeld for Truth Dig.
The Daily Beast interviews police advocating for MDMA-assisted therapy to treat PTSD in their colleagues.
In his newsletter Ecstatic Integration, Jules Evans asks: “Is it strange that a state office of government should be promoting and legislating on what seems, at first sight, to be a spiritual concept?” He’s writing about the draft rules for the Colorado Office of Natural Medicine’s psilocybin program, which includes requirements for preparing clients such as “discussion of the concept of trusting inner guidance, which may include discussion topics such as Inner Healing Intelligence, Inner Genius, The Self, Wise Mind, Soul, or Spirit.”
Willamette Week reports that a Portland psilocybin service center is closing just six months after opening. Co-owner Jenna Kluwe told the alt-weekly that they expected more clients: “The numbers just weren’t where they needed to be.”
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