High-dose psilocybin more effective than antidepressant according to meta-analysis; DEA hearing on two obscure drugs; DEA administrator speaks out against illegal ketamine prescribing

Plus: MDMA’s mirror image molecules and where is public health?

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.

Meta-analysis finds that high-dose psilocybin is more effective than antidepressant

The Food and Drug Administration’s recent rejection of MDMA-assisted therapy as a PTSD treatment has meant more scrutiny of psychedelic study design — especially the role of “functional unblinding,” which results when study participants can guess whether they received a psychedelic drug or placebo. Participants’ expectations can affect their experiences and the outcomes of studies. In a new meta-analysis published in the British Medical Journal, researchers analyzed 19 psychedelics studies to better understand the relative efficacy of various psychedelics versus placebos and the antidepressant escitalopram. 

The team of Taiwanese researchers found that only high doses of psilocybin showed greater efficacy in decreasing symptoms of depression than escitalopram (an SSRI antidepressant), but the other psychedelics included in the analysis — LSD, MDMA, ayahuasca, and low psilocybin doses — did not. Additionally, placebo effects were stronger among participants given escitalopram than those given high-dose psilocybin, which could mean that after accounting for those placebo effects, high-dose psilocybin appears to have a sizable effect on depressive symptoms. “Taken together, our study findings suggest that among psychedelic treatments, high dose psilocybin is more likely to reach the minimal important difference for depressive symptoms in studies with adequate blinding design,” the authors write.

DEA hearing on two obscure hallucinogenic drugs

The Drug Enforcement Administration will hold a 10-day hearing in November to discuss the agency’s proposal to classify two currently unscheduled hallucinogenic substances as Schedule I drugs. The DEA defines Schedule I drugs as having high abuse potential and no accepted medical use in the U.S. The substances under consideration for rescheduling, known as DOI and DOC, are frequently used by psychedelics researchers to understand how psychedelics work in the brain.

According to a pre-hearing document sent by the DEA to Students for a Sensible Drug Policy (SSDP) and shared with The Microdose, the hearing will be held at the DEA Hearing Facility in Arlington, Virginia on weekdays between November 12 and 25. If the DEA schedules the two drugs, the move “would essentially shut down vital research — including that being done by the 22 SSDPers who use DOI/DOC in their labs,” says Gina Giorgio, SSDP’s director of Strategy and Development. (For more on how scheduling DOI and DOC would affect researchers, read our 5 Questions for undergraduate researcher Alyssa Gillies.) The Microdose reached out to the DEA for comment but did not receive a response.

The DEA attempted to classify DOI and DOC as Schedule I drugs in 2022 but withdrew their plan after researchers and activists pushed back on the proposal. This most recent proposal attempt has also seen significant pushback: during the proposal’s public comment period in April, the DEA received over 150 responses calling for the agency to reconsider. The agency had scheduled a June 10 hearing for the proposal, but a DEA judge postponed it in May, citing a lawsuit the psychedelics company Panacea Plant Sciences filed against the agency. 

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DEA administrator speaks out against illegal ketamine prescribing

In the wake of federal charges brought against doctors who allegedly supplied ketamine to the late actor Matthew Perry, the Drug Enforcement Administration’s top administrator Anne Milgram appeared on the CBS show Meet the Nation to highlight the agency’s dedication to prosecuting medical professionals involved with drug diversion. The agency is “targeting and investigating doctors, nurse practitioners, others who are violating this duty of trust to their patients by over prescribing medicine or prescribing medicine that isn't necessary.” On the show, Milgram compared the illicit ketamine market to the beginning of the opioid epidemic, when “many Americans became addicted to controlled substances in doctors' offices and through medical practitioners that then turned into street addiction.”

MDMA’s mirror image molecules

The drug called ecstasy, or MDMA, is what’s known as a racemic mixture: it contains two molecular structures in equal proportion, known as R-MDMA and S-MDMA, which are mirror images of each other. To understand whether R-MDMA and S-MDMA might produce different effects, researchers at University of Basel in Switzerland conducted a clinical trial with 24 participants who were given opaque capsules of R-MDMA, S-MDMA, or mannitol, a sugar alcohol, to serve as a placebo. 

The results, published in Neuropsychopharmacology, suggest that S-MDMA produces stronger subjective effects than R-MDMA; participants reported stronger visual effects and disturbances and had higher scores on standard measures of mystical experience. After S-MDMA, participants also showed higher blood pressure and cortisol levels compared to MDMA, and were more likely to experience depressive symptoms in the three days after taking the drug. Those effects could be due to the researchers’ finding that S-MDMA appears more potent than R-MDMA; in racemic MDMA, R-MDMA essentially serves as an inhibitor for some of S-MDMA’s effects. “Overall,” the researchers concluded, “the present findings do not presently indicate relevant beneficial effects of R-MDMA or S-MDMA over MDMA in substance-assisted therapy in patients.”

Where is public health?

As psychedelics use rises, public health experts could play an important role in public education, harm reduction, and tracking health outcomes. But according to a new paper from health scientists published in Social Science & Medicine, psychedelics are not yet on the radar of most university public health departments. The researchers reviewed information from accredited public health programs at over 200 universities and found that just 10% had psychedelics research or education programs. Some of those universities conducted psychedelics research in other departments, like neuroscience or psychology, but the researchers’ analysis found few collaborations between public health researchers and other researchers conducting psychedelic studies. 

The analysis also found that leadership of psychedelic science programs are disproportionately white and male and that few programs engage with or recognize the contributions of Indigenous people and ways of knowing. “Rather than being a leader or catalyst of the Western psychedelic resurgence, public health seems as unfamiliar with psychedelics as [psychedelic research centers] are with public health,” the authors write. “Given public health is designed to equitably prevent harm and promote health and wellness at community, population, and societal levels, these obstacles must be overcome to equitably scale psychedelic benefits.”

• According to the Wall Street Journal, FDA officials have recently interviewed four people familiar with Lykos Therapeutics’ trials about whether side effects like suicidal ideation went unreported. 

• Psychedelic Alpha’s Josh Hardman wrote that he has an inside line to a Lykos employee who has seen the Complete Response Letter the U.S. Food and Drug Administration sent to Lykos Therapeutics. In two recent posts, Hardman breaks down what changes we’re likely to see in the company’s future clinical trial designs to address the FDA’s concerns. These include documenting seemingly “positive” effects like euphoria, and better defining the type of psychotherapy to be used in MDMA treatment. 

• After reports of mushroom edibles manufactured by the company Diamond Shruumz sickening dozens of people, the FDA issued consumer warnings, but people are still getting sick. And we still don’t know what’s in those gummies. NPR’s Will Stone reports on the legal gray area around these gummies and why it’s tricky to find out what’s in them.

• Psychedelics are often presented as an alternative to conventional antidepressants, but in DoubleBlind, Jules Evans and Shayam Suseelan write that “pill shaming” has risks. “The adverse effects of these meds are talked up, while psychedelic side effects are minimized or not mentioned at all,” they write. “This can encourage people to come off SSRIs too quickly and hope for a miracle cure from psychedelics, which, in turn, can lead to a destabilization that is amplified by psychedelics.”

You’re all caught up! Have a great weekend. We’ll be off on Monday. See you on Wednesday with a new episode of the Altered States podcast.

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