Psilocybin changes people’s brains after their first trip; Anthropologists share first evidence of traditional psilocybin use outside of the Americas
Plus: A pair of ketamine mechanism studies; Trump’s executive order revives analysis into Republicans’ pro-psychedelics shift
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.
Psilocybin changes people’s brains after their first trip, a new study led by UC San Francisco’s Robin Carhart-Harris, found. The paper, published in Nature Communications on May 5, examined how lasting psilocybin’s effects are on brain function and anatomy. The researchers gave a 25 mg dose of psilocybin to 28 healthy participants who had never tried a psychedelic before. They took measurements of participants’ brains before, during and after the dose, and also documented participants’ psychological experience and well being.
During the 25 mg trips, the researchers observed increases in ‘brain entropy,’ or signal complexity in electroencephalography measurements of participants’ brains. That entropy predicted improved well being, as reported by participants a month later.
In addition to EEG recordings during the psilocybin trip, participants had brain scans before the psilocybin dose and one month after. For these scans, the authors used functional magnetic resonance imaging (fMRI) to track blood flow between brain regions and diffusion tensor imaging (DTI) to map the brain’s white matter communication network. DTI measurements showed thinning of white matter tracts stretching from participants’ prefrontal cortex to subcortical brain regions a month after their psilocybin dose. This could mean connections between the two areas are being pruned, or new connections are being made, but aren’t yet insulated with myelin. “If verified in subsequent work, this finding may be viewed as evidence of anatomical ‘neuroplasticity’ after first-ever psychedelic use in humans,” the authors write. Further studies will need to be done to understand if the brain changes last beyond one month post-dosing.
Neuroscientist and biomedical engineering professor Alex Kwan of Cornell University told the Guardian the study results were “exciting,” but added that the study participant pool was small, and said DTI technology provides a limited and indirect view of brain connections.
Anthropologists share the first evidence of psilocybin use in traditional populations outside of the Americas
Researchers’ understanding of traditional psychedelic use comes almost entirely from documentation of Indigenous groups in the Americas. For example, Indigenous use of psilocybin mushrooms and peyote in Mexico, and ayahuasca in South America.
In a recent preprint (a draft version of a scholarly manuscript shared publicly before formal peer review) researchers report evidence of psilocybin mushroom use in southern Africa, specifically Lesotho and South Africa. The authors conducted 34 interviews with traditional healers and non-healers (often, adolescent cattle herders) from the Basotho ethnic group. The interviews revealed a majority (21) were familiar with psilocybin mushrooms (specifically, the Psilocybe maluti species endemic to southern Africa) and reported magical, healing, initiation and recreational uses for the fungi.
The authors report Basotho healers’ use of small amounts of P. maluti mushrooms in psychoactive brews likely “predate the mid-twentieth-century popularization of psilocybin.” Their findings also reinforce the belief that psilocybin was being used on a global scale and in different ways before it was popularized in the U.S.
Researchers and clinicians can learn from traditional healers who have been administering psychedelics for generations, the authors reason. For example, Basotho interviewees shared how the psychoactive brews influenced dreaming, providing a possible direction of study. Basotho healers also include other psychoactive plants in their brews, including the hallucinogenic bulb of the flowering plant Boophone disticha. “As scholars continue to consider the cognitive and therapeutic impacts of combining psilocybin with other substances, Basotho recipes suggest that the combination of psilocybin with alkaloids from B. disticha may be worthy of study,” the authors write.
As psilocybin mushrooms grow on six out of seven continents, more cases of Indigenous psychedelic use are likely being overlooked, the authors reason, adding that such practices should be documented before they disappear. “It’s generally been thought that traditional (healing/shamanic) use of psilocybin mushrooms was basically confined to Mesoamerica, but here’s the first evidence of similar traditional use (going back to at least the early 20th Century) in Southern Africa - fascinating!” neuroscientist Matthew Wall, who wasn’t involved with the research, wrote on LinkedIn.
A pair of ketamine mechanism studies aim to “reverse engineer” the drug’s antidepressant effects.
For some, ketamine offers rapid relief from depression symptoms. In an effort to “reverse engineer” those effects, scientists recently published studies in Cell and Science Advances detailing ketamine’s molecular mechanisms in the brain, and ways to harness them.
Scientists believe opioid receptors play a role in ketamine’s antidepressant action. In the Cell report, study authors specifically examined opioid receptors on certain regulatory interneuron cells in the prefrontal cortex. They suggest ketamine targets certain opioid receptors on these cells, leading to its antidepressant effects.
Hoping to mimic ketamine with fewer side effects, the authors were able to replicate the drug’s antidepressant effects in mice by instead using small doses of three drugs that act on the same pathway. The drugs acted on glutamate, serotonin and opioid receptors. “This synergistic strategy could produce rapid antidepressant effects at much lower doses of each compound,” said lead author, neuroscientist and psychiatrist Conor Liston from Weill Cornell Medicine in a news release about the study. “By avoiding higher doses, we can avoid side effects.”
Another study, published in Science Advances on May 1, included many of the same authors and focused on ketamine’s longer-term effects. They found the TrkB and mGluR5 receptors in brain cells are necessary for ketamine’s antidepressant action. They enable “cross talk” that’s enhanced by ketamine. Involvement of the mGluR5 receptor in ketamine’s antidepressant effects is novel, author Francis Lee said.
Next, the researchers want to advance their work to clinical trials, testing if combined small doses of existing drugs can mimic ketamine’s effects in humans. Perhaps also pairing a low dose of ketamine with drugs targeting mGluR5 receptors could deliver lasting relief with fewer side effects, the authors suggest.
Trump’s executive order revives analysis into Republicans’ pro-psychedelics shift
Following President Trump’s April 18 executive order to expedite psychedelic treatments, journalists are once again reflecting on the GOP’s shifting attitude towards the drugs. After years of conservative opposition to psychedelics, leading Republicans are now at the forefront of advancing the movement to increase access to these drugs, writes Andrew Jacobs in a New York Times piece. Psychedelic users are no longer looked down on by conservative politicians as liberal degenerates and draft dodgers, Jacobs wrote. He credits Rick Doblin for focusing on veterans as a group that could benefit from psychedelic therapy. “Drug reform advocates found a highly effective proxy for persuading even the most calcified antidrug warrior: the American military veteran,” Jacobs writes.
Indeed, normalization of psychedelics by figures like Doblin and decriminalization activists in Oregon and Colorado surely paved the way for the executive order, writer Michelle Lhooq noted in a recent post on Substack. She writes the “cosmic Right” was able to achieve a political victory liberal activists spent decades working towards. “While pharma companies like Lykos and Compass have spent hundreds of millions of dollars trying to get these drugs rescheduled through the clinical-trials-to-FDA pipeline, Rogan’s influencer clout turned out to be a direct line into the President’s approval,” Lhooq writes, referring to podcaster Joe Rogan’s text exchange with Trump that apparently expedited his executive order.
In a Washington Post article, Rachel Roubein reports the order may have been in the works prior to Rogan’s text exchange with the President. She spoke with anonymous federal officials familiar with the internal deliberations. “The basic principles of an executive order were sketched out by the time Trump sought to elevate the issue, the officials said.”
More news from this week:
Results of a clinical trial published May 7 in JAMA Network Open show a single dose of psilocybin can help people with cocaine use disorder abstain from using the drug. The trial was unique in that a majority of participants were Black and low income.
In an opinion piece for Bloomberg, Lisa Jarvis argues the hype around ibogaine is outpacing the science. While anecdotes shared by veterans, including those at the recent White House event, are compelling, studies of the drug are few and small, she writes. For example, the often cited Stanford study enrolled just 30 veterans. The drug also comes with potentially dangerous risks, such as fatal cardiac events. Not to mention the lengthy, sometimes 24-hour, psychedelic experience ibogaine users endure. Compared to widely studied psychedelics like psilocybin, ibogaine is more of a mystery, Jarvis writes. “Getting there requires a careful process that unfortunately doesn’t come with shortcuts — even if politicians wish it did.”
In an opinion piece for STAT, professors Jerel Ezell and Sugy Choi write the psychedelic revolution is leaving people of color behind. The two are studying why racial minorities aren’t benefiting from psychedelic research, even though they may have the most to gain. For example, Ezell and colleagues have analyzed how Black, Latino, and Indigenous people tend to have higher rates of opioid overdose deaths compared to white people. Yet, non-white people remain underrepresented in psychedelic trials for conditions like opioid use disorder.
Following Trump’s executive order, legal experts Mason Marks and I. Glenn Cohen discussed its implications in a Q&A from the Petrie-Flom Center at Harvard Law School.
Psychedelic Alpha’s Josh Hardman did a sprawling interview with Americans for Ibogaine CEO W. Bryan Hubbard. The conversation skipped Hubbard’s trademark pitch about ibogaine’s benefits, and launched right into next steps following Trump’s executive order, relations with Gabon and infighting within the pro-ibogaine movement.
Department of Defense-funded trials will begin giving U.S. soldiers MDMA-assisted therapy for PTSD next year, the Guardian reported. However, psychedelic advocates caution against the treatment model that would return soldiers to military service after they process their trauma. “What we find is that people are somewhat more likely to relapse [into a PTSD response] after treatment if they go back into a stressful situation,” Rick Doblin told the Guardian.
Our very own Jane C. Hu was on Scientific American’s Science Quickly podcast discussing psychedelic research, attitudes, and the rise of ibogaine.
In a commentary for Medscape Australia, doctor Toby Gardner writes about the challenges Australia has faced since being the first country in 2023 to allow MDMA-assisted therapy outside of clinical trials. “The current reality is one of constrained access, shaped by cost, time and workforce limitations,” Gardner writes.
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