Psychedelic Research Recap September 2024

Welcome back to our monthly update on psychedelic research!

In September, we cover a variety of experiments on psilocybin and its therapeutic potential, from treatment for treatment-resistant depression in veterans to low-dose psilocybin for headache disorders. We will also look at the mechanisms of action of psychedelics, investigating blood flow in the brain and brain connectivity.

Several studies provide more information on the dose-dependent effects of mescaline, harmine (ayahuasca component), and microdoses of LSD. Finally, we will cover the safety of psychedelics (in clinical trials).

This month’s recap is made possible by our supporting members.

Check out the research link overview for all the studies we didn’t add to the database.

Psilocybin’s Potential

Four studies have investigated the therapeutic effects of psilocybin for various mental health conditions. The first is an open-label trial that examined the effects of psilocybin in U.S. military veterans with severe treatment-resistant depression. Fifteen veterans received a single 25 mg dose of psilocybin. At three weeks post-treatment, 60% showed a significant reduction in depression symptoms, and 53% met criteria for remission. Some participants maintained these improvements at 12 weeks. The study suggests psilocybin may offer a promising option for veterans who have not responded to other treatments.

In a follow-up to a previous double-blind, randomized controlled trial, researchers compared the long-term effects of psilocybin therapy to escitalopram (Lexapro), a conventional antidepressant, in patients with moderate-to-severe major depressive disorder. At six months, both treatments led to sustained reductions in depressive symptoms. However, the psilocybin group showed greater improvements in social functioning, sense of meaning in life, and psychological connectedness. Although no significant differences in the main depression measure were found in the original publication (this is the 11th analysis of the data), this does add to the growing body of research on psilocybin’s potential as an effective treatment for depression (though I wonder how much regulators and payers care about these other outcomes).

Another study explored the antidepressant effects of psilocybin and LSD in patients undergoing psychedelic-assisted therapy in Switzerland, where such treatment is legally permitted under certain conditions. The study compared the subjective drug effects between 28 patients and 28 healthy volunteers from a controlled trial. While overall drug effects and mystical experiences were similar, patients reported lower levels of ego dissolution. The researchers found that relaxation during the therapy sessions was the strongest predictor of antidepressant outcomes, highlighting the importance of the therapeutic setting.

A small open-label study investigated low-dose psilocybin as a potential treatment for chronic, short-lasting unilateral neuralgiform headache attacks (SUNHA), a debilitating headache disorder. Four patients received ascending doses of psilocybin (5–10 mg) with psychological support. Although the study was terminated early due to recruitment challenges, two participants experienced a significant reduction in daily headache attacks. The findings suggest that psilocybin may potentially treat SUNHA, but more research is needed.

Studies Involving Healthy Volunteers

Seven recent studies have explored the effects of psychedelics in healthy individuals, shedding light on their pharmacology and potential therapeutic applications.

A randomized, double-blind, placebo-controlled study investigated the dose-dependent effects of mescaline in healthy subjects. Sixteen participants received varying doses of mescaline (100–800 mg) across five sessions. The study found that mescaline induced dose-dependent subjective effects and increased heart rate and blood pressure. The effects were primarily mediated by 5-HT2A receptors, as co-administration with ketanserin significantly reduced mescaline’s effects. The study found no upper limit to the subjective experience, implying higher doses may further intensify effects. However, increased intensity correlated with more adverse effects, especially nausea and vomiting.

Another study examined the impact of combining meditation with DMT-harmine (‘pharmahuasca’, similar to ayahuasca). This double-blind, placebo-controlled study involved 40 experienced meditators during a three-day mindfulness retreat. Participants who received DMT-harmine reported greater mystical-type experiences, non-dual awareness, and emotional breakthroughs compared to the placebo group. One day later, they also reported increased psychological insight. These findings suggest that DMT-harmine may enhance certain aspects of meditation (in experienced meditators).

A Phase I trial assessed the safety and tolerability of pure oral harmine (without DMT), a component of the ayahuasca brew. In this open-label study, 25 healthy volunteers received single ascending doses of harmine. The study determined that doses below 189 mg per 70 kg body weight could be administered with minimal adverse events, while higher doses were associated with vomiting, drowsiness, and limited psychoactivity.

Exploring the physiological correlates of psychedelic experiences, a re-analysis of a study involving intravenous DMT examined the role of the autonomic nervous system. Seventeen participants received 20 mg of DMT, and the study found that balanced activity between the sympathetic and parasympathetic nervous systems was linked to stronger feelings of spirituality and insight during the DMT experience. Furthermore, this balance predicted improved well-being two weeks later.

An open-label study (we previously covered the pre-print) investigated the role of memory in the therapeutic effects of psilocybin by co-administering it with midazolam, a medication known to impair memory. Eight healthy participants received psilocybin (25 mg) along with midazolam. The study found that midazolam partially impaired memory of the psychedelic experience while allowing the conscious experience to occur. The degree of memory impairment was inversely associated with participants’ salience, insight, and well-being. This suggests that memory of the experience may play a role in the lasting therapeutic effects of psilocybin.

Another study compared the effects of LSD, d-amphetamine, and MDMA on brain connectivity in healthy volunteers. In this double-blind, placebo-controlled, crossover trial involving 28 participants, researchers found that all three substances reduced network integrity. LSD uniquely reduced the integrity of the default-mode network (DMN) and had more pronounced effects on network segregation and connectivity compared to the amphetamines (under which you can classify MDMA, though more commonly it’s referred to as an empathogen/entactogen).

A re-analysis of a randomized controlled trial investigated the effects of LSD microdosing on creativity. Eighty healthy adult males received either 10 micrograms of LSD or placebo every third day for six weeks. Creativity was assessed using multiple tests at baseline, during acute dosing, and after the regimen. The study found no significant effects of LSD microdosing on creativity measures, suggesting that microdosing may not enhance creativity in measurable ways.

Lastly, a pooled analysis of nine studies examined predictors of LSD effects in healthy participants. The analysis included 213 subjects from double-blind, placebo-controlled, crossover studies. The researchers found that the LSD dose was the most influential predictor of the subjective experience. Pre-drug mental states, personality traits, and previous hallucinogen experiences also significantly affected the responses. Factors like sex and body weight did not significantly influence the effects.

Demand and Safety of Psychedelic Therapies

The studies we have covered until now have focused on the potential use of psychedelic-assisted therapies in treating mental health conditions (and the prerequisite studies in healthy subjects). The following reviews provide important insights into the demand for such treatments, their safety profiles, and considerations for integrating them into healthcare systems.

An economic analysis estimated the number of people in the United States who might be eligible for psilocybin-assisted therapy (PSIL-AT) for major depressive disorder (MDD) and treatment-resistant depression (TRD). Based on data from approximately 14.8 million adults with MDD, the study found that between 24% (about 2.2 million people) and 62% (around 5.6 million people) could be eligible for PSIL-AT. The variation depended on factors like exclusion criteria and coexisting health conditions.

A systematic review and meta-analysis examined the safety of classic psychedelics such as LSD, psilocybin, and DMT when used in clinical settings. Analyzing data from 214 studies involving 3,504 participants, the researchers found that serious adverse events were rare. In healthy participants, no serious adverse events were reported. Among participants with existing mental health conditions, about 4% experienced serious adverse events, including worsening depression or psychosis. Non-serious adverse events requiring medical attention were also uncommon. However, the study noted that the quality of adverse event reporting varied, suggesting a need for standardized monitoring and reporting practices in future research.

Another review looked at the acute subjective effects of psychedelics and their connection to therapeutic benefits and risks. The authors discussed how current methods of measuring these experiences might have limitations. They pointed out that while some acute experiences during a psychedelic session can predict positive outcomes, inconsistencies in how these effects are measured make it difficult to draw clear conclusions. The review recommended developing better tools to assess the full range of subjective experiences during psychedelic therapy, which could help improve both research and clinical practice.

The Other Psychedelic Studies from September 2024

In addition to the studies we’ve discussed, here is a brief recap of two animal studies we covered this month.

• A rat-based study examined how different serotonin receptors influence the claustrum’s response to psychedelics, discovering that this brain region is rich in 5-HT2C receptors on glutamatergic neurons and that both serotonin and the psychedelic drug DOI have opposite effects on synaptic signaling mediated by these 5-HT2C receptors, challenging the previous belief that 5-HT2A receptors were primarily responsible.
• A pilot case study reported that administering a single low dose of 1cp-LSD (5 micrograms) to a 13-year-old dog with separation-related anxiety significantly reduced the animal’s anxiety after two hours, with no adverse effects or signs of a psychedelic experience observed during the 5.5-hour observation period.

What you can find on Blossom

Last month, we added 18 studies to the database of over 2150 research publications. Our link overview provides links to an additional 117 studies.

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