Psychedelic Research Recap April 2023
Psychedelic Research Recap April 2023
April was a month marked by nearly a dozen brain imaging studies on the effects of psychedelics. Jumping out from the pack is the highly anticipated extended DMT study which now has data on the psychological and physiological effects. Other studies (of the 20 total this month) investigate psychedelics for stuttering, its impact on narcissism, and our perception of time.
Welcome back to consensus reality
Last September, Lisa Luan presented the first results of the extended DMT study at ICPR. Since then, everyone has been eagerly awaiting the results of the DMT study, where 11 participants received a bolus (one big dose) and then an infusion to keep them at the same approximate level of high (both physiologically – blood plasma concentration, and psychologically, though the trip became slightly less intense at the end). The results have come back positive, meaning that the method of administration was effective, and participants were safe and tolerated (i.e. didn’t go bonkers) the infusion.
The participants in the study received multiple infusions, each with a strength between a very low dose to a dose that they consistently rated 9-10/10 on the intensity scale. Within 12 minutes after the infusion, they were back on earth with both feet.
Unlike many of the studies I cover here, this one isn’t looking directly at the application in mental health care. The study is primarily investigating what happens during the DMT experience. Extending it to over 30 minutes may help provide a clearer picture than what has been discovered in shorter (10-15min) trips after smoking or injecting only at the start.
More data from this study will come out later this year. It lays the groundwork for further explorations with extended DMT infusion, first theorized six years ago (in the scientific literature, though psychonauts probably have dreamt of this for much longer).
Sticking with DMT, a pharmacokinetics study sheds more light on how the body processes DMT (in this case, that from Small Pharma – SPL026). I covered the study when it came out as a pre-print, but it’s good to see it now being published so even more people have access to the information on how DMT and the body interact.
Narcissistic personalities, stuttering, long-term neurocognitive effects, and more outcomes
Before I dive back into the brain, there are more studies to cover that look at the outcomes of psychedelics. There is no big study that came out that looked at clinical populations, though MAPS did report – in a sparse press release – that their Phase IIIb results were on par with earlier published results.
An interview study of more than 100 people who had used ayahuasca found no significant change in self-reported narcissism. The study asked participants to complete questionnaires before, right after, and three months after the ceremonial use of ayahuasca. This is the fifth study (in our database) to look at narcissism, with onlya large survey finding connectedness and empathy correlated with decreased levels of narcissism.
By analysing posts on Reddit, researchers map out the effects of psychedelics on stuttering. Though the data is very rough (it’s just a scrape of what people have said online without any verification), 75% report benefitting from psychedelics (versus 10% saying it was detrimental). Future studies could dive into the mechanisms and possible therapeutic combinations that could help about 1% of the adult population.
However promising, negative responses to psychedelics are also possible, and a survey plus interview study dives into potential causal factors. Risk factors include unsafe environments, prior psychological vulnerabilities, unknown (or high) drug substances, and doing psychedelics at a young age. The researchers conducted interviews with only 15 people, so larger studies should be done to verify if these themes are common factors for others.
Four ketamine infusions, in those with treatment-resistant depression (TRD), led to improvements in cognition that lasted up to five weeks later. This open-label study matches more than a dozen other studies that find improvements in cognitive function after using psychedelics. But the small trial is in conflict with a 2022 meta-analysis that finds no effect on cognition after ketamine.
A re-analysis of microdosing (up to 20μg) LSD finds that LSD reduces the influence of our expectations (the top-down model) on what we think time should feel like. This aligns with other studies that point towards relaxed priors (expectations).
Finally, a Phase I trial conducted by ATMA Journey Centers finds psilocybin to be safe and without unhealthy changes in blood pressure.
Whole brain imaging
Seven more psychedelic brain imaging studies were published in April. One study focused on LSD’s impact on whole-brain effective connectivity, revealing decreased brain connectivity and increased self-inhibition in certain regions. An analysis of data from psilocybin therapy for treatment-resistant depression (TRD) found an elevated response to music after treatment, with significant correlations between ALFF in music-related clusters and subjective effects felt during dosing sessions.
A re-analysis of a ketamine trial on late-in-life treatment-resistant depression found increased neural complexity markers 30 minutes post-infusion, but no relationship between complexity and depressive symptom reduction. Another ketamine study, this time in mice, revealed that repeated ketamine administration leads to a dosage-dependent decrease of dopamine neurons in the midbrain and an increase in the hypothalamus, with divergently altered innervations in various brain areas.
A whole-brain simulation examined the entropic effects of serotonin 2A receptor activation, showing that increased entropy is primarily localized in visuo-occipital regions and is closely related to the brain’s anatomical connectivity. Another comparative study looked at the effects of nitrous oxide, ketamine, and LSD and found that all three drugs reduced connectivity within certain networks while enhancing connections between different networks, particularly in areas important for conscious experiences.
Finally, a double-blind study combining EEG with transcranial magnetic stimulation (TMS) found that psilocybin produces a chaotic pattern of brain activity but didn’t significantly impact the Perturbational Complexity Index (PCI) when compared to placebo.
These studies – which often go above my paygrade – collectively offer valuable insights into the neurobiological mechanisms underlying the effects of psychedelics and other substances on the brain. Researchers are uncovering potential biomarkers and therapeutic targets for various psychiatric conditions by identifying commonalities in how these substances affect brain connectivity. Moreover, the innovative use of neuroimaging techniques, such as fMRI, EEG, and TMS, is broadening our understanding of how these substances alter the brain’s dynamic properties and organisation.
The other studies that came out in April
A surveyasked people where they gathered information on psychedelics. Alas, there were more options than only Blossom (though other sites offer more info for recreational users). Internet websites (I’ll take it as a win), friends, discussion forums, books, and scientific journals were among the most often mentioned sources. Among the most trusted are journal articles, non-profits in the space, and university researchers.
Another survey, this time in Canada, adds more info on what psychedelics are being used in the land of hockey players. No surprises are found in the data, though slightly over half report a challenging psychedelic experience (also see earlier). Conversely, four out of five report positive life changes from psychedelics.
Finally, several esteemed researchers put forth a critique of the mystical experience measurements that are commonly used in psychedelic research. The article maps out the zeitgeist through which the current measures were developed and shapes a path towards non-mystical approaches to the overwhelming – especially after 30 minutes of DMT infusion – experiences one can have on psychedelics.
Papers Published in April 2023
18 studies from the Blossom database published this month.
Altered State of Consciousness and Mental Imagery as a Function of N, N-dimethyltryptamine Concentration in Ritualistic Ayahuasca Users
This observational study (n=24) analysed mental imagery during ayahuasca use among Santo Daime church members. Results showed increased feelings of boundlessness and ego dissolution, correlating with peak DMT concentration, while mental imagery measures didn't significantly differ. The study suggests DMT drives the primary ayahuasca experience with long-term use possibly reducing its impact on mental imagery.
Group format psychedelic-assisted therapy interventions: Observations and impressions from the HOPE trial
The HOPE trial reports qualitative observations from an open‑label pilot of group‑format psilocybin‑assisted therapy in people with cancer‑related depressive disorders, based on participant written reports and therapist feedback. It synthesises those impressions into practical recommendations for protocol design, screening, space and music considerations, therapist team structure and group process to inform future group‑based psychedelic therapy studies.
Reporting of harms in clinical trials of esketamine in depression: a systematic review
This systematic review (s=10 trials) evaluates the quality of adverse event (AE) reporting in published clinical trials studying esketamine for resistant depression. It reveals that 41.5% of serious AEs and 39% of non-serious AEs were not reported in the published articles compared to ClinicalTrials.gov, with the majority being psychiatric and cardiovascular events and 94% concerning patients from esketamine groups.
“How Do I Learn More About this?”: Utilization and Trust of Psychedelic Information Sources Among People Naturalistically Using Psychedelics
This online survey (n=1221) examines people's information-seeking behaviour using psychedelics naturally, revealing that most participants rely on their own experimentation and experiences, Internet websites, friends, discussion forums, books, and scientific journals. The study also found that articles in scientific journals, psychedelic nonprofits, and university researchers were the most trusted sources, while government agencies and pharmaceutical companies were the least trusted.
Self-reported effects of classic psychedelics on stuttering
Analysing self‑reports posted on Reddit, the authors found that nearly three‑quarters of people who stutter reported overall positive effects from classic psychedelics—notably reduced stuttering and greater speech control—while about 10% reported negative behavioural effects. These preliminary findings suggest classic psychedelics may merit formal investigation as an adjunct in psychedelic‑assisted speech therapy.
A Phase I trial to inform clinical protocols for the safe administration of psilocybin-assisted psychotherapy
In this Phase I trial of 25 mg psilocybin in 14 healthy adults, transient but clinically tolerable increases in blood pressure and heart rate were observed with no unexpected or long-term adverse events, supporting focused, limited cardiovascular screening for safe clinical use. Participants also reported full mystical experiences and a statistically significant reduction in QIDS-SR16 scores at eight weeks, indicating preliminary therapeutic benefit.
Neural complexity EEG biomarkers of rapid and post-rapid ketamine effects in late-life treatment-resistant depression: a randomized control trial
In older adults with treatment‑resistant depression, a single sub‑anaesthetic ketamine infusion produced transient increases in EEG neural complexity (Lempel‑Ziv complexity and multiscale entropy) 30 minutes post‑infusion and subsequent reductions in MSE at later post‑rapid timepoints. These time‑varying, system‑wide complexity changes — detectable beyond the gamma oscillation window — suggest neural complexity is a promising non‑linear, amplitude‑independent biomarker of ketamine’s cortical effects, although it did not predict clinical improvement.
A whole-brain model of the neural entropy increase elicited by psychedelic drugs
Using a whole‑brain model of serotonergic neuromodulation, the authors reproduce the global increase in spontaneous neural entropy caused by 5‑HT2A receptor agonists and provide the first model‑based mechanistic explanation for this effect. They further show that entropy increases are largest in visuo‑occipital regions and that the whole‑brain reconfiguration is better explained by the topology of anatomical connectivity than by receptor density.
Whole-brain mapping reveals the divergent impact of ketamine on the dopamine system
This pre-print brain-mapping study in mice (2023) shows that repeated ketamine administration decreases dopamine neurons in the midbrain and increases in the hypothalamus. It also reveals further evidence for the plasticity-increasing effects of ketamine.
LSD microdosing attenuates the impact of temporal priors in time perception
Pre-registered re-analysis of Yanakieva et al. (2019) shows that LSD microdoses (5–20 μg) reduce the influence of precision-weighted local temporal priors, thereby attenuating the typical under-reproduction bias in time perception. Controlling for those precision-weighted local priors eliminated the LSD effect, indicating the drug acts by downweighting local priors.
Neurocognitive effects of subanesthetic serial ketamine infusions in treatment resistant depression
This open-label study (n=66) finds that four ketamine infusions (35mg/70kg) led to improvements in cognition both immediately (measured after the first and fourth infusion) and up to five weeks later. As seen in other studies, antidepressant effects reverted to baseline at five weeks.
Perspectives on the therapeutic potential of MDMA: A nation-wide exploratory survey among substance users
In a nation-wide survey of 918 people with alcohol or substance use disorders, most respondents supported medical research into MDMA, believed MDMA-assisted therapy might be useful, and 58.8% were willing to try it; support and belief did not differ by race or ethnicity, though small disparities arose in willingness and concerns. These findings indicate broadly positive patient-level attitudes toward MDMA-assisted therapy and point to areas to address for equitable access and more diverse research participation.
Ketamine vs Electroconvulsive Therapy for Major Depressive Episode: A Systematic Review and Meta-analysis
This systematic review & meta-analysis of five RCTs (ketamine: n=141; ECT: n=137) compared the efficacy & safety of ketamine and electroconvulsive therapy (ECT) in adults with major depressive episodes. The results suggested that ECT was superior to ketamine in post-treatment depression ratings, response rates, and remission rates one week after treatment. However, there was no significant difference between the groups in the number of sessions to response and remission or cognitive outcomes.
Psychedelic-induced mystical experiences: An interdisciplinary discussion and critique
This review (2023) discusses the limitations and biases in using psychometric assessments to measure mystical experiences in psychedelic research. The authors argue that the existing operationalizations of mystical experiences fail to acknowledge their Christian bias and suggest more culturally-sensitive approaches. They also propose complementary non-mystical approaches to understanding similar phenomena for more robust theoretical and empirical approaches.
A transdiagnostic systematic review and meta-analysis of ketamine's anxiolytic effects
This transdiagnostic meta-analysis of 14 randomised controlled trials (most with high risk of bias) found that ketamine produced significant anxiolytic effects versus placebo at acute (<12 h; SMD −1.17), subacute (24 h; SMD −0.44) and sustained (7–14 days; SMD −0.40) time points. Subacute and sustained anxiety improvements correlated with antidepressant effects but not with peak dissociation, suggesting ketamine provides rapid and 1–2 week anxiety relief across clinical settings.
Examining the Therapeutic Effect of Ceremonial Ayahuasca on Narcissistic Personality and Antagonistic Externalizing in Adults
In a sample of 314 adults, ceremonial ayahuasca use was associated with modest self-reported reductions in some narcissistic antagonism facets (lower entitlement-exploitativeness, higher leadership authority, reduced NPD proxy) lasting up to three months. Effects were small, mixed across measures and not corroborated by informants, indicating no meaningful change and highlighting the need for further targeted research, especially in high-antagonism samples with antagonism-focused therapy.
Prevalence and associations of challenging, difficult or distressing experiences using classic psychedelics
This survey study (n=2822) examined the prevalence and associations of challenging, difficult, or distressing experiences using classic psychedelics in a subsample of respondents (n=613) who reported lifetime classic psychedelic use. Of those, 59% indicated no challenging experiences, 9% indicated having a difficult experience lasting more than one day, and 2.6% reported seeking medical/psychiatric/psychological assistance.
Single-dose psilocybin for a treatment-resistant episode of major depression: Impact on patient-reported depression severity, anxiety, function, and quality of life
This re-analysis of the COMPASS Phase IIb RCT with psilocybin (25/10/1mg; COMP360) finds significantly higher scores on patient-reported depression severity, anxiety, positive affect, functioning, quality of life, and cognitive function. Though the main finding of the study was less impressive than hoped, all patient-reported measures show that the high dose of psilocybin (25mg) led to better outcomes.