Psychedelic Research Recap November 2023
Psychedelic Research Recap November 2023
This November, we saw promising developments across various areas of psychedelic research. To start, an innovative study explored novel routes of administering ayahuasca-analogue compounds, potentially improving tolerability. Additionally, several surveys shed light on the impacts of psychedelic experiences on measures like alcohol use and spiritual well-being.
We also saw advances in unravelling the complex mechanisms of classic psychedelics and their therapeutic metabolites. Beyond pharmacology, perspectives were offered on providing post-trial care provisions for psychedelic study participants. Quantitative analysis revealed insights into first-time ayahuasca experiences in depressed individuals.
In November, 14 articles were added to the database (inching us ever closer to 2000 articles), from epidemiological insights to tracking psychedelic states via heart rate dynamics.
In this recap, I’ll highlight findings across pharmacokinetics, substance use disorders, adverse reactions, and mechanisms of action.
Check out the monthly link overview for all studies that we didn’t add to the database.
Ayahuasca Enters Clinical Trials
This first-in-human pilot study tested novel DMT and harmine formulations to overcome the limitations of traditional ayahuasca. Oral administration induced fewer side effects than botanical ayahuasca but showed high interindividual pharmacokinetic variability in absorption. The unpredictable dose-response relationship and subjective effects cast doubt on meeting regulatory standards for clinical use.
However, combined intranasal DMT with buccal harmine yielded substantially improved pharmacokinetic profiles. The approach demonstrated more predictable systemic exposure and was well-tolerated. Allowing self-titration of repeated nasal DMT puffs promoted safety and tolerability. While expectation effects remain, the method appears valuable for future psychiatric research. Overall, bypassing oral administration significantly enhanced precision, consistency, and acceptability – making way for translational ayahuasca research. In other words, this research could be the first step towards making ayahuasca more suitable as a medicine within the Western paradigm.
An interview study helps further examine ayahuasca’s subjective effects on first-time users. The quantitative analysis of self-reports from depressed patients and healthy controls identified five categories of experiences. These included altered consciousness, cognitive changes, bodily reactions, and audiovisual phenomena. Notably, individuals with depression reported more negative somatic effects. The study highlights subjective axes of psychedelic experiences that could inform therapeutic approaches.
The final ayahuasca study gathered perspectives from ayahuasca ceremony leaders on special considerations for participants with eating disorders. The analysis identified screening procedures, managing purging/diets, assessing risks, and integrating with conventional treatment. Findings emphasized careful screening and support to promote safe, beneficial experiences for this population. As ayahuasca use increases globally, developing knowledge on these topics is pressing yet complex.
Psychedelic Survey Studies in November 2023
This month featured several noteworthy survey studies investigating the impacts of naturalistic psychedelic use across dimensions of substance use, spirituality, and mental health.
First, a retrospective online survey found psychedelic experiences were associated with reduced alcohol consumption and dependency. Subjects reporting improvements initially had more severe alcohol use disorder and lower psychological flexibility. Changes correlated with mystical experience intensity and increased flexibility afterwards.
Another cross-sectional survey assessed the Spiritual Well-Being Scale among psychedelic users and non-users. The analysis found religious well-being showed superior reliability and validity compared to existential well-being. Intriguingly, spiritual well-being followed a U-shaped curve regarding psychedelic use frequency (those with no or frequent use both scored better on the well-being scales than those with infrequent use).
Finally, an online survey of over 800 Norwegian adults revealed primarily recreational (46%) or therapeutic (42%) motivations for memorable psychedelic experiences. Most reported improvements in self-perceived mental health conditions despite adverse reactions in a subset.
Together, these surveys demonstrate promise but also risks of naturalistic psychedelic use.
Reviewing the Vast Universe of Psychedelic Research
This month featured insights into the complex pharmacology of ibogaine for treating substance use disorders. One review examined its modulation of multiple addiction-related targets, emphasizing a multi-target approach given its actions on opioid, serotonin, NMDA, and other receptors.
Additionally, a scientometric analysis tracked ibogaine publications over 30 years, revealing rising interest and evolving focus – from cocaine and alcohol initially to opioids and psychedelics more recently.
In other developments, a mini-review explored classic psychedelics like psilocybin and LSD, looking beyond their primary 5-HT2A agonism at interactions with 5-HT1A, 5-HT2C, and neurotrophin receptors. It highlighted pursuing non-hallucinogenic derivatives and roles in protein modification.
Additionally, a systematic review investigated psychedelic interactions with drugs like antidepressants, antipsychotics, and recreational substances. Effects ranged from attenuated to potentiated, emphasizing the need to elucidate underlying pathways (especially if psychedelics want to be used as licensed medicines, the interactions with many common medications are still relatively unknown).
Tracking Psychedelic States
This month also featured insights into tracking psychedelic states via physiological and neuroimaging metrics. One preprintintroduced a Bayesian framework assessing heart rate dynamics across psychedelics like DMT and ketamine. It revealed consistent increases in heart rate variability and entropy, relating to subjective effects and complementary to brain signals.
Additionally, a reanalysis of psilocybin data found functional connectomes became more individualized under the drug. Isolating default mode network patterns predicted subjective drug experiences characterized by altered within-network and between-network connectivity.
Papers Published in November 2023
15 studies from the Blossom database published this month.
The Integration of Classic Psychedelics into Current Substance Use Disorder Treatment Models
This review (2023) discusses the potential integration of classic psychedelic-assisted therapies (PAT) into current clinical practices for substance use disorders (SUDs). With promising results from initial studies, the authors suggest that classic psychedelic-assisted therapies could become legally available options for SUD patients in the future. The article outlines contemporary evidence-based treatments for SUDs and proposes that classic psychedelic-assisted therapies can be broadly compatible with existing mainstream SUD treatment paradigms, offering a new avenue for exploration in addressing these disorders.
Overcoming the clinical challenges of traditional ayahuasca: a first-in-human trial exploring novel routes of administration of N,N-Dimethyltryptamine and harmine
This open-label within-subject study (n=10) compared the oral administration of a capsule (containing DMT and harmine) with combined intranasal administration of an oromucosal harmine tablet and an intranasal DMT spray at two doses. The research aimed to improve the pharmacokinetics and tolerability profiles of ayahuasca-analogue formulations. Results indicate that the combined buccal/intranasal administration substantially attenuated common side effects and yielded significantly improved pharmacokinetic profiles. This suggests it may be an innovative approach for the safe and patient-oriented administration of DMT/harmine for treating affective disorders.
5-MeO-DMT for post-traumatic stress disorder: a real-world longitudinal case study
This first longitudinal case study reports that a single inhaled dose of toad‑derived 5‑MeO‑DMT produced rapid, clinically significant and sustained reductions in PTSD symptoms, hopelessness and suicide risk in a 23‑year‑old woman, with the participant endorsing a complete mystical experience and no drug‑related serious adverse events. Improvements persisted to 12 months but were accompanied by acute nausea, overwhelming subjective effects and later night terrors, and the authors emphasise the single‑case design is non‑generalizable and requires controlled replication.
Drug-drug interactions involving classic psychedelics: A systematic review
This systematic review of 52 studies (n=7102) investigates drug-drug interactions between classic psychedelics (LSD, psilocybin, mescaline, DMT, 5-MeO-DMT, and ayahuasca) and various drugs, including antidepressants, antipsychotics, anxiolytics, mood stabilizers, and recreational drugs. The findings reveal diverse interactions, ranging from attenuated to potentiated effects, with a few cases reporting no changes. Despite a lack of serious adverse events in most studies, the review emphasizes the need for a comprehensive understanding of potential interactions and explores molecular pathways underlying observed effects.
Reduction of alcohol use and increase in psychological flexibility after a naturalistic psychedelic experience: a retrospective survey
In a retrospective survey of 160 people, a naturalistic psychedelic experience was associated with significant reductions in drinking days per week and AUDIT scores and with increased psychological flexibility. Greater reductions in alcohol use were linked to higher baseline AUD severity and lower baseline psychological flexibility, and were associated with the intensity of the mystical experience and with increases in psychological flexibility.
Spiritual Well-Being Among Users and Non-Users of Psychedelics: A Cross-Sectional Study
This cross-sectional survey (n=517) assessed the psychometric properties of the Spiritual Well-Being Scale (SWBS) concerning existential well-being (EWB) and religious well-being (RWB). The study found that the RWB factor exhibited superior psychometric indices for validity, group discrimination, and reliability, showing a U-shaped pattern in the association between psychedelics and spiritual well-being, where non-users and frequent users had higher RWB and EWB indices than occasional users.
Epidemiology of classic psychedelic substances: results from a Norwegian internet convenience sample
In a cross-sectional internet convenience sample of 770 self‑selecting Norwegian adults reporting a memorable classic psychedelic experience (predominantly psilocybin), most used psychedelics for recreational or therapeutic reasons and reported self‑perceived improvements in mental health and substance‑use symptoms, with many preparing, processing and integrating the experience though few received therapist support. Adverse reactions were generally mild and short‑lived but lasted one year or more in 4.2% of participants, including persistent flashbacks in 2.9%.
A quantitative textual analysis of the subjective effects of ayahuasca in naive users with and without depression
Using quantitative textual analysis of open-ended reports from first-time ayahuasca users (9 with treatment-resistant depression, 20 healthy controls), the study identified five core experiential clusters—altered states of consciousness, cognitive changes, somatic alterations, auditory experiences and visual perceptual content—and found that participants with depression reported more aversive bodily reactions. These findings align with central axes of the psychedelic experience and may inform therapeutic applications of ayahuasca.
Ayahuasca ceremony leaders' perspectives on special considerations for eating disorders
This qualitative study (n=15) explores the perspectives of ayahuasca ceremony leaders, primarily from the West/Global North, on the suitability of ceremonial ayahuasca use for individuals with eating disorders (EDs). The analysis identifies categories such as screening for EDs, purging and dietary restrictions, potential risks, and complementarity with conventional ED treatment. The findings suggest the need for careful screening and extra support to ensure safe and beneficial ayahuasca ceremony experiences for individuals with EDs.
The entropic heart: Tracking the psychedelic state via heart rate dynamics
The authors introduce a Bayesian framework to estimate heart-rate entropy (and Bayesian mean HR and HRV) under psychedelics and apply it to data from LSD, DMT, psilocybin and sub‑anaesthetic ketamine. They report consistent increases in mean HR, high‑frequency HRV and heart‑rate entropy during the psychedelic state, with heart‑rate entropy predicting subjective dimensions and correlating with brain entropy, suggesting a cost‑efficient autonomic marker for tracking subjective and neural psychedelic effects.
Beyond the 5-HT2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action
This mini-review (2023) provides insights into the complex mechanisms of action of serotonergic psychedelics, such as psilocybin and LSD, emphasizing their activation of serotonin receptors, particularly 5-HT2A receptors, leading to alterations in perception, cognition, and emotions. The review explores the role of neuroplasticity in their therapeutic potential for mental health conditions and discusses interactions with other serotonin receptor subtypes and neurotrophin receptors. Additionally, it highlights the emerging interest in developing non-hallucinogenic derivatives to retain therapeutic benefits while minimizing the risk of adverse reactions and explores the potential of psychedelics in post-translational modification of proteins as part of their mechanism of action.
Main targets of ibogaine and noribogaine associated with its putative anti-addictive effects: A mechanistic overview
This review (2023) examines ibogaine as a potential treatment for substance use disorders (SUDs). The lack of randomised, controlled studies on its safety and efficacy and the elusive mechanisms of action have been barriers to clinical use. The review suggests that ibogaine and its metabolite, noribogaine (NOR), modulate multiple targets associated with SUDs, emphasizing a complex, multi-target approach to understanding its pharmacology.
Three Decades of Research on the Development of Ibogaine Treatment of Substance Use Disorders: A Scientometric Analysis
This review (2023) examines the interest in ibogaine's therapeutic potential for substance use disorders over three decades (1993-2022). The study identifies a linear growth of publications in the first and third decades, with academic research centers in the United States and Canada being the most productive. Major keywords shifted from cocaine, tobacco, morphine, and alcohol in the first two decades to opioids and psychedelics in the third decade, indicating evolving research trends.
When the Trial Ends: The Case for Post-Trial Provisions in Clinical Psychedelic Research
This perspective article (2023) discusses the ethical considerations of providing post-trial access (PTA) in psychedelic clinical trials. It highlights the unique aspects of psychedelic trials, such as the legal status of psychedelics, the researcher-participant relationship, and the extended therapeutic process, as factors supporting the case for introducing PTA. The authors also advocate for a broader focus on post-trial care beyond access and provide an overview of potential provisions for psychedelic clinical trials, emphasizing the development of infrastructure for the post-legalisation psychedelic medicine ecosystem.
Psilocybin induces acute and persisting alterations in immune status in healthy volunteers: An experimental, placebo-controlled study
This double-blind placebo-controlled paper (n=60) explores the effects psilocybin (12mg/70kg) has on a range of inflammatory markers associated with stress-related psychiatric disorders. Blood samples, MRI and questionnaires were used to assess different aspects of the immune response. Psilocybin immediately reduced levels of the inflammation-inducing TNF-α while other markers were unchanged. After seven days, TNF-α returned to baseline while levels of IL-6 and CRP were reduced in the psilocybin group, which were associated with more persisting positive mood and social effects.