Psychedelic Research Recap June 2023
Psychedelic Research Recap June 2023
June was jam-packed with psychedelic research, with (again) adding one paper a day to the database (30 total & 100+ to the Junelink overview).
We got new insights into the mechanisms through which psychedelics work their magic (from new receptors to the long-awaited ‘critical learning’ paper). Other clinical results covered everything from DMT for depression to psilocybin’s effect on memory. Outside the clinic, several survey studies find positive effects of psychedelics on grief and smoking cessation. Finally, several articles dive into research methods and placebo effects.
The mechanisms behind how psychedelics work their magic
Two studies in mice are updating how we think about how psychedelics work. The first comes from Gul Dölen’s lab and shows how psychedelics (from ketamine to mescaline) open a ‘social reward learning period’. The seminal work, presented at conferences before (but in review for over a year), builds a common bridge between psychedelics. The underlying neurological explanation concerns restoring the oxytocin-mediated long-term depression (lowering) in the nucleus accumbens (part of the ‘reward’ system).
On this level, and also in mice, another groundbreaking study argues that the BNDF (brain-derived neurotropic factor, implied in neuronal growth) receptor TrkB (‘turk-bee’) is the relevant target for antidepressants. In other words, this pathway is argued to be independently responsible for antidepressant effects from the serotonin (5-HT2a) receptor activation. Studies from other labs are on the way to confirm these findings.
Going back to the psychological level, self-compassion is argued to lead to positive outcomes in those treated with psilocybin-assisted therapy for alcoholism (AUD). An interview study finds that trial participants were better able to process emotions related to past events, promoting self-compassion, self-awareness, and feelings of interconnectedness, which laid the foundation for better regulation of negative emotions and improved the quality of relationships.
Another mechanism, the reduction of learned helplessness, is argued for in a review of the psychedelic-assisted therapies literature. The authors argue for the utility of the learned helplessness model in psychedelic research due to its robustness across species, well-described neurobiology, and substantial overlap with neural circuits involved in psychedelic actions.
If psychedelics lose their magic when combined with other drugs is a question for which there are but a few direct comparison studies. A systematic review tries to fill this gap in the literature by diving into all known combinations, including from research in the 60s. The findings reveal varied effects when psychedelics are combined with other drugs including antidepressants, antipsychotics, anxiolytics, mood stabilizers, and recreational drugs. Adding to this literature is a clinical trial with CBD and ayahuasca where no interaction effects were found.
One of the direct comparisons we have going on is the psilocybin vs escitalopram (SSRI) trial. For the latter group, responsiveness to emotional faces was reduced. Another analysis of the same trial finds that in both groups there were significant personality changes (but no significant difference between groups). An online survey also finds that those who use antidepressants (SSRIs/SNRIs) often experience weaker effects than expected when taking psilocybin.
New clinical results from psychedelic trials
Two studies investigated the effects of DMT. Thefirst was another infusion study of DMT in healthy volunteers. Just likein the study in April, participants tolerated the infusion well. This time the effects were spread out over an even more extended period, up to 90 minutes.
The second study looked at inhaled (vaporized) 5-MeO-DMT (a similar molecule but still very distinct effects) and the antidepressant effects of 6 to 18mg. The study was conducted with 16 people suffering from treatment-resistant depression (TRD) and in both phases eight people participated. The headline result is that in the Phase II (up to three doses) study 87.5% (7 of 8) were in remission seven days after the final administration.
The HOPE trial, where psilocybin-assisted therapy (PAT) is tested in those suffering psychologically from a cancer diagnosis, has published positive findings in reducing depressive symptoms. Earlier this year, we already heard about the positive qualitative experiences of participants. The current study confirms earlier positive findings in palliative care but adds that a large part of the treatment was done in a group model. New results from earlier studies A re-analysis of a study with psilocybin for depression, this time looking at the EEG measures, finds that EEG theta power doubled in amplitude two weeks after psilocybin administration. The power increase correlated with improvements in depression symptoms, but the main study didn’t find a significant effect versus placebo.
Another re-analysis examines the effects of LSD microdosing (10μcg; 14x; 6w) on sleep in healthy adult male volunteers. This is one of the only clinical trials with microdoses, where the dose is controlled, but participants spend most of the time at home. A sleep tracker showed longer sleep (almost 30 minutes) on the night after microdosing compared to the placebo group.
Sticking with sleep and with re-analyses of trial data, one study looked at daytime and sleep-related declarative memory consolidation in healthy trial participants. The results showed that psilocybin didn’t improve memory consolidation, but importantly, it also didn’t negatively affect memory consolidation.
Finally, an analysis of the interaction between music and a moderate dose of LSD finds that the combination led to changes in the time-varying brain activity of the task-positive state, with music potentially having a long-term influence on the resting state, particularly on states involving task-positive networks. The study concludes that music, as a crucial component of “setting,” may influence the resting state during a psychedelic experience.
Smoking cessation, grief improvement, belief changes and more survey results
In line with clinical studies, a survey study of over 150 people finds that after a psychedelic experience, respondents significantly reduced the number of cigarettes smoked. Those who had a (fuller) mystical experience and those who were initially less psychologically flexible were the ones who improved the most.
An even larger survey study of over 350 people finds improvements in grief symptoms after a psychedelic experience. This was correlated with emotional breakthroughs during the trip and negatively correlated with challenging experiences.
Going one step larger, a survey of over 1600 people investigated how they integrated ayahuasca experiences. The participants described the integration experiences along three lines: overall appraisal (easy, challenging, or long-term/ongoing), beneficial tools facilitating integration (connecting with a like-minded community, yoga, meditation, journaling), and integration challenges (feeling disconnected or reconciling new understandings with old life). The findings suggest that integration can be challenging and time-consuming, but addressing these challenges may facilitate positive growth.
Bringing together elements of the two previous studies is a survey of 340 people who went to ayahuasca ceremonies and re-experienced adverse life events (e.g. combat-related trauma). Reexperiencing was associated with cognitive reappraisal, psychological flexibility, discomfort during ceremonies, and greater reductions in trait neuroticism post-ceremony.
A pre-print of a longitudinal survey (given over multiple points of time) challenges a long-held finding relating to psychedelics and beliefs. The 650-person survey does find that those who use psychedelics ascribe ‘mind perception’ to more (non-)living targets (e.g. plants, animals) – this was also found in another longitudinal survey. But participants didn’t change their assessment along the Atheist-Believer scale – contradicting the earlier findings.
The other psychedelic studies that came out in June 2023
Here are the other psychedelic studies – with enough significance that they have been added to the database – from June 2023: A review covers ‘placebo’ and proposes a new framework around ‘set and setting’, inspired by the field of psychedelic science.
Looking at the methodology of psychedelic trials, a commentary suggests that causal mediation analysis using objective biomarkers could help establish causal pathways between treatment and outcome, providing greater confidence in the efficacy of psychedelic therapies before they are approved as regular medicines.
A review of the literature brings together everything we know about psychedelic-assisted therapy for treating addictions.
A prospective survey found that participants of an ayahuasca retreat significantly increased in nature-relatedness and -appreciation (and gratitude) one week and one month later. Ratings of the trip on mystical experience and awe correlated weakly with these changes.
Psilocybin use has drastically increased (x2) between 2018 and 2021 among young adults. The use of LSD stayed relatively flat, a cohort study of over 11.000 people found.
Do we know if microdosing is a placebo? A recent review argues there isn’t enough evidence to claim it’s predominantly so.
A small RCT (with 27 people) compared ketamine versus midazolam (benzodiazepine) whilst exposure therapy was given in both groups. The PTSD symptoms improved equally in both groups, but the ketamine group showed lower amygdala and hippocampus reactivation to trauma memories than midazolam recipients. Finally, an economic analysis assesses the cost-effectiveness of psilocybin-assisted psychotherapy (PAT) versus conventional medication, cognitive behavioural therapy (CBT), and the combination of the two for difficult-to-treat depression (in the UK). The decision model simulates patient outcomes (response, remission, and relapse) and analyses costs and quality-adjusted life years (QALYs) over six months. PAT was not cost-effective unless therapists’ (and drug) prices declined.
Papers Published in June 2023
28 studies from the Blossom database published this month.
Harnessing placebo: Lessons from psychedelic science
This review/hypothesis article (2023) proposes a new framework inspired by the field of psychedelic science, specifically focusing on the concept of “set and setting” to understand better and utilize the placebo effect in clinical settings. The authors argue that randomised controlled trials (RCTs), while helpful in evaluating the efficacy of drugs, can overlook the significance of contextual and personal factors that interact with and shape drug effects, and suggest an integrative approach that acknowledges the synergy between drug and non-drug factors for improved patient care.
Sub-acute effects of psilocybin on EEG correlates of neural plasticity in major depression: Relationship to symptoms
In a double‑blind, placebo‑controlled within‑subject study of 19 individuals with major depression, a single 0.3 mg/kg dose of psilocybin produced a twofold increase in auditory‑evoked theta (4–8 Hz) power at two weeks that correlated with reductions in GRID‑HAM‑D‑17 scores, whereas placebo produced no change. This sustained theta enhancement—interpreted as an EEG correlate of long‑term potentiation—may serve as a biomarker of psilocybin‑induced neuroplasticity underlying its antidepressant effects.
Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression
This open-label, randomised trial (n=403) compared the effectiveness of iv ketamine (35mg/70kg, 6x, 3w) and electroconvulsive therapy (ECT) in treating treatment-resistant major depression (TRD). The results showed that 55.4% of patients in the ketamine group and 41.2% in the ECT group responded to the treatment, indicating ketamine was noninferior to ECT. ECT was associated with a temporary decrease in memory recall, while ketamine was associated with dissociation. Both treatments had similar improvements in patient-reported quality of life, with ECT having musculoskeletal adverse effects.
Impact of a Naturalistic Psychedelic Experience on Smoking: A Retrospective Survey
This retrospective online survey (n=173) examined the impact of a psychedelic experience on tobacco use among smokers. The results showed a significant decrease in the mean number of cigarettes smoked daily and tobacco dependency following a psychedelic experience. Participants who reduced or quit smoking had more intense mystical experiences during the psychedelic session and initially lower psychological flexibility. The study found that an increase in psychological flexibility after the psychedelic experience and personal motives for undergoing the session were significant positive predictors of smoking reduction or cessation.
Psychedelic Experiences After Bereavement Improve Symptoms of Grief: The Influence of Emotional Breakthroughs and Challenging Experiences
This survey (n=363) investigated the effects of psychedelic use on grief symptoms among individuals who had experienced a bereavement event. The results indicated significant improvements in grief symptoms following a psychedelic experience, with a large effect size (Cohen's d = 0.83). Emotional breakthroughs during the psychedelic experience were positively associated with improved grief symptoms, while challenging experiences had the opposite effect.
A phase 1/2 trial to assess safety and efficacy of a vaporized 5-methoxy-N,N-dimethyltryptamine formulation (GH001) in patients with treatment-resistant depression
In a Phase 1/2 trial of 16 adults with treatment‑resistant depression, inhaled 5‑MeO‑DMT (GH001) was evaluated as single doses (12 mg, 18 mg) and as an individualized regimen of up to three ascending doses in one day. GH001 was well tolerated and produced ultra‑rapid antidepressant effects, with remission at day 7 in 7/8 (87.5%) patients in the individualized dosing group, markedly higher than the single‑dose arms.
Interactive Effects of Ayahuasca and Cannabidiol in Social Cognition in Healthy Volunteers: A Pilot, Proof-of-Concept, Feasibility, Randomized-Controlled Trial
In a small randomised, placebo-controlled pilot trial in healthy volunteers, 600 mg oral cannabidiol given before ayahuasca produced no detectable interaction on facial emotion recognition, empathy tasks or subjective effects — both groups showed reduced reaction times and decreases in anxiety/sedation with no between-group differences. Ayahuasca with or without CBD was generally well tolerated, supporting feasibility of further, larger trials to confirm these null-interaction findings.
Learned Helplessness As a Potential Transdiagnostic Therapeutic Mechanism of Classic Psychedelics
This review/opinion article (2023) suggests that the reversal of and resilience against learned helplessness could be a key therapeutic mechanism of classic psychedelics in treating mood and substance use disorders. The authors argue for the utility of the learned helplessness model in psychedelic research due to its robustness across species, well-described neurobiology, and substantial overlap with neural circuits involved in psychedelic actions.
Overcoming blinding confounds in psychedelic randomized controlled trials using biomarker driven causal mediation analysis
This commentary (2023) suggests that causal mediation analysis using objective biomarkers could help establish causal pathways between treatment and outcome, providing greater confidence in the efficacy of psychedelic therapies before they are approved as regular medicines. This cautious approach is recommended to avoid potential drawbacks such as expanding indications based on low-quality evidence and unstable efficacy over time.
Psychedelics reopen the social reward learning critical period
This mice study shows that psychedelics (including ketamine & MDMA) open a social reward learning critical period. The duration of the drugs' effects in humans is proportional to the time it takes for the critical period to reopen. Additionally, the restoration of oxytocin-mediated long-term depression in the nucleus accumbens is associated with the reinstatement of social reward learning in adulthood. The study also found that reorganising the extracellular matrix is a common mechanism underlying the critical period reopening caused by psychedelic drugs.
Life after Ayahuasca: A Qualitative Analysis of the Psychedelic Integration Experiences of 1630 Ayahuasca Drinkers from a Global Survey
A global qualitative analysis of open‑ended responses from 1,630 ayahuasca drinkers identified three core aspects of post‑ceremony integration—overall appraisal (easy, challenging, ongoing), beneficial tools (community, somatic practices, journaling), and integration challenges (disconnection, reverting to old life)—and found integration is often lengthy and difficult yet can promote growth. The authors argue this challenges psychotherapy‑centred models of psychedelic aftercare and propose an expanded definition of integration that emphasises communal and somatic approaches alongside working through adjustment challenges.
Psychedelic therapy in the treatment of addiction: the past, present and future
This review (2023) charts the resurgence of interest in psychedelic therapy for treating addiction, beginning with historical studies from the mid-late 1900s, then examining real-world evidence from naturalistic, observational, and survey-based studies, and contemporary clinical trials ranging from first-in-human to Phase II. It also explores translational human neuropsychopharmacology techniques like fMRI and PET to understand the therapeutic mechanisms of psychedelics.
Assessment of the acute effects of 2C-B vs psilocybin on subjective experience, mood and cognition
In a within‑subjects, double‑blind, placebo‑controlled study of 22 psychedelic‑experienced volunteers, 20 mg 2C‑B produced acute psychedelic alterations of moderate experiential depth but elicited less dysphoria, subjective impairment, auditory changes and ego‑dissolution than 15 mg psilocybin. Both drugs produced comparable psychomotor slowing, spatial memory impairments and transient pressor effects, while 2C‑B’s subjective effects were shorter in duration (largely resolving within ~6 hours).
Effect of LSD and music on the time-varying brain dynamics
Analysing fMRI from 15 participants under LSD and placebo with an intervening music run, the study finds that music interacting with LSD alters time-varying dynamics of a task‑positive brain state, while LSD alone changes dynamics of a state combining DMN, somatosensory and visual networks. Crucially, the authors report that music may have a lasting influence on resting‑state dynamics, particularly for networks involved in task‑positive processing.
Prevalence and therapeutic impact of adverse life event reexperiencing under ceremonial ayahuasca
Among 339 ayahuasca retreat participants, reexperiencing of adverse life events during ceremonies was common—particularly sexual assault among women, combat trauma among veterans and in those with lifetime PTSD—and was linked to cognitive reappraisal, psychological flexibility and acute discomfort. Those who reexperienced adverse events showed larger reductions in trait neuroticism at follow-up, suggesting such reexperiencing may contribute to the therapeutic effects of ceremonial ayahuasca.
Attenuation of psilocybin mushroom effects during and after SSRI/SNRI antidepressant use
In a retrospective survey of psilocybin mushroom users, serotonergic antidepressants (SSRIs, SNRIs) were associated with substantially higher odds of weakened psilocybin effects—about 47% for SSRIs and 55% for SNRIs versus 29% for the non‑serotonergic antidepressant bupropion—and this attenuation persisted for up to three months after discontinuation. Sensitivity analysis excluding fluoxetine did not materially change the post‑discontinuation result.
Effects of ayahuasca on gratitude and relationships with nature: An open-label, naturalistic study
In an open-label naturalistic study of 54 retreat participants, ayahuasca use was associated with significant increases in gratitude, nature relatedness and nature appreciation at one week and one month post-retreat, with weak-to-moderate correlations between these increases and mystical-type experiences and awe but not ego dissolution. The findings suggest ayahuasca-occasioned mystical and awe experiences may lead to personality changes beneficial for mental health and prosocial behaviour, though further research is required.
Hallucinogen use among young adults ages 19-30 in the United States: Changes from 2018 to 2021
In a longitudinal US cohort of 11,304 young adults aged 19–30 surveyed 2018–2021, past‑year LSD use remained stable (≈3.7% to 4.2%) while non‑LSD hallucinogen use (e.g. psilocybin) roughly doubled from 3.4% to 6.6%. Use was more likely among males, white participants and those from higher socio‑economic backgrounds, and less likely among Black participants and those without a college‑educated parent.
Psychedelics promote plasticity by directly binding to BDNF receptor TrkB
This mice study investigated the antidepressant and neuroplastic effects of psychedelics, specifically lysergic acid diethylamide (LSD) and psilocin. The trial centres around their high-affinity binding to TrkB, a BDNF receptor implicated in antidepressant mechanisms. These substances bind to TrkB with affinities 1,000-fold higher than other antidepressants (SSRIs), and their effects on neurotrophic signalling, plasticity, and antidepressant-like behaviour in mice depend on this TrkB binding and promotion of endogenous BDNF signalling. Interestingly, these effects are independent of serotonin (5-HT) 2A receptor activation, suggesting that TrkB is a primary target for antidepressants.
Long term structural and functional neural changes following a single infusion of Ketamine in PTSD
This pilot RCT study (n=27) investigated the potential of a single ketamine infusion (35mg/70kg), followed by brief exposure therapy, to enhance the extinction of trauma memories in individuals diagnosed with PTSD. Participants were randomly assigned to receive either ketamine or midazolam after retrieval of the traumatic memory, and underwent trauma-focused psychotherapy 24 hours later for four days. While PTSD symptoms improved equally in both groups, post-treatment ketamine recipients showed lower amygdala and hippocampus reactivation to trauma memories than midazolam recipients, suggesting that ketamine may enhance the post-retrieval extinction of trauma memories.
Cost-effectiveness of psilocybin-assisted therapy for severe depression: exploratory findings from a decision analytic model
This study assesses the cost-effectiveness of psilocybin-assisted psychotherapy (PAP/PAT) versus conventional medication, cognitive behavioural therapy (CBT), and the combination of the two for difficult-to-treat depression (in the UK). The decision model simulates patient outcomes (response, remission, and relapse) and analyses costs and quality-adjusted life years (QALYs) over a 6-month period. PAT was not cost-effective unless therapists' (and drug) prices declined.
Personality change in a trial of psilocybin therapy v. escitalopram treatment for depression
In a double‑blind randomized phase 2 trial for moderate-to-severe depression, both psilocybin therapy and escitalopram produced similar personality changes consistent with improved mental health (notably reduced neuroticism, disagreeableness and impulsivity, and increased openness), with only a possible selective increase in absorption after psilocybin. Changes following escitalopram were moderated by pre-trial positive expectancy, whereas expectancy did not moderate responses to psilocybin.
Arketamine as adjunctive therapy for treatment-resistant depression: A placebo-controlled pilot study
This double-blind, cross-over study (n=10) finds that arketamine (35mg/70kg, the 'right-handedness of ketamine) isn't superior to placebo, but does find it to be safe in a population with treatment-resistant depression (TRD).
Classical and non-classical psychedelic drugs induce common network changes in human cortex
This fMRI analysis study (n=74 total) looks at how three different drugs -; nitrous oxide, ketamine, and lysergic acid diethylamide (LSD) -; affect the way different parts of the brain communicate with each other. By comparing brain scans taken before and during drug use, the study found that all three drugs reduced connectivity within certain networks in the brain, while enhancing connections between different networks. These effects were seen in areas of the brain that are important for our conscious experiences.
Meditation Trips: A Thematic Analysis of the Combined Naturalistic Use of Psychedelics With Meditation Practices
This survey study (n=1315) of psychedelic users finds that a majority (67%) also meditated and nearly 40% combined both. From written accounts (n=256), six themes were identified, including compatibility between states, enhancement of experiences, positive changes in relating to the world, negative effects, meditation as a preparatory tool, and contextual considerations. Findings suggest meditation techniques could facilitate combining psychedelics, enabling lower, therapeutically important doses.
Reducing the Harms of Nonclinical Psychedelics Use Through a Peer-Support Telephone Helpline
This data analysis study (n=884) examines the impact of a psychedelic helpline on mitigating risks associated with nonclinical psychedelic use. The findings suggest that 65.9% of callers experienced a de-escalation in psychological distress due to the helpline. Additionally, 29.3% reported they could have been harmed, 12.5% might have dialed 911, and 10.8% could have visited an emergency room had it not been for their interaction with the helpline, implying the helpline may prevent harmful outcomes and alleviate strain on emergency and medical services.
Self-Transcendent Positive Emotions as a Potential Mechanism Underpinning the Effects of Meaningful Psychedelic Experiences on Connectedness to Nature
This retrospective survey (n=236) of those who had a meaningful psychedelic experience finds that self-transcendent positive emotions (STPE) predicted positive changes in connectedness to nature. The proposed mechanism (through exploratory analysis of the data) suggests that acute STPE can lead to experiencing more of that in daily life, which leads to feeling more connected to the natural world.
The Canadian Psychedelic Survey: Characteristics, Patterns of Use, and Access in a Large Sample of People Who Use Psychedelic Drugs
This survey (n=2045) of Canadian psychedelic users finds psilocybin, MDMA and LSD are the most commonly used. It also reports positive (82%) life changes and challenging experiences (52%). Motivations for use include fun, self-exploration, general mental well-being, and personal growth.