Psychedelic Research Recap October 2022
October was a relatively quiet month for psychedelic research. Following on from ICPR in the Netherlands in September, many researchers likely flocked to New York for the 15th edition of Horizons as the psychedelic conference circuit is in full swing. If you’re interested in attending a psychedelic conference, you can check out what’s coming up here.
Nonetheless, we still gained some valuable new insights into the world of psychedelics. Natural language processing (NLP) was used to successfully predict clinical outcomes using data from a trial exploring psilocybin on treatment-resistant depression (TRD). The first real-world study assessing esketamine for TRD yielded positive results. At the same time, new evidence suggests people who microdose may build up a tolerance.
Psychedelics put to the test
Surprisingly, there have been no published studies assessing the effectiveness of esketamine outside of the laboratory setting despite its legal availability in certain circumstances until now. This real-world study using Spravato (esketamine, up to 84mg, multiple dosings) found the response rate (64%) and rate of remission (41%) to be similar to findings from clinical trials at the three-month mark.
A separate study found that ketamine tablets were safe to use and significantly reduced both depression and anxiety in a relatively large sample of participants (n=664) taking the tablets at home.
Researchers at Maastricht University published the preprint from another naturalistic study where they used fMRI to assess functional connectivity (FC, how areas of the brain communicate) in members of the Santo Daime church following ayahuasca intake. Changes in FC were similar across participants and less unique than previously thought.
At the University of Copenhagen, researchers used the Mystical Experience Questionnaire to assess the association between psilocybin-induced lasting increases in mindfulness and the mystical experience. Using the Mindful Attention and Awareness Scale (MAAS) to measure mindfulness after three months, MAAS scores were found to be positively correlated with MEQ scores indicating that the phenomenology of the psilocybin experience induces a shift toward mindful living.
Reanalysing old data leads to new insights
Researchers affiliated with COMPASS Pathways used natural language processing (NLP) to assess the audio from psychological support sessions in the COMP360 trial for TRD. The NLP model used predicted clinical outcomes with high accuracy (85%). COMPASS plans to explore the use of NLP in their upcoming world-first Phase III trials of COMP360 for TRD, which they announced earlier in October.
At Imperial College London, researchers reanalysed data from a placebo-controlled citizen science microdosing study to investigate whether tolerance develops during microdosing. After conceptualizing tolerance as the decreasing probability of correctly guessing active microdoses with more microdoses, models showed that correct microdose guess probability decreased with the number of microdoses taken (p=0.09), indicating tolerance developed.
By reanalysing data from the TRANSFORM-1 and TRANSFORM-2 trials, researchers from Janssen Pharmaceuticals found that treating participants with esketamine plus an antidepressant improved symptoms of depression regardless of their baseline irritability level and increased odds of achieving a response.
A brain imaging study examined the difference between those who regularly used ayahuasca and control subjects. It found evidence for a thicker corpus callosum (the section that connects brain regions), but this effect didn’t survive multiple comparisons.
Looking inside the brain
A comprehensive review from some of the world’s experts explains the neural basis of how psychedelics work. It covers serotonin receptors, changes in structural plasticity, and the long-term effects of psychedelics. The discussion covers the future of psychedelics, including non-hallucinogenic compounds.
A separate review explores how psychedelics modulate the brain’s Default Mode Network (DMN). While we see an acute disruption within the DMN and increased functional connectivity between resting-state networks, it’s still too early to say exactly how these changes correlate with well-being outcomes.
Researchers have produced a nuanced mechanism through which MDMA alleviates the symptoms of PTSD. This mechanism relates to the increase of brain-derived neurotrophic factor (BDNF) in fear memory learning pathways which act together with MDMA’s pro-social effects to explain the therapeutic effects of MDMA.
Ethical considerations going forward
This review outlines recommendations for current practice in preparatory sessions in substance-assisted psychotherapy (SAPT), providing information on safety measures and screening procedures, preparation of set and setting, session contents, methods, roles, prerequisites, and appropriate conduct of therapists.
Data from the US National Survey on Drug Use and Health was used to explore the associations between naturalistic lifetime MDMA and psilocybin use. Race and ethnicity significantly moderated the associations between MDMA and psilocybin use and psychological distress and suicidality. For white participants, MDMA and psilocybin use lowered the odds of all distress, whereas these associations were far fewer for racial and ethnic minorities.
A review of early psychedelic studies from the first wave of psychedelic research finds that most would not pass ethical review today. The errors made in early research largely involved people of colour and related to issues around dosing, lack of consent, inadequate setting, and lack of scientific hypotheses. The authors make restorative justice and cultural competency suggestions.
Reviews & the rest
A meta-analysis found that the standard mean difference for electroconvulsive therapy (ECT), when compared to ketamine in treating depression, suggests ECT is more efficacious than ketamine for depression severity.
In a separate meta-analysis, researchers found that psilocybin, LSD and ayahuasca all led to short and long-term reductions in depressive symptoms when administered with psychological support in the clinical setting.
This review uses preclinical and clinical research to explore mescaline’s pharmacological and behavioural effects. The pharmacological mechanisms of mescaline are similar to those of other classical psychedelics, i.e. binding at the 5HT2A receptor. Mescaline can improve well-being and mental health conditions, particularly alcohol use disorder.
Papers Published in October 2022
23 studies from the Blossom database published this month.
Changes in mental health, wellbeing and personality following ayahuasca consumption: Results of a naturalistic longitudinal study
In a naturalistic longitudinal study of 53 ayahuasca‑naïve attendees, a single facilitated ceremony produced broad 1‑month improvements in depression, anxiety, stress, substance use, personality traits, relationships and spirituality. Baseline characteristics—particularly high negative emotionality and body dissociation and low self‑efficacy—predicted greater benefit while facets of the mystical experience did not, indicating potential for personalised treatment and warranting randomised controlled trials.
Preliminary evidence of links between ayahuasca use and the corpus callosum
Using MRI data from 22 ayahuasca users and 22 matched controls, the study found preliminary evidence of greater corpus callosum thickness in users—most notably in the isthmus—and a positive association between callosal thickness and number of past ayahuasca sessions in the rostral body, although these effects did not survive corrections for multiple comparisons. These results suggest possible links between ayahuasca use and callosal structure but require replication in larger, ideally longitudinal, samples before clinical conclusions can be drawn.
Low doses of lysergic acid diethylamide (LSD) increase reward-related brain activity
This double-blind placebo-controlled study (n=18) explored the effects of two microdoses of LSD (13 & 26μg) on reward processing using a monetary incentive delay task. LSD increased three reward-related ERP components, reflecting increased hedonic, motivational, and affective processing of feedback, indicating that LSD increases reward-related activity in humans.
MDMA-Assisted Psychotherapy for Borderline Personality Disorder
This review (2022) makes the cases for using MDMA-assisted therapy (MDMA-AT) in the treatment of borderline personality disorder (BPD). The authors draw parallels between using MDMA-AT to treat disorders similar to BPD, such as PTSD, and provide considerations for designing future clinical trials.
A Pilot Study of Ketamine Infusion after Suicide Attempt: New Frontiers in Treating Acute Suicidality in a Real-World Medical Setting
In an open‑label pilot of 16 medically hospitalised recent suicide attempters, a single intravenous ketamine infusion (0.5 mg/kg) produced rapid, large reductions in suicidality and depression at 24 hours and 5 days (Cohen’s d 1.7–8.8) that were sustained up to six months. The study indicates ketamine is a feasible, rapidly acting intervention for acute suicidality in real‑world Consultation‑Liaison settings.
The neural basis of psychedelic action
This comprehensive review (2022) explains the neural basis of how psychedelics work. It covers serotonin receptors, changes in structural plasticity, and the long-term effects of psychedelics. The discussion covers the future of psychedelics, including non-hallucinogenic compounds.
Default Mode Network Modulation by Psychedelics: A Systematic Review
This systematic review shows that classical psychedelics (LSD, psilocybin, ayahuasca) consistently cause acute disruption of resting-state connectivity within the Default Mode Network and increase cross-network functional connectivity, but it remains unclear how central DMN modulation is to their therapeutic effects. The article synthesises existing evidence and highlights gaps to guide future mechanistic research.
A rapid scoping review of harm reduction strategies for ecstasy (MDMA) users in recreational settings
This rapid scoping review maps a wide range of drug-specific, behavioural and peer-related harm-reduction strategies used by ecstasy (MDMA) users in recreational settings and shows users obtain guidance from diverse sources including friends, clubs and user-oriented websites. It also finds many user-facing websites lack evidence citations and that adherence to strategies varies with users' goals and experience, indicating a need for more effective, evidence-informed communication.
Intranasal esketamine effectively treats treatment-resistant depression in adults regardless of baseline irritability
This post hoc analysis of two Phase III double-blind studies assessed the effects of baseline irritability on clinical outcomes in participants with treatment-resistant depression (TRD) (n=560) treated with intranasal ketamine (esketamine) plus an oral antidepressant (ESK + AD). ESK + AD improved symptoms of depression regardless of baseline irritability level and increased odds of achieving a response in all participants.
Therapeutic (Sub)stance: Current practice and therapeutic conduct in preparatory sessions in substance-assisted psychotherapy-A systematized review
Using data from 83 sources, this review outlines recommendations for current practice in preparatory sessions in substance-assisted psychotherapy (SAPT), providing information on safety measures and screening procedures, preparation of set and setting, session contents, methods, and roles, prerequisites, and appropriate conduct of therapists.
Evidence for tolerance in psychedelic microdosing from the self-blinding microdose trial
A placebo-controlled self-blinding trial (n=240) found that the probability of correctly guessing a microdose decreased with the number of prior microdoses (β = −.017±.007; p = .009), indicating tolerance development; this effect was significant for LSD/LSD-analogues (β = −.026±.007; p < .001) but not for psilocybin (β = .013±.014; p = .36), suggesting microdosers may need dosing breaks and that psilocybin could be better suited for long-term use.
Maintenance ketamine treatment for depression: a systematic review of efficacy, safety, and tolerability
This review (2022) uses data from three randomised-controlled trials (RCTs), eight open-label trials and 30 case series to explore the efficacy, safety and tolerability of using ketamine in the treatment of depression. Ketamine was found to have sustained antidepressant effects when administered intravenously, intranasally, orally and possibly intramuscularly and was found to be well-tolerated.
Mescaline: The forgotten psychedelic
This review (2022) explores mescaline's pharmacological and behavioural effects using preclinical and clinical research. The pharmacological mechanisms of mescaline are similar to those of other classical psychedelics i.e. binding at the 5HT2A receptor. Mescaline can improve well-being and mental health conditions, particularly alcohol use disorder.
A proposed mechanism for the MDMA-mediated extinction of traumatic memories in PTSD patients treated with MDMA-assisted therapy
The paper proposes that MDMA facilitates extinction of traumatic memories in PTSD by increasing BDNF availability in fear‑memory circuits, thereby enhancing synaptic plasticity for relearning and extinction. It argues this molecular action, together with MDMA’s pro‑social effects that strengthen the therapeutic alliance, explains the clinical benefits of MDMA‑assisted therapy.
Race and ethnicity moderate the associations between lifetime psychedelic use (MDMA and psilocybin) and psychological distress and suicidality
Using NSDUH data (2008–2019; N = 484,732), the authors found that race and ethnicity significantly moderate the associations between lifetime MDMA and psilocybin use and past‑month psychological distress and past‑year suicidality. MDMA and psilocybin were linked to reduced odds of distress and suicidality among White participants, but showed far fewer protective associations for racial and ethnic minority groups, highlighting the need for more research on identity-related moderators.
Psychedelic therapy for depressive symptoms: A systematic review and meta-analysis
This meta-analysis (s=6) explored the therapeutic effects of psilocybin, LSD and ayahuasca on depressive symptoms in the clinical setting. When administered with psychological support, all psychedelics led to significant reductions in depressive symptoms at all measured timepoints (1-day, 1-week, 3-5 weeks, and 6-8 weeks). Some limitations include the small sample sizes used in most individual studies and the use of a cross-over design for long-term follow-up, which made it difficult to include those results in the meta-analysis.
Lasting increases in trait mindfulness after psilocybin correlate positively with the mystical-type experience in healthy individuals
In healthy volunteers, a medium–high dose of psilocybin produced a significant increase in trait mindfulness at three months that correlated positively with the intensity of the acute mystical-type experience. Higher baseline trait mindfulness was also associated with lower 5‑HT2A receptor binding in the right amygdala.
Associations between MDMA/ecstasy use and physical health in a U.S. population-based survey sample
Using US National Survey on Drug Use and Health data (2005–2018), the study found that lifetime MDMA (ecstasy) use was associated with lower risk of overweight/obesity and reduced odds of past-year heart condition/cancer, hypertension and diabetes, and with higher odds of reporting better overall health. These associations remained after adjustment for multiple confounders, though the authors note longitudinal studies and clinical trials are needed to test causality.
Receptor-informed network control theory links LSD and psilocybin to a flattening of the brain’s control energy landscape
This paper (2022) combines data of the brain’s resting state under the influence of LSD and cortical mapping of 5-HT2A receptors within the framework of network control theory to validate the central tenets of the REBUS model of psychedelics. In accordance with this model, LSD-induced flattening of the brain’s energy landscape, corresponding to greater flexibility for state transitions and more dwell time in brain states than encode bottom-up activity (e.g. salience network) and decreased persistence of states dominated by top-down (frontoparietal) activity.
At-home, sublingual ketamine telehealth is a safe and effective treatment for moderate to severe anxiety and depression: Findings from a large, prospective, open-label effectiveness trial
This open-label (real-world evidence) paper (n=1247) argues that at-home sublingual ketamine (tablets for under the tongue) is both safe (only four patients dropped out) and effective (remission of 32% for depression and anxiety). Patients only spoke with a 'guide' (not a therapist) over video as the study was conducted during Covid. The results look promising, though the study sponsor (Mindbloom) has come under scrutiny recently.
Effects of classic psychedelic drugs on turbulent signatures in brain dynamics
Using a novel turbulence framework that quantifies vorticity (local synchrony) and extends metastability to space and time, the study shows that LSD and psilocybin produce consistent yet discriminable compression of the brain’s functional hierarchy, most notably altering the default mode network. These results quantify how two psychedelics modulate hierarchical brain dynamics and support their proposed mechanistic role relevant to therapeutic applications.
Nootropic effects of LSD: Behavioral, molecular and computational evidence
This double-blind placebo-controlled study (n=25) assessed the effects of LSD on metabolic pathways associated with neural plasticity, to gain insight into the relationship between neural plasticity, ageing and LSD-induced cognitive gains in both humans and rodents. LSD treatment in humans (50μg) enhanced performance in a visuospatial memory task, and in a novel object recognition task in rodents indicating that LSD has nootropic effects.
Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder
In a double‑blind randomised clinical trial of adults with alcohol dependence receiving psychotherapy, two high‑dose psilocybin sessions reduced the percentage of heavy drinking days over 32 weeks to 9.7% versus 23.6% with active placebo (mean difference 13.9 percentage points; 95% CI 3.0–24.7; P = .01). Psilocybin was well tolerated with no serious adverse events, supporting further study of psilocybin‑assisted therapy for alcohol use disorder.