Psychedelic Research Recap January 2022
Researchers in the field of psychedelics hit the ground running at the turn of the new year. January brought with it the largest published clinical trial with psilocybin to date. While ketamine was shown to effectively treat patients with alcohol use disorder, the same can’t be said for PTSD. A host of reviews provide food for thought on a range of psychedelics and their mechanism of action.
You can find all the papers in our database and those that weren’t added in our January Link Overview.
Participants in the Lab
Over the past month, a substantial amount of research involving human participants has been published. A plethora of research papers exploring the therapeutic effects of ketamine have emerged, notable for alcohol use disorder and PTSD. The results of the largest trial with psilocybin to date were also published.
This trial (n=96) assessed the effectiveness of 1) three weekly ketamine infusions (0.8 mg/kg i.v. over 40 minutes) plus psychological therapy, 2) three saline infusions plus psychological therapy, 3) three ketamine infusions plus alcohol education, or 4) three saline infusions plus alcohol education, in people with alcohol use disorder (AUD). Participants in the ketamine groups abstained from alcohol for a significantly longer number of days at 6-month follow-up, while the greatest abstinence was in the ketamine plus therapy group. A positive outcome for the team at Awakn Life Sciences.
A similarly designed study (n=158) assessed eight repeated doses of intravenous ketamine administered twice weekly at a low dose (14mg/70kg; n=53), standard dose (35mg/70kg; n=51) ketamine or placebo (n=54) in veterans and active service members with PTSD. The standard dose of ketamine reduced MADRS scores significantly more than placebo. However, the trial failed to find a significant dose-related effect of ketamine on PTSD symptoms measured using the CAPS-5.
One of the many endeavours of COMPASS Pathways, this Phase I RCT found that 10mg and 25mg doses of psilocybin are generally well-tolerated when administered to up to 6 participants simultaneously. Participants (n=89) each received one-to-one psychological support during the sessions in the largest published trial with psilocybin to date.
Adult couples (n=8) who self-reported active MDMA use were interviewed. Couples collaborated on becoming “set” for their experience and described positive effects on communication, intimate bonding, and providing a relationship “tune-up,” among other durable changes to the relationship. These findings suggest the possibility of informed, non-problematic adult use of MDMA for cognitive and relational enhancement.
A meta-analysis assessed patient-level data on the effects of psychedelics on suicidality across seven clinical trials. It was found that, relative to baseline, psychedelic therapy was associated with large effect sizes and sustained decreases in suicidality. The effect size was medium at six months, while reductions in suicidality were significant at all time points except 7-8 weeks.
Positives for Safety
Researchers analysed data from participants (n=142) in clinical trials who had received LSD and psilocybin to assess the prevalence of recurring drug-like experiences in the days after administration of these substances. 13 participants (9%) reported recurring drug-like experiences (LSD: 7, psilocybin: 2, both: 4) which were considered mild and perceived as neutral to pleasant. No reports met the criteria for hallucinogen-persisting perception disorder (HPPD).
In another study, researchers assessed the occurrence of serotonin syndrome (SS) associated with MDMA use and reported it to the FDA Adverse Event Reporting System (FAERS). In each of the 20 reported cases of SS, people had also taken one or more substances with serotonergic properties in addition to MDMA, including amphetamines, stimulants and opioids. There were no reports of sole MDMA use leading to SS.
What’s going on in the brain?
A neuroimaging study (n=4) used positron emission tomography (PET) with a 5-HT2A receptor agonist radioligand (that would light up on scans) and cortical regions of interest (ROIs) to determine the regional occupancy of 5-HT2A receptors after oral administration of a psychoactive dose of psilocybin (10mg/70kg). Three areas with the greatest occupancy were within the default mode network (DMN). There was high variability across individuals.
In an open-label study (n=15), the dynamic organisation of spontaneous cortical activity during wakefulness and altered consciousness induced by both subanaesthetic and anaesthetic doses of ketamine were assessed using EEG. The anaesthetic doses of ketamine tended to shift the configuration toward brain states with low spatial variability. In contrast, subanaesthetic ketamine was associated with a richer repertoire of spatially distributed patterns of brain activity.
Researchers at Imperial College London developed and validated a new scale to measure psychological insight gained during a psychedelic experience: the Psychological Insight Scale (PIS). A survey study (n=279) found the PIS is complementary to current measures used in psychedelic studies. As measured by the PIS, insight was found to mediate the long-term psychological outcomes after a psychedelic experience.
Review Time
Franz X. Vollenweider and John W. Smallridge explore the neurobiological mechanisms through which psychedelics exert their effects in light of recent research in a new review. The pharmacological and neuroplastic effects are discussed as well as the hypothesised functional network models of psychedelic states.
David E. Olson discusses the biochemical signalling pathways activated by psychedelics and related neuroplasticity-promoting molecules in a separate review. The ability of psychedelics to promote structural and functional plasticity in the prefrontal cortex (PFC) and the implications this has for stress-related disorders are discussed.
A systematic review of clinical trials included a total of 705 individuals that were treated with either ibogaine or noribogaine. It was found that such interventions may be useful for treating substance use disorders, alleviating withdrawal symptoms and cravings. Importantly, a number of severe adverse effects, including death, that have been recorded in the trials are discussed.
Another review explored the positive and negative aspects of different formulations and routes of administration of DMT. Alternative ways to oral administration in tandem with a monoamine oxidase inhibitor (ayahuasca/pharmahuasca) are discussed as well as the role of endogenous DMT in normal brain function.
Finally, this review focuses on using ketamine to treat mood disorders in women. Some of the topics discussed are the cause of depression in women, the preclinical research on the neurobiological effects of ketamine and how these effects interact with ovarian hormones.
Outside of the Lab
A retrospective analysis (n=537) assessed the effectiveness of intravenous ketamine therapy in community-based practices, i.e. real-world care settings. Over half of the participants showed a response at 14-31 days post-infusion and 28.9% remitted, whilst 73% exhibited a reduction in suicidal ideation. However, remission status was weakly inversely correlated with depression severity.
A case is made for the inclusion of psychedelic-using communities in bioethical discussions that guide normative elements of psychedelic medicalisation. It is argued that these communities have a degree of epistemic expertise regarding psychedelics and that these communities are uniquely and heavily affected by psychedelic medicalisation.
Eduardo E. Schenberg and Konstantin Gerber question the epistemic authority of western science and medicine in over 30 years of research on ayahuasca. Given the traditional use of ayahuasca, the researchers propose new approaches to maintain epistemically fair research and ensure these peoples traditional knowledge and biocultural heritage is maintained. Without adequate regulation, the rights of indigenous people, as well as the sustainability of the Amazon itself, face threat.
Papers Published in January 2022
39 studies from the Blossom database published this month.
Psychedelic Group Therapy
This book chapter (2022) discusses the differences between individual psychedelic therapy and psychedelic therapy conducted in groups.
Psilocybin use is associated with lowered odds of crime arrests in US adults: A replication and extension
Using nationally representative NSDUH data (2015–2019, N = 211,549), the study found lifetime psilocybin use was associated with lowered odds of several types of past-year arrests (adjusted ORs 0.30–0.73). Peyote and mescaline showed limited protective associations for specific offences, most other substances were unrelated or linked to higher arrest odds, and causality remains unestablished.
Evaluating the Potential Use of Serotonergic Psychedelics in Autism Spectrum Disorder
This review evaluates evidence that serotonergic psychedelics (5‑HT2A agonists such as LSD, psilocybin and DMT) may ameliorate social deficits and co‑occurring anxiety and depression in autism spectrum disorder. It highlights neurobiological constraints (synaptic, serotonergic, prefrontal and thalamocortical dysfunction), mixed and sometimes adverse outcomes in historical paediatric trials, and concludes that rigorous contemporary studies are needed to determine whether benefits outweigh risks and whether 5‑HT2A is a viable therapeutic target.
Ketamine as an adjunctive therapy for major depression - a randomised controlled pragmatic pilot trial (Karma-Dep Trial)
This first pragmatic randomised pilot trial of four once-weekly adjunctive ketamine infusions in hospitalised patients with major depression found the infusions were generally safe and well tolerated but produced no significant difference in HRSD-24 scores versus midazolam. The study indicates a definitive trial of adjunctive ketamine is feasible.
Structure-based discovery of nonhallucinogenic psychedelic analogs
This cell and mice study (2022) presents structures of the serotonin receptor 5-HT2RA bound to psilocin, LSD, serotonin and the non-hallucinogenic analogue lisuride. The researchers were then able to design arrestin-biased ligands that displayed antidepressant-like activity in mice without hallucination effects. The research presented here provides a foundation for the design of safe and effective non-hallucinogenic psychedelic analogues.
Classic Psychedelic Drugs: Update on Biological Mechanisms
This review synthesises recent molecular-to-systems evidence that classic psychedelics act primarily at serotonergic receptor subtypes in cortico‑thalamic and cortico‑cortical feedback circuits, modulating excitatory–inhibitory balance and promoting neuroplasticity in regions that integrate sensation, cognition, emotion and the sense of self. Neuroimaging and behavioural data link these circuit-level changes to altered self‑experience, emotion regulation and social cognition, which may help explain psychedelics' therapeutic potential in psychiatric disorders.
Expert Opinion on Psychedelic-Assisted Psychotherapy for People with Psychotic Symptoms
Experts concluded that blanket exclusion of people with psychotic symptoms from psychedelic trials is not universally justified and that highly supportive psychedelic-assisted psychotherapy may benefit some individuals. Treatment outcomes are likely to depend on factors such as symptom type, illness duration and severity, quality of the therapeutic alliance, trauma history and level of social support.
Flashback phenomena after administration of LSD and psilocybin in controlled studies with healthy participants
In a pooled analysis of 142 healthy participants from six double-blind, placebo-controlled crossover studies, 13 (9.2%) reported brief, mainly visual reoccurring drug-like experiences after LSD and/or psilocybin (7.8% following LSD, 8.3% following psilocybin, 14.3% after both), which were predominantly mild, neutral-to-pleasant and occurred within a week. None met DSM‑5 criteria for HPPD or reported daily-life impairment, suggesting flashbacks are relatively common but not clinically significant in controlled settings.
Psychedelic injustice: should bioethics tune in to the voices of psychedelic-using communities?
The paper argues that psychedelic‑using communities should be included in bioethical discussions guiding the medicalisation of psychedelics because their embodied experience gives them epistemic expertise and they are disproportionately affected by medicalisation. Even acknowledging claims that such groups may be less able to engage in deliberative reasoning, the author contends they must be consulted to redress and prevent epistemic injustice.
Reported Cases of Serotonin Syndrome in MDMA Users in FAERS Database
Analysis of FAERS reports found 20 cases of serotonin syndrome in MDMA-exposed individuals, but every case involved concomitant use of one or more other serotonergic substances (e.g. amphetamines, stimulants, opioids) and none implicated MDMA as the sole agent. This finding is consistent with clinical-trial data, which have not reported serotonin syndrome with MDMA alone.
Therapeutic effect of an ayahuasca analogue in clinically depressed patients: a longitudinal observational study
In a longitudinal observational study of 20 clinically depressed patients, a single ayahuasca analogue ceremony was associated with large reductions in Beck Depression Inventory scores and high remission rates that were sustained at 1 month and 1 year, together with increased mindfulness and life satisfaction. Improvements correlated with experienced ego dissolution and oceanic boundlessness during the ceremony, although additional mental‑health treatments or later psychedelic use may have contributed to the 1‑year outcomes.
Administration of N,N-dimethyltryptamine (DMT) in psychedelic therapeutics and research and the study of endogenous DMT
This comprehensive review (2022) explores the positive and negative aspects of different formulations and routes of administration of DMT. Alternative routes to oral administration in tandem with a monoamine oxidase inhibitor (ayahuasca/pharmahuasca) are discussed as well as the role of endogenous DMT in normal brain function.
Biochemical Mechanisms Underlying Psychedelic-Induced Neuroplasticity
This review (2022) explores our current understanding of the biochemical signalling pathways activated by psychedelics and related neuroplasticity-promoting molecules. The ability of psychedelics to promote structural and functional plasticity in the prefrontal cortex (PFC) and the implications this has for many stress-related neuropsychiatric disorders like PTSD are some of the topics discussed.
Human Cortical Serotonin 2A Receptor Occupancy by Psilocybin Measured Using [11C]MDL 100,907 Dynamic PET and a Resting-State fMRI-Based Brain Parcellation
Using [11C]MDL 100,907 PET and resting‑state fMRI‑derived cortical parcellation in four healthy volunteers, a single oral psychoactive dose of psilocybin produced mean cortical 5‑HT2A receptor occupancy of 39.5% (±10.9%), with the highest occupancy (63–75%) in default mode network regions (subgenual anterior cingulate and bilateral angular gyri). Significant inter‑individual variability was observed, supporting further study of how regional 5‑HT2A occupancy relates to acute and lasting effects of psilocybin.
The Need for Psychedelic-Assisted Therapy in the Black Community and the Burdens of its Provision
This paper (2021) explores why psychedelic-assisted therapy and psychedelic medicines are specifically needed in the Black community. The authors argue that the trauma inflicted on Black, Indigenous and other People of Colour (BIPOC) by everyday, white imposed, negative race-based experiences could be healed using psychedelics. The authors argue that psychedelic research and organizations must recruit BIPOC populations.
Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: a double-blind, randomized, placebo-controlled multi-center clinical trial
This double-blind RCT (n=158) assessed 8 repeated doses of intravenous ketamine administered twice weekly at a low dose (0.2 mg/kg; n = 53), standard dose (0.5 mg/kg; n = 51) ketamine or placebo (n=54) in veterans and service members with PTSD. It was found that the standard dose of ketamine reduced MADRS scores significantly more than placebo. However, the trial failed to find a significant dose-related effect of ketamine on PTSD symptoms measured using the CAPS-5.
Decreases in Suicidality Following Psychedelic Therapy: A Meta-Analysis of Individual Patient Data Across Clinical Trials
This meta-analysis (2022) assessed patient-level data on the effects of psychedelics on suicidality across seven clinical trials. It was found that, relative to baseline, psychedelic therapy was associated with large effect sizes and sustained decreases in suicidality. The effect size was medium at 6 months was significant at all time points except 7-8 weeks.
Depression, Estrogens, and Neuroinflammation: A Preclinical Review of Ketamine Treatment for Mood Disorders in Womens
This preclinical review synthesises evidence on ketamine's rapid antidepressant effects in the female brain, emphasising how ovarian hormones modify its neurobiological actions. It highlights interpretative challenges in preclinical studies and proposes neuroinflammation as a key pathway mediating ketamine–estrogen interactions in women’s depression.
Evenings with Molly: Adult Couples’ Use of MDMA for Relationship Enhancement
This interview study assessed the experiences of adult couples (n=8) who self-reported active MDMA use. Four overarching themes were identified: Conscious Use, A Tool for Exploring, Planned Recovery, and Difficult Experiences. Couples collaborated on becoming set for their experience and described positive effects on communication, intimate bonding, and providing a relationship “tune-up,” among other durable changes to the relationship. These findings suggest the possibility of informed, non-problematic adult use of MDMA for cognitive and relational enhancement.
The relationship between dissociation and antidepressant effects of esketamine nasal spray in patients with treatment-resistant depression
In post-hoc analyses of two phase 3 trials in treatment-resistant depression, dissociative symptoms after esketamine (peak CADSS scores) were not significantly correlated with or mediators of antidepressant response on the MADRS. Dissociation decreased across repeated doses while the antidepressant benefit persisted, indicating the therapeutic effect is independent of dissociative side-effects.
Knowledge, Perceptions, and Use of Psychedelics among Individuals with Fibromyalgia
This survey study (n=354) sought to characterize the knowledge, perceptions and past use of psychedelics among people with fibromyalgia (FM). It was found that 29.9% of respondents reported past use of a psychedelic, and perceptions of benefit from use were generally neutral (59.4%) or positive (36.8%). Less than 3% reported that using psychedelics negatively impacted their overall health or pain symptoms. 11 out of 12 patients using psychedelics specifically to treat pain reported improvements in their symptoms.
Linkages between Psychedelics and Meditation in a Population-Based Sample in the United States
This survey (n=536) showcases a possible synergy between meditation and psychedelic use. Those who experienced ego dissolution also found meditation to be more effective, which also served as lowering the barrier to meditation and motivation to practice it. Those who meditated (about half of the original larger survey) also were more likely to use psychedelics and experience ego dissolution.
The Psychedelic Renaissance in Clinical Research: A Bibliometric Analysis of Three Decades of Human Studies with Classical Psychedelics
This bibliometric analysis (2021) sought to characterize and visualize trends in the top-cited 100 articles in the field of psychedelics. 54% of articles were published from 2010-2020 while they were cited between 82 and 668 times. The results are discussed in terms of growth, access and diversity within the field and ultimately provide insight into the second wave of psychedelics research as a whole.
Overcoming epistemic injustices in the biomedical study of ayahuasca: Towards ethical and sustainable regulation
This commentary (2022) questions the epistemic authority of western medicine in over 30 years of research on ayahuasca. Ayahuasca has long been used by indigenous peoples in countries like Brazil, Peru and Colombia, and the researchers propose new approaches to maintain epistemically fair research and ensure these peoples traditional knowledge and biocultural heritage is maintained. Without adequate regulation, the rights of indigenous people, as well as the sustainability of the Amazon itself, face threat.
Lifetime use of MDMA/ecstasy and psilocybin is associated with reduced odds of major depressive episodes
In a nationally representative sample of 213,437 US adults, lifetime MDMA/ecstasy use was associated with lower odds of lifetime (aOR 0.84), past‑year (aOR 0.84) and past‑year severe (aOR 0.82) major depressive episodes, and psilocybin use was associated with modestly reduced odds of past‑year (aOR 0.90) and past‑year severe (aOR 0.87) MDEs. Other substances were either unrelated or linked to increased MDE odds, and the authors call for experimental studies to test causality and therapeutic potential.
MDMA/ecstasy use and psilocybin use are associated with lowered odds of psychological distress and suicidal thoughts in a sample of US adults
This survey study (n=484,732) found that MDMA use was associated with reduced odds of suicidal thoughts in the past year. Lifetime psilocybin use was associated with reduced odds of past year psychological distress and past-year suicidal thoughts. LSD was associated with increased odds of past-year suicidal thinking.
Validation of the Psychological Insight Scale: A new scale to assess psychological insight following a psychedelic experience
The authors developed and validated the six- to seven‑item Psychological Insight Scale (PIS) to assess post‑psychedelic insight, finding a single principal component explaining 73.6% of variance and excellent internal consistency (average Cronbach’s α = 0.94) with supporting criterion and convergent validity. PIS scores significantly mediated the relationship between emotional breakthrough during the experience and long‑term well‑being, suggesting insight is a key mechanism linking acute psychedelic effects to sustained psychological outcomes.
The effects of psilocybin on cognitive and emotional functions in healthy participants: Results from a phase 1, randomised, placebo-controlled trial involving simultaneous psilocybin administration and preparation
In the largest randomised, double‑blind, placebo‑controlled phase 1 trial of psilocybin to date (n=89), healthy participants received a single oral dose of 10 mg or 25 mg psilocybin (or placebo) simultaneously in small groups with one‑to‑one psychological support. Both doses were generally well tolerated with no serious adverse events and produced no clinically relevant short‑ or long‑term differences in cognitive performance (CANTAB global and domain scores) or emotional processing compared with placebo.
Exploring the Credibility of Psilocybin-assisted Therapy and Cognitive-behavioral Therapy for Depression
This survey study (n=803) assessed the credibility rating of cognitive-behavioural therapy (CBT) and psilocybin-assisted therapy (PAT) among individuals reporting depressive symptoms. CBT was rated as more credible than PAT, while men and lifetime psychedelic users rated PAT more credible than women and non-users with few other predictors accounting for variance in credibility.
MDMA related neuro-inflammation and adenosine receptors
This review (2022) explores the cellular mechanisms involved in MDMA neuroinflammatory effects. The protective effects of adenosine receptors is also discussed.
5-HT2CR Is as Important as 5-HT2AR in Inducing Hallucinogenic Effects in Serotonergic Compounds
This rodent study (2022) shows that the activation of serotonin receptors (5-HT) by mescaline derivatives via 5-HT2CR, alone or in concert with 5-HT2AR, produces comparable hallucinogenic effects to activation via divergent 5-HT2CR- and/or 5-HT2AR signalling pathways. Given that many believe 5-HT2AR activation is the route through which psychedelics exert their effects, these findings show that 5-HT2CR is as important as 5-HT2AR in inducing these effects.
Ayahuasca, a psychedelic beverage, modulates neuroplasticity induced by ethanol in mice
This mouse study investigated the effects of ayahuasca (35.2 µg DMT) on alcohol withdrawal in mice and found that it exerted an anxiolytic effect and attenuated the behavioral sensitization to alcohol. Furthermore, it prevented alcohol-induced changes on 5-HT1a receptor and prodynorphin levels in the hippocampus and reduced ethanol effects in the dynorphin/prodynorphin in the striatum.
Efficacy and safety of esketamine nasal spray by sex in patients with treatment-resistant depression: findings from short-term randomized, controlled trials
Pooled analyses of three short-term randomised controlled trials found that esketamine nasal spray plus a newly initiated oral antidepressant produced greater reductions in MADRS total score than antidepressant plus placebo in both women and men with treatment‑resistant depression, with no significant sex effect or treatment-by-sex interaction. Overall safety was similar between sexes, although nausea, dissociation, dizziness and vertigo were reported more frequently in women.
Frequency analysis of symptomatic worsening following ketamine infusions for treatment resistant depression in a real-world sample: Results from the canadian rapid treatment center of excellence
This retrospective analysis (n=164) assessed the rates of symptomatic worsening in patients with unipolar and bipolar treatment-resistant depression (TRD) following a two-week course of IV ketamine. Using the QIDS-SR16 to assess symptoms, it was found that clinically significant worsening for those with unipolar TRD fluctuated between 1.83% to 5.49%, while no participants with bipolar TRD reported symptomatic worsening. Rates of symptomatic worsening were similar to conventional antidepressants.
Human behavioral pharmacology of psychedelics
This commentary (2021) provides an overview of the human behavioural pharmacology of the classic psychedelic; psilocybin, LSD and DMT. Special considerations when conducting human research with psychedelics are discussed as well as the subjective, physiological, and clinical effects of these substances.
Methodological challenges in psychedelic drug trials: Efficacy and safety of psilocybin in treatment-resistant major depression (EPIsoDE) - Rationale and study design
This paper (2022) details the rationale and study design for an upcoming double-blind placebo-controlled trial (n=144) which will assess the safety and efficacy of using psilocybin in a cohort with treatment-resistant depression.
Microdosing with psychedelics to self-medicate for ADHD symptoms in adults: A prospective naturalistic study
This prospective survey study (n=247) finds that those who microdose psychedelics to manage ADHD symptoms experience benefits from it. Participants scored higher on well-being after two and four weeks. The study design, a prospective survey, makes it possible to draw causal inferences (microdosing causing the improvement), but the study had a large drop-out rate (n=46 at 4 weeks).
Pharmacogenomics of ketamine: A systematic review
This review (2021) explores the pharmacogenomic predictors of ketamine's clinical benefits and adverse effects. The review identified three predictors; 1) brain derived neurotrophic growth factor (BDNF) was associated with reduced antidepressant and anti-suicidal effects, 2) CYB2B6 was associated with more severe dissociative effects and 3) NET was associated with greater cardiovascular complications. Limitations include small sample sizes and heterogeneity of study design.
Psilocybin: crystal structure solutions enable phase analysis of prior art and recently patented examples
The authors solved the crystal structures of two anhydrous psilocybin polymorphs (Polymorphs A and B) by Rietveld refinement against laboratory and synchrotron PXRD supported by DFT, and used those structures together with the known Hydrate A to perform quantitative phase analysis of historical and recent samples. They demonstrate that all examined material from 1963–2021 is accounted for as mixtures of these three forms (notably a claimed “isostructural variant” is ~81% Polymorph A/19% Polymorph B), concluding no additional crystalline forms are required and recommending revision of certain patent characterisations.