Psychedelics Research Recap November 2021
November proved to be another productive month for psychedelic research. A variety of surveys looked at how psychedelics alter beliefs, reduce opioid use, and the effects of microdosing. A finished Phase I trial clears 5-MeO-DMT for the next step, cannabis intensifies a psychedelic experience, and psychedelics may help with Alzheimer’s.
This month, our team also enjoyed the Horizons Conference and we expect some more awesome research papers to come out soon. These include new findings on psilocybin for smoking cessation, psilocybin for anorexia (of which we cover one review this month), and how psychedelics can open a ‘critical period’ where learning/change can happen, possibly providing a unified theory of psychedelic action.
You can find all the papers in our database, and the ones that weren’t added in our November Link Overview.
Psychedelic use in the wild
It will still be some years until (classical) psychedelics will be initiated into the therapist’s office. At this time, psychiatrists, practising in the UK, feel that they don’t have the training to deliver psychedelic-assisted therapy. The majority of them (77%) are positive that psychedelics have therapeutic potential. So without widespread access, many researchers find valuable data in surveys (such as the ongoing Global Drug Survey 2021).
Maybe surprising to none who have read one or more psychedelic papers, those who take them have mystical experiences. What was interesting about the current study is that Qui & Minda used text-mining to reduce any possible bias from their end. From a survey and trip-report analysis (n=1424), those who had a complete mystical experience were also those who had the best well-being outcomes.
An ongoing discussion in the field is the causality and necessity of mystical experiences to improvements in well-being. Chris Letheby‘s new book ‘The Philosophy of Psychedelics’ covers the psychedelic experience and its implications in much more detail. A group of researchers is making the case to use Semantic Scale Network (SSN) analysis to develop newer scales. They also analysed the MEQ and find overlap with measures of awe, inspiration, depression, spirituality, and more.
Back to the world of recreational users, another survey, by Brandon Weiss and colleagues, investigates the changes in personality after a psychedelic experience. They replicated earlier findings and see an increase in agreeableness and a decrease in neuroticism. Interestingly, they suggest that psychedelics may be used to treat interpersonal elements of personality pathology as well as loneliness.
Psychedelics can change our beliefs, and a survey that we covered as a pre-print before, ‘Psychedelics alter metaphysical beliefs,’ sees that recreational users shifted towards more panpsychism and fatalism. It was not examined if this is a case of transference of beliefs from others (e.g. a facilitator/shaman). An ethnographic study, by David Dupuis, did just that and finds that the ability of psychedelics to induce hyper suggestibility in the absence of appropriate guidelines might lead to problematic effects.
Those who recently had used psychedelics, in a sample of people who used drugs in Vancouver, had 55% reduced odds of daily opioid use. Though causality can’t be determined, and only a small part (6%) of respondents used psychedelics, it provides another signal for psychedelics.
Microdosing psychedelics has found many supporters and seems to help many improve their well-being. What leads to these effects is hotly debated (see our microdosing page), with many researchers thinking that placebo, expectancy, regression-to-the-mean, and other such effects may play a large role. A large-scale (n=8703) survey tries to add another data point to this discussion but also suffers from several methodological issues and conflicts of interest.
How psychedelics work
There are many factors that help explain why psychedelics can help with mental health & substance use disorders and generally can improve well-being. A review by Shaklia Meshkat and colleagues examine the pharmacogenetics of ketamine, meaning they look at genetic variations and the influences it has on the outcomes after ketamine. Those with less brain-derived neurotrophic growth factor (BDNF) respond less well to treatment or need a higher dose. They also find CYB2B6 to be associated with more dissociative effects, and NET with higher blood pressure.
More work on the interaction of genes and psychedelics was done by Aurora Savino & Charles Nichols. Their study in rats finds that the expression of genes (co-expression networks) becomes less centralized and more complex (increased entropy) after chronic exposure to LSD. This mirrors human research where similar effects (increased entropy) have been observed at the molecular level.
Looking at the effects of psychedelics through the lens of behavioural pharmacology is done in an academic book chapter by Justin Strickland and Matthew Johnson. The chapter provides a great overview of the intersection between molecules (pharmacology) and mysticism.
Do psychedelics work less well for those who are using antidepressants (e.g. SSRIs such as escitalopram)? Studies with MDMA for PTSD are pointing towards less effect, even after tapering off SSRIs. But a new study that gave participants escitalopram before psilocybin treatment didn’t see a drop in positive mood effects. It did show a reduction in bad drug effects such as adverse cardiovascular effects. But, the relatively short pretreatment with escitalopram (10-20mg for 14 days) may not be typical of how SSRIs are being used (usually for years).
More psychedelics for more indications
Psychedelics seem to have transdiagnostic effects, meaning that they can be applied to multiple mental health disorders. For instance, we’ve seen research on the effectiveness of psilocybin for depression, as well as for smoking cessation. Depression, PTSD, and various addictions have been discussed in much detail before, but that is not where the transdiagnostic ability of psychedelics stop.
Albert Garcia-Romeu and colleagues make the case for classical psychedelics in the treatment of Alzheimer’s. One way psychedelics can help is to relieve comorbid depression and anxiety. Possibly even more interesting, and speculative is preclinical data that indicates a potential for psychedelics to slow or reverse brain atrophy, enhance cognitive function, and slow progression of Alzheimer’s.
Psychedelics, psilocybin in particular, are being investigated for the treatment of anorexia, and eating disorders in general. The classical psychedelics aren’t the only ones that could help as a review of ketamine for anorexia points out. Johanna Keeler and colleagues argue that the ability of ketamine to induce neuroplasticity, neurogenesis, and synaptogenesis and the antidepressant effects can all contribute to it being a viable treatment. Alas, we are only aware of several case studies and one small study investigating this more.
Another avenue less explored is the possibility of psilocybin to help prevent suicidal behaviour. A review by Robertas Strumila and colleagues puts forward several reasons why this could be a good route to investigate further. A study in mice finds more data points for how psilocybin may help reduce cravings for alcohol as it seems to restore a deficiency in a receptor for glutamate (mGluR2).
5-MeO-DMT has been associated with improvements in mental health in reports from (intentional) recreational users. If this business trip (coined due to its short duration) can become a medicine is a question being investigated by at least three companies. One of these, GH Research, has published a successful Phase I safety trial in cooperation with researchers from Maastricht University. There was a lot of variance between the subjective experiences of the subjects (n=22) and they recommend using dose escalation in further trials. Also reported this month were the positive results of reduced PTSD, alcohol misuse, and increased psychological flexibility after veterans (n=51) underwent treatment with ibogaine or 5-MeO-DMT.
The rest of the research
There are challenges to scaling up psychedelic implementation and it’s good to consider the roadblocks at this moment in time. To get psychedelics to community clinics several challenges need to be overcome such as 1) poor clinical practice (e.g. see reporting this month by Shayla Love), and 2) lack of infrastructure.
Using psychedelics alone can be an intense experience, combining it with cannabis is associated with even more intense experiences. Joanna Kuc and colleagues find increases in MEQ, EDI, and fast increasing changes of challenging experiences (CEQ) when combining classical psychedelics and cannabis.
Papers Published in November 2021
20 studies from the Blossom database published this month.
Recreational Psychedelic Users Frequently Encounter Complete Mystical Experiences: Trip Content and Implications for Wellbeing
Using text mining of over 2,000 first‑person trip reports and psychometric data from a large survey (N = 1,424), this mixed‑methods study finds that recreational psychedelic users commonly report complete mystical experiences — incidence varying by drug type and dose — and that such experiences are strongly associated with improved psychological wellbeing.
Identification of an optimal dose of intravenous ketamine for late-life treatment-resistant depression: a Bayesian adaptive randomization trial
This double-blind, randomised study (n=33) sought to identify the optimal dose of intravenous ketamine for late-life (mean age=62) treatment-resistant depression (TRD). Varying doses of ketamine (0.1 mg/kg-0.5 mg/kg) were compared to an active placebo (midazolam 0.03 mg/kg). It was found that 0.5 mg/kg is an effective initial IV ketamine dose in TRD.
The readiness of psychiatrists to implement psychedelic-assisted psychotherapy
This pilot mixed-methods study of psychiatrists in one NHS mental health trust found widespread familiarity with and majority support for controlled therapeutic use of psychedelics, with trainees better informed than non‑training-grade psychiatrists. Despite positive attitudes, clinicians across grades reported low preparedness to deliver psychedelic-assisted psychotherapy and identified substantial training needs and wider societal and professional uncertainties as barriers to implementation.
A phase 1, dose-ranging study to assess safety and psychoactive effects of a vaporized 5-methoxy-N,N-dimethyltryptamine formulation (GH001) in healthy volunteers
In a phase 1 dose-ranging study in 22 healthy volunteers, inhaled GH001 (5‑MeO‑DMT) was well tolerated and produced dose-related increases in psychedelic intensity, with individualized dose escalation yielding the largest mystical and ego‑dissolution effects (PES, MEQ, EDI, 5D‑ASC) while cognition, mood, well‑being, vitals and adverse events remained largely unaffected or mild. These findings indicate individualized dose escalation may be preferable to single fixed doses when aiming to maximise therapeutic psychedelic experiences.
Examining Psychedelic-Induced Changes in Social Functioning and Connectedness in a Naturalistic Online Sample Using the Five-Factor Model of Personality
In a naturalistic online sample, prospective assessments before and after psychedelic use showed reduced Neuroticism alongside increases in Agreeableness and perceived social connectedness, with reductions in Neuroticism covarying with Agreeableness increases consistent with shared emotion‑regulation processes. These changes—largely independent of demographics, setting and acute factors but modestly amplified by baseline trait levels—suggest psychedelics may help address interpersonal aspects of personality pathology and loneliness.
Psilocybin, a Naturally Occurring Indoleamine Compound, Could Be Useful to Prevent Suicidal Behaviors
This review (2021) presents a framework to understand the basis for using psilocybin to treat individuals with suicidal behaviours. The positive effects psilocybin has on suicidal behaviours are discussed, specifically its role as a 5-HT2A receptor agonist and its ability to increase neuroplasticity and suppress inflammation.
Psychedelics as Tools for Belief Transmission. Set, Setting, Suggestibility, and Persuasion in the Ritual Use of Hallucinogens
Drawing on ethnographic fieldwork at a shamanic centre in the Peruvian Amazon, the paper shows that psychedelics induce a state of hypersuggestibility that powerfully facilitates the ritual transmission of beliefs, yet they also provoke doubt, ambivalence and reflexivity so that enculturation hinges on the recipient’s active experiential testing rather than on “brainwashing”. The author further examines the sustainability of the resulting social affiliation and the attendant ethical challenges of globalising these practices.
Acute effects of psilocybin after escitalopram or placebo pretreatment in a randomized, double-blind, placebo-controlled, cross-over study in healthy subjects
In a randomised, double-blind, placebo-controlled crossover study in healthy volunteers, 14 days of escitalopram pretreatment attenuated psilocybin-induced bad drug effects, anxiety and adverse cardiovascular effects while not reducing positive mood effects. Escitalopram also did not alter psilocin pharmacokinetics, QTc, circulating BDNF or HTR2A/SLC6A4 expression, and the authors note further work is needed with longer pretreatment and clinical populations.
Intranasal ketamine for acute cluster headache attacks-Results from a proof-of-concept open-label trial
In an open‑label pilot in chronic cluster headache, intranasal ketamine did not meet the predefined 50% pain reduction at 15 minutes but produced a significant mean 59% reduction at 30 minutes (69% of evaluable patients ≤4/10) with no serious adverse events. These results indicate intranasal ketamine may be an effective acute treatment at 30 minutes and warrant larger controlled trials, with caution regarding ketamine’s abuse potential.
Ketamine as a Treatment for Anorexia Nervosa: A Narrative Review
This review (2021) explores the use of ketamine to treat Anorexia Nervosa (AN). The ability of ketamine to induce neuroplasticity, neurogenesis and synaptogenesis is discussed in relation to AN. Furthermore, the known antidepressant effects of ketamine may be beneficial to people with AN as depression is often experienced comorbidly.
Adults who microdose psychedelics report health related motivations and lower levels of anxiety and depression compared to non-microdosers
In a large mobile-app survey of 8,703 adults, psilocybin was the most commonly reported microdose and users described diverse dosing and “stacking” practices with predominantly health and wellness motives. Compared with non-microdosers, microdosers—despite more often reporting a history of mental‑health concerns—reported lower levels of depression, anxiety and stress, suggesting perceived mental‑health benefits that merit longitudinal study.
Psilocybin targets a common molecular mechanism for cognitive impairment and increased craving in alcoholism
This rat study demonstrated a causal link between reduced prefrontal mGluR2 receptor function and both impaired executive control and alcohol craving. It finds that psilocybin restored mGluR2 expression and reduced alcohol relapse behaviour, identifying a potential biomarker strategy for treating alcohol dependence.
Self-Medication for Chronic Pain Using Classic Psychedelics: A Qualitative Investigation to Inform Future Research
Semi‑structured interviews with 11 people who self‑medicated chronic pain with classic psychedelics revealed substantial subjective reductions in pain and identified two recurrent processes—Positive Reframing and Somatic Presence—alongside adjunct practices (mindfulness, breathwork, movement) that participants credited with improving wellbeing and pain experience. Although qualitative and not causal, these patient‑involvement findings were used to inform the design of a forthcoming controlled trial of psychedelic therapy for chronic pain.
Couple Therapy with MDMA - Proposed Pathways of Action
This theoretical paper synthesises neurobiological, neurochemical and psychobehavioural evidence to propose mechanisms—such as increased empathy, communication, attachment security and social bonding, and reduced avoidance—by which MDMA-assisted couple therapy may facilitate interpersonal and systems-level healing. The authors introduce a clinical model for MDMA-assisted couple therapy and outline implications for intervention development, delivery and future research.
Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder
In an open‑label study of 24 patients with major depressive disorder, psilocybin therapy produced an enduring increase in cognitive flexibility for at least four weeks and altered anterior cingulate cortex (ACC) biochemistry (reduced glutamate and N‑acetylaspartate) alongside increased ACC–posterior cingulate cortex dynamic functional connectivity (dFC). Paradoxically, larger post‑treatment ACC–PCC dFC increases were associated with smaller cognitive gains, while greater baseline ACC dFC predicted better baseline flexibility but less subsequent improvement, suggesting a nuanced relationship between neural and cognitive flexibility in therapeutic response.
Psychedelic experience dose-dependently modulated by cannabis: results of a prospective online survey
In a prospective online survey of 321 people, concomitant cannabis use during a serotonergic psychedelic experience was associated with dose-dependent increases in acute subjective effects — linear increases in mystical experiences, visual phenomena and ego dissolution, and a quadratic increase in challenging experiences, with no effect on emotional breakthrough. However, the observational design and self-report measures limit causal inference and the clinical implications of these interactions.
Psychedelics as Novel Therapeutics in Alzheimer’s Disease: Rationale and Potential Mechanisms
This theory-building paper (2021) makes a case for using psychedelics to treat Alzheimer's Disease (AD). The effects psychedelics have on neuroplasticity, inflammation and brain functional connectivity are discussed in relation to the pathophysiology of AD. Additionally, results from animal studies have shown psychedelics positively impact learning and memory which could have implications for the treatment of AD.
Translating Psychedelic Therapies From Clinical Trials to Community Clinics: Building Bridges and Addressing Potential Challenges Ahead
Australian clinicians and researchers identify five categories of challenges—inherent risks, poor clinical practice, inadequate infrastructure, problematic perceptions and divisive relationships—that could impede translation of psychedelic-assisted therapies from trials to community clinics. They propose strategies including public-sector support for research and training, funding for equitable access, and the creation of a broadly endorsed multidisciplinary advisory body to guide policy, implementation and professional cohesion.
Effects of Ketamine Versus Midazolam on Neurocognition at 24 Hours in Depressed Patients With Suicidal Ideation
This double-blind, parallel-group trial (n=78) compared the effects of intravenous ketamine versus midazolam on neurocognition in depressed patients with significant suicidal ideation. While ketamine rapidly reduced suicidal ideation and improved reaction time and cognitive control, these neurocognitive improvements were independent of changes in depression or mood.
Relationships between reduction in symptoms and restoration of function and wellbeing: Outcomes of the Oral Ketamine Trial on Suicidality (OKTOS)
This open-label trial (n=30) examined the effects of weekly oral ketamine treatment over six weeks on functional recovery in adults with chronic suicidality. It finds that while depression and suicidality scores improved, effect sizes for social functioning and wellbeing were smaller, suggesting that symptom reduction alone may not restore full functioning.