Psychedelic Research Recap February 2023
Psychedelic Research Recap February 2023
February presented another productive month for psychedelic research. This recap of the 21 most exciting articles covers intracellular neuroplasticity, brain measures, outcomes from psychedelic-assisted therapy (PAT), psychedelics for new indications, and well-being measures.
Psychedelics promote neuroplasticity through intracellular serotonin receptors
For many years it’s been known how psychedelics interact with the serotonin receptors in the brain. The places of interest, the binding, and the resulting neuroplasticity have been studied in detail. What happened inside a brain cell (neuron) wasn’t studied in detail.
New research from the Olson lab forever changes how we look at (classical) psychedelics. Imagine a neuron as a house. Before, we only looked at who was at the door (receptors on the surface of a neuron). Now, we also know what happens inside the house (receptors inside the neuron).
Through several clever experiments, Maxemiliano Vargas and colleagues find that the activation of serotonin 2a receptors inside the neurons is causing neuroplasticity. No neuroplasticity was observed in experiments where they only activated the outside neurons (by preventing psychedelics from entering). But the downstream effects were observed if they let non-psychedelic compounds, like serotonin itself, inside a neuron.
The researchers theorize, and show in mice, that possibly the psychedelic (hallucinogenic) effects are caused by the receptors on the outside of a neuron (which still elicit effects inside a neuron), and thus that this effect can be separated from the neuroplastic (which is likely related to therapeutic outcomes – but again still hotly debated).
Analysing the outcomes of psychedelic-assisted therapies
A re-analysis of the COMPASS Phase IIb trial dives deeper into the outcomes experienced by participants. It confirms that the 25mg dose of psilocybin had significantly better outcomes than the 10mg and the placebo (1mg) dose. It expands by analysing positive (increased) and negative (decreased) affect scores, ratings of anxiety (improved), and fewer lost (and unproductive) days. On the quality of life measures, only one measure (EQ-5D-3L) reached significance between the 25mg and placebo groups.
A survey study found that a reduction in death anxiety mediates the relationship between the subjective mystical experience of psychedelics and life satisfaction. Though the study is correlational, it fits within the narrative that a reduction in death anxiety (due to the mystical experience) is related to subsequent improvements in well-being. The study also found that psychological insight was a better predictor (than MEQ) of subsequent well-being outcomes (which is also echoed in a recent publication in March).
Next to the mystical experience or insights gained during therapy, the setting also dramatically influences how PAT is experienced. The COMPASS study (from two paragraphs earlier) is described as having a minimally interventive setting, but this can’t be said of the smoking cessation study. A retrospective analysis breaks apart the room attributes (e.g. scented oil), tasks given to the participants (e.g. smoking diary), and prompts given (e.g. adopting a non-smoker identity). An important yet understudied aspect of what in PAT specifically leads to or amplifies the positive outcomes.
One way of analysing the outcomes of PAT is through the lens of wellness. Two articles analyse wellness; the first is a survey of non-recreational users of psychedelics. It finds common benefits from different psychedelics (e.g. increased self-awareness, improved social connection). A second survey, which compared psychedelic users to those using cannabis and alcohol, finds greater psychological strengths and well-being scores in psychedelic users.
Measuring the effects of psychedelics on the brain
Several studies investigate brain measures during and after using psychedelics (including ketamine). How psychedelics, believed to leave the body within 24 hours, affect these changes is an active area of research.
The first study we cover here indicates that six ketamine infusions increase the connectivity (RSFC) between the left amygdala and the left medial superior frontal gyrus in patients with depression. The amygdala is a brain region associated with processing emotions, including fear and anxiety, while the medial superior frontal gyrus is involved in executive functions such as decision-making, working memory, and attentional control. This change correlated with improvements in depression scores.
The second study investigated changes in brainwaves after treatment with six ketamine tablets. During the experience, there were significant changes in alpha waves, and after the experience, significant in theta and low-beta waves were observed.
Looking at the brain under the influence of LSD has been done with fMRI (BOLD). Compared to placebo, LSD increased the complexity of brain dynamics (which is in line with earlier research around increased entropy under the influence of psychedelics). This study used the Ising model and concepts from statistical physics to measure the increased disordered state.
A study on EEG measures (brain activity over time) of the influence of DMT brings together the results from the previous two studies. It records a suppression in alpha brain waves (and partial beta suppression), and increased complexity of brain signals under the influence of DMT. Though psychedelics (and ketamine) work through different routes, similar underlying dynamics are expected to occur.
Finally, a pre-print study in rodents finds that DOI (a lesser-known psychedelic substance of the amphetamine class; effects somewhat similar to LSD) finds a decrease in synchronization under the influence of the drug.
Psychedelics for new indications
A recurring theme of these monthly recaps is the variety of indications where psychedelics can be helpful. A reviewcovers the four studies (with 150 patients) that have studied the effects of psilocybin on addiction. Overall, the results are positive, but this coverage shows that we’re working with very limited datasets.
Ketamine as a possible treatment for cocaine use disorder (CUD) is currently not something that is widely used. Researchers did have data on using ketamine as an anaesthetic (versus other compounds) and analysed the outcomes of 3800 patients. This analysis suggests that ketamine may help treat CUD. Currently, eight trials with ketamine are planned, ongoing, or completed studying the use in addictions (6 for alcoholism, 2 for opioid use).
The use of ibogaine for addiction is better known but still very risky as heart problems (e.g. arrhythmia) aren’t uncommon. Researchers are studying a new class of oxa-iboga alkaloids (related compounds) that present a better safety profile. In the second edition of a pre-print, researchers examine the efficacy and safety in rats.
Psychedelic studies on borderline can be counted on one hand. A small trial (22 participants) adds to this literature by studying the effects of ketamine versus an active placebo (midazolam). The study doesn’t find a significant difference between the two groups, though this could be because the study is underpowered (a trend was found in favour of ketamine).
Comparing different psychedelics
Descriptions of psychedelic experiences and brain measures give us some insight into the differences between the different compounds. But changes could result from different participants, the setting (as discussed above), and many other factors. Two studies sidestep these challenges by comparing two psychedelics in a randomized study (participants randomly get one psychedelic or the other – and the other a week or so later).
The first study compared 2C-B (20mg; one of the most popular ‘research chemicals’) to psilocybin (15mg). It finds that 2C-B elicited alterations in consciousness of a psychedelic nature but with a shorter duration of self-reported effects than psilocybin. The study categorised 2C-B (at least at that dose) as a subjectively “lighter” psychedelic.
The second study compared methylone (200mg; a common MDMA alternative) to MDMA (100mg). The results showed that methylone could significantly increase blood pressure and heart rate and induce pleasurable effects similar to MDMA, including stimulation, euphoria, well-being, enhanced empathy, and altered perception. The effects did come up faster with methylone and dissipated faster too.
The other studies that came out in February
A survey of psychedelic therapists (who participated in the Usona Phase II trial) finds that most (88%) had experience with psychedelics. The reasons for use ranged from personal development to recreation (fun).
A review of 33 studies concludes that psychedelics aren’t addictive or toxic at low doses but can be harmful at high doses. Physiologically the most considerable risk was identified for MDMA, though psychological (relating to set & setting) risks may be more critical.
All the talk about the measures and effects of psychedelic-assisted therapy is just hot air if we don’t look at how this will be implemented in practice. That is where a new commentary by the European equivalent of the FDA (the EMA) comes into play. The authors (including researchers from the University of Copenhagen) propose how drug developers can get psychedelics approved in the EU, and how the EMA can help to get regulatory approval.
And finally, another study investigates how psychedelics and group therapy can be combined. Again, no more than a handful of studies have looked at this possibility, and the analysis is a welcome addition. The authors analyse current literature and use Irvin Yalom’s 11 therapeutic factors of group therapy to discuss the benefits of group PAT, including increased group connectedness and interpersonal learning.
Papers Published in February 2023
28 studies from the Blossom database published this month.
Can psychedelics enhance group psychotherapy? A discussion on the therapeutic factors
This article discusses the therapeutic potential of psychedelic-assisted group psychotherapy (PAGP), which has received less attention than individual psychedelic-assisted psychotherapy models. The authors analyse current literature and use Irvin Yalom's 11 therapeutic factors of group therapy as a framework to discuss the benefits of PAGP, including increased group connectedness and interpersonal learning.
Psychedelics and psychological strengths
Across three online surveys (N = 3,157), classical psychedelic users reported greater psychological strengths and well‑being and lower distress than non‑users or alcohol/cannabis users, effects that persisted after controlling for demographics, expectancy, other drug use and meditation and were fully mediated by self‑transcendence and strongest in those citing a ‘growth’ motivation. Causality cannot be inferred, but the results extend prior evidence that psychedelic use is associated with broadly adaptive psychological profiles.
The classic psychedelic DOI induces a persistent desynchronized state in medial prefrontal cortex
This pre-print (2023) rodent study found that DOI caused changes in brain activity (specifically the mPFC) that differed from normal patterns. During rest, when brain activity is usually synchronized, the drug causes a decrease in synchronization and an increase in gamma activity.
N,N-dimethyltryptamine affects EEG response in a concentration dependent manner - a pharmacokinetic/pharmacodynamic analysis
Using population PK/PD modelling of intravenous DMT in 13 healthy volunteers, the study quantified concentration–response relationships for EEG, showing complete suppression of alpha power (EC50,e ≈ 71 nM), partial suppression of beta power (EC50,e ≈ 137 nM) and an increase in Lempel–Ziv complexity (EC50,e ≈ 54 nM). Beta power and complexity exhibited high between‑subject variability (CV ≈ 75–77%) while alpha was more consistent (CV 29%), indicating alpha power may be the most robust biomarker for dose selection.
A pilot randomized controlled trial of ketamine in Borderline Personality Disorder
This randomised controlled trial (n=22) is the first to study ketamine (35mg/70kg) in Borderline (BPD) in a placebo-controlled study. The study didn't report statistically significant differences between the ketamine and midazolam (active placebo) groups, though it did show a positive trend.
Pharmacological effects of methylone and MDMA in humans
In a randomised, double‑blind, placebo‑controlled crossover trial in 17 experienced psychostimulant users, a single oral dose of methylone (200 mg) produced sympathomimetic effects and stimulant/entactogenic subjective effects similar to MDMA (100 mg) but with a faster onset and shorter duration. These results indicate methylone’s acute pharmacological profile and abuse potential in humans are comparable to those of MDMA.
Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors
The study shows that psychedelics promote cortical neuroplasticity by selectively activating intracellular 5-HT2A receptors rather than surface receptors, explaining why serotonin does not elicit the same growth effects. This identifies location-biased 5-HT2A signalling as a therapeutic target and raises the possibility that serotonin may not be the endogenous ligand for intracellular 5-HT2ARs.
A Retrospective Study to Determine the Impact of Psychedelic Therapy for Dimensional Measures of Wellness: A Qualitative Analysis of Response Data
This retrospective thematic analysis of 93 qualitative responses from 65 adults who used psychedelic medicines therapeutically identified themes of mysticism/spirituality, functional improvement and self‑awareness, social connection, effects on medical and mental health, neutral impressions and difficult experiences. Participants reported multidimensional improvements across spiritual, physiological, psychological and social domains, suggesting psychedelic use is associated with broad qualitative changes that may enhance overall wellness and inform future mechanistic research.
Novel Class of Psychedelic Iboga Alkaloids Disrupts Opioid Use
This preprint (2023, v2) animal in vivo and human in vitro study examines a new class of oxa-iboga alkaloids (10 & 40 mg/kg) concerning their effects on opioid addiction in rats and their cardiotoxic effects on human heart cells. In contrast to noribogaine, oxa-iboga analogs exhibited no risk of inducing arrhythmia in adult human primary cardiomyocytes, and oxa-noribogaine induced acute and long-lasting suppression of morphine self-administration in rats in response to both single and repeated dosing regimes.
Repurposing ketamine to treat cocaine use disorder: Integration of artificial intelligence-based prediction, expert evaluation, clinical corroboration, and mechanism of action analyses
This analysis of ketamine data (3800 patients who received ketamine for anaesthesia, and the same number of controls) suggest that ketamine may be useful for treating cocaine use disorder (CUD).
Spectral changes of EEG following a 6-week low-dose oral ketamine treatment in adults with major depressive disorder and chronic suicidality
In adults with major depressive disorder and chronic suicidality, a 6‑week low‑dose oral ketamine regimen produced a transient reduction in centro‑parietal alpha power immediately post‑treatment that returned toward baseline by four‑week follow‑up, while theta and low‑beta bands showed delayed changes emerging after treatment cessation. Decreases in occipital theta correlated with improvements in depression and stress scores, suggesting EEG spectral shifts may track clinical response.
Examining associations between MDMA/ecstasy and classic psychedelic use and impairments in social functioning in a U.S. adult sample
In a nationally representative US sample (N = 214,505), lifetime MDMA/ecstasy use was associated with lower odds of three of four past‑year social‑functioning impairments (difficulty dealing with strangers, difficulty participating in social activities, and being prevented from participating), and lifetime mescaline use was associated with lower odds of difficulty dealing with strangers, whereas other substances showed no protective association or higher odds. These cross‑sectional findings cannot establish causality and indicate the need for experimental studies to test whether MDMA or mescaline can causally improve social functioning.
The therapeutic potential of psychedelics: the European regulatory perspective
This commentary (2023) showcases the support, and open questions, from the European regulatory perspective. It highlights the difficulties facing psychedelic trials (e.g. blinding), and showcases the support EMA can offer in ensuring the trials get done in a way that will lead to regulatory approval.
Therapeutic effect of psilocybin in addiction: A systematic review
This review (2023, s=4) finds that only 151 patients (and one clinical trial) have been through trials with psilocybin (6-40mg) for addiction (alcohol & smoking). Still, the findings were positive and larger trials are underway.
Pilot study suggests DNA methylation of the glucocorticoid receptor gene (NR3C1) is associated with MDMA-assisted therapy treatment response for severe PTSD
In a pilot sub-study of a Phase 3 trial (MDMA n=16, placebo n=7), changes in DNA methylation across HPA-axis genes predicted PTSD symptom reduction, with two CpG sites surviving FDR correction and the MDMA group showing greater methylation change at one NR3C1 (glucocorticoid receptor) site. These preliminary findings suggest NR3C1 methylation may be associated with response to MDMA‑assisted therapy and warrant replication in larger cohorts.
Hofmann vs. Paracelsus: Do Psychedelics Defy the Basics of Toxicology?-A Systematic Review of the Main Ergolamines, Simple Tryptamines, and Phenylethylamines
This review (s=33) of psychedelic compounds (e.g. LSD & psilocybin) finds that they aren't addictive or toxic at low doses, but can be harmful at high doses. Physiologically the biggest risk was identified for MDMA, though psychological (relating to set & setting) risks may be more critical.
LSD-induced increase of Ising temperature and algorithmic complexity of brain dynamics
Using pairwise maximum-entropy (Ising) models and algorithmic-complexity measures on fMRI from 15 subjects, the study shows that LSD raises individualized Ising temperatures, shifting brain dynamics further into an above-critical, more disordered (paramagnetic) regime. This shift is accompanied by reduced homotopic interhemispheric connectivity and increased algorithmic complexity (notably BDM), and the derived Ising archetypes correlate strongly with a structural connectome template (r ≈ 0.6).
Functional connectivity of the amygdala and the antidepressant and antisuicidal effects of repeated ketamine infusions in major depressive disorder
This open-label study (n=39) of ketamine (35mg/70kg infusion, x6) for major depressive disorder (MDD) found that after ketamine treatment, the resting-state functional connectivity (RSFC) between the left amygdala and the left medial superior frontal gyrus of MDD patients increased significantly. This change was positively correlated with a reduction in depressive symptoms.
Reconsidering “dissociation” as a predictor of antidepressant efficacy for esketamine
This post hoc analysis (n=576) examined the relationship between acute dissociation and the antidepressant efficacy of esketamine in treatment-resistant depression by combining data from the TRANSFORM-1 and TRANSFORM-2 clinical trials. It found no clinically significant association between dissociation and antidepressant effect for esketamine, suggesting the need for improved characterization of drug experiences relevant to therapeutic outcomes.
Reduced death anxiety as a mediator of the relationship between acute subjective effects of psychedelics and improved subjective well-being
This survey study (n=201) finds that reductions in death anxiety mediated the effects of the (acute) mystical experience on life satisfaction. Death anxiety did not mediate any of the effects of psychological insight.
A neurophenomenological approach to non-ordinary states of consciousness: hypnosis, meditation, and psychedelics
This review (2022) proposes a unified neurophenomenological (NP) approach to studying non-ordinary states of consciousness (psychedelics, meditation, hypnosis). By focusing on the experience (phenomenology; e.g. interviews) and combining it with neurophysiological measures, a rich explanatory framework could emerge.
Effective connectivity of functionally anticorrelated networks under LSD
This double-blind placebo-controlled study (n=25) assessed whether a change in anticorrelated networks (default mode network (DMN)/salience network (SN)) underlies the peak effects of LSD (100μg) using fMRI. Inhibitory effective connectivity from the SN to DMN became excitatory, and inhibitory effective connectivity from DMN to DAN decreased under the peak effect of LSD suggesting that diminution of the functional anticorrelation between resting state networks that may be a key neural mechanism of LSD and underlie ego dissolution.
Lysergic acid diethylamide-assisted therapy in patients with anxiety with and without a life-threatening illness A randomized, double-blind, placebo-controlled Phase II study
This double-blind cross-over trial (n=42) finds that LSD (2x 200 μg) significantly reduced anxiety (STAI-G) scores up to three months after treatment. The patients, both with and without a life-threatening illness, also improved on measures of depression (HAM-D, BDI). Those with more subjective drug effects and mystical-type experiences had better outcomes.
Patients' recovery and non-recovery narratives after intravenous ketamine for treatment-resistant depression
This qualitative study (n=21) uses interviews to characterize participants' experiences of intravenous (IV) ketamine infusions for treatment-resistant depression. 43% of participants had experienced remission. Five of the non-remitters were characterized as having experienced partial recovery based on their subjective experience.
Prospective associations of psychedelic treatment for co-occurring alcohol misuse and posttraumatic stress symptoms among United States Special Operations Forces Veterans
This prospective study (n=86) evaluated the effects of ibogaine & 5-MeO-DMT treatment on risky alcohol use & PTSD symptoms among US Special Operations Forces Veterans. It found a significant reduction in alcohol use from pre-treatment to 1-month, 3-months, and 6-months post-treatment, and large differences between responders and non-responders in PTSD symptom and cognitive functioning change, suggesting that psychedelic-assisted therapy may hold promise for individuals with complex trauma and alcohol misuse.
Psilocybin-assisted therapy mediates psycho-social-spiritual change in cancer patients as assessed by the NIH-HEALS
This pre-print open-label trial (n=30) assessed psycho-spiritual change in cancer patients with major depressive disorder after a single dose of psilocybin (25mg). Participants underwent individual and group preparation and integration sessions, while the NIH-HEALS was used to assess psycho-spiritual change. Across all three factors (Connection, Reflection and Introspection) of the NIH-HEALS, psilocybin led to positive changes at all time points.
Single-dose psilocybin-assisted therapy in major depressive disorder: A placebo-controlled, double-blind, randomised clinical trial
This double-blind placebo-controlled study (n=56) found that one psilocybin-assisted therapy (16mg/70kg, 2 prep + 3 integration meetings) session significantly reduced depressive symptoms (MADRS & BDI) in those suffering from a major depressive disorder (MDD, n=26). Fourteen days after the intervention, 54% of those in the psilocybin group met remission criteria (<10 on MADRS).
Subacute effects of a single dose of psilocybin on biomarkers of inflammation in healthy humans: An open-label preliminary investigation
This open-label study (n=16) assessed the effects of a single dose of psilocybin (15mg/70kg) on biomarkers of inflammation in healthy participants. Blood samples before and one day after the administration revealed that psilocybin did not significantly impact any of the selected biomarkers.