Psychedelic Research Recap September 2022
September was an exciting month for many psychedelic researchers. In Europe, researchers and entrepreneurs from all over the world gathered in the Netherlands for ICPR 2022 to discuss the latest research and what the future holds for psychedelic medicine. As a field, there is still much to tease out before these medicines become widely accessible, but one thing is for sure: research shows no sign of slowing down.
Over the past month, we gained some positive insights into the effectiveness of ketamine infusions and esketamine using real-world data (i.e. data not from clinical trials). The official results of the first trial using LSD to treat generalised anxiety disorder (GAD) were published, and researchers continue to learn more about what psychedelics are doing in the brain.
What’s going on in the real world?
Even if clinical trial results are positive, it doesn’t necessarily mean that the results can be replicated in a real-world setting. While most psychedelics are yet to move beyond the clinical trial setting for reasons surrounding their current scheduling and safety, ketamine is widely used as an off-label treatment for many mental health disorders.
For the first time, researchers explored the effectiveness of esketamine (Spravato) in patients with treatment-resistant depression (TRD) in a naturalistic setting. While the study was open-label, the overall response (64%) and remission rates (41%) were similar to the positive outcomes found in clinical trials with esketamine. Esketamine was also found to be safe and well tolerated.
A separate study exploring the effectiveness of ketamine infusions for TRD from a sample of patients attending a private clinic found similar positive results. Of the 424 patients, 72% experienced a clinical response while 38% achieved remission. The infusions also had positive effects on scores of suicidal ideation and anxiety.
Using data from clinical trials and real-world effectiveness estimates, researchers compared the cost-effectiveness of esketamine to intravenous ketamine. Using the quality-adjusted life years (QALYs) metric, it was found that esketamine is not cost-effective compared to intravenous ketamine for patients with TRD. Both types of ketamine add roughly two QALYS, but the cost of esketamine is disproportionately higher.
Sticking with ketamine, a recent meta-analysis assessed the moderators underlying the antidepressant effect of intravenous ketamine in the clinical trial setting. Moderators of the robust antidepressant effect were the level of treatment resistance (i.e. more failed SSRIs) and studies that used a cross-over design (smaller placebo effect).
An open-label study exploring the effects of subcutaneous esketamine on suicidal ideation (SI) in patients with major depressive disorder (MDD) and bipolar depression (BD) finds that esketamine led to significant reductions in SI at the end of the study. However, there was no statistically significant difference between the two subpopulations.
A look inside the brain (and gut)
An interesting theory put forward is that psychedelics can increase serotonin production from the gut (where 95% is made), which can then move more easily into the brain by making the blood-brain barrier (BBB) more permeable.
At the University of Zurich, researchers conducted a follow-up analysis of a randomised-controlled trial (RCT) with psilocybin. Using MRI techniques, they found that self-inhibition of visual areas of the brain (EVA, FG) leads to the complex imagery seen by participants. The results align with the REBUS model and highlight (again) how the bottoms-up processes of the brain are amplified under the influence of psychedelics.
The same researchers also found that psilocybin led to a pattern of decreased top-down effectivity between the default mode network (DMN), salience network (SN), and central executive network (CEN) to the amygdala in a separate analysis.
Using fMRI data from veterans and first-responders who underwent MDMA-assisted therapy, this follow-up analysis finds a correlation between reductions in PTSD and increased amygdala-hippocampal connectivity and reduced amygdala-precuneus connectivity during memory recall.
Classic psychedelics have been known to promote neuroplasticity. However, the mechanisms remain unknown. This review explores specific aspects of psychedelic-induced neuroplasticity, such as the effects on particular proteins, receptors, and the areas of the brain involved.
Using data from a DMT study, this follow-up describes how it’s metabolised in the brain. Researchers also employed a simulation (100 people at doses from 1-10mg) to delineate further DMT’s effects (both the chemistry and the subjective effects) in the first study to explore DMT’s pharmacokinetics -dynamics.
Psychological insights
This analysis of the psilocybin vs escitalopram for depression study finds that those in the psilocybin arm of the study experienced significantly decreased rumination. Only those in the psilocybin arm who responded (>50% symptom reduction) had reduced thought suppression. Ego dissolution and psychological insight, for the psilocybin group, correlated with decreases in rumination and thought suppression.
An analysis of 15 studies finds that ego-dissolution and connectedness (during psychedelic-assisted therapy) lead to a higher chance of improving mental health and well-being. The mechanism of ego-dissolution doesn’t seem to continue after the acute session, whilst connectedness is more sustained. Interestingly, the scores on both measures weren’t correlated, indicating two distinct processes.
This review hypothesises how changes due to psychedelics and psychosis have different (positive and negative) outcomes. Through the lens of self-entropic broadening theory (broader attentional scope, hyperassociative thinking), psychedelics lead to low self-focus (awe, ego dissolution, mystical experiences), whilst psychosis leads to high self-focus (hyperreflexivity, self-referential processing).
A review investigating the subjective (experiential) measures used in psychedelic trials found good correlations between mystical experiences (MEQ), oceanic boundlessness and therapeutic/mood outcomes. Similar results (with fewer participants studied) are also found for challenging experiences, psychological insight, and emotional breakthroughs. However, not much comment is made about the construct validity of the measures.
LSD for anxiety, psychedelics for pain, surveys & the rest
Early this year, researchers at the University of Basel completed the world’s first trial using LSD to treat anxiety, and now the official results are here. It was found that LSD (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.
If you’re interested in discovering more about psychedelics and anxiety, check out our previous article exploring this particular area of research and why it is lacking.
This case series highlights how low doses of psilocybin have been able to help those suffering from chronic pain conditions. All individuals were not helped by conventional treatments and achieved robust relief through psilocybin (with minimal cognitive and somatic adverse effects).
This case study describes how a teenager self-treated their psychosis (accompanied by complex PTSD and suicidal ideations) through high-dose LSD and low-dose DMT sessions. The hypothesis argues that psychedelics were able to break down the defensive system and allow for the integration of traumatic memories.
A survey of psychologists found that several factors make it more likely for psychologists to have a positive attitude towards psychedelics. These include younger age, male, more knowledge about psychedelics, not religious, (in)direct experience.
This re-analysis of a national drug survey found that those who use classical psychedelics reported fewer sick leave than the general public. Though a relatively small change (3%), the cost savings could theoretically be $2-$3 billion for the United States economy (this is a thought experiment, many other factors not in the model could also explain this correlation).
Papers Published in September 2022
22 studies from the Blossom database published this month.
Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity
This chemistry paper (2022) simulates the docking of 75 million molecules (tetrahydropyridines, THP) on the serotonin 2a (5-HT2a) receptor. The initial screening led to 17 molecules that were further refined down to two molecules ((R)-69 & (R)-70). These two had antidepressant effects (in mice) but didn't show (acute) psychoactive activity (head-twitch response, change in movement).
Classic and dissociative psychedelics induce similar hyper-synchronous states in the cognitive-limbic cortex-basal ganglia system
Both classic (LSD, DOI) and dissociative (ketamine, PCP) psychedelics induced widespread hypersynchrony of high‑frequency oscillations (HFOs) across the cognitive‑limbic cortex‑basal ganglia system in freely moving rats, with strong phase locking and sub‑millisecond interregional delays, whereas firing‑rate changes were predominantly inhibitory and not specific to psychedelic drugs. This HFO hypersynchrony could disrupt cross‑system information integration and plausibly underlies psychedelic‑induced alterations in perception and cognition, highlighting a potential target for antipsychotic interventions.
Safety, effectiveness and tolerability of sublingual ketamine in depression and anxiety: A retrospective study of off-label, at-home use
A retrospective study of at‑home, off‑label self‑administration of sublingual rapid‑dissolve ketamine tablets found the treatment to be safe, well tolerated and to produce significant reductions in PHQ‑9 and GAD‑7 scores in 47.6% of patients after three doses, with higher response rates following a six‑dose course. These results suggest sublingual ketamine is a feasible alternative to intravenous ketamine for treatment‑resistant depression and anxiety.
Facing death, returning to life: A qualitative analysis of MDMA-assisted therapy for anxiety associated with life-threatening illness
In an interpretative phenomenological analysis of participant narratives from a pilot phase 2 trial, MDMA-assisted therapy for anxiety related to life‑threatening illness was reported to facilitate processing of trauma and grief, evoke mystical/existential experiences and reduce physiological arousal, yielding improved coping, reduced psychological symptoms, greater vitality and a reconnection to life. These accounts suggest MDMA‑AT may bolster emotional resilience in the face of illness relapse, though trial limitations temper conclusions and indicate the need for further study.
Population pharmacokinetic/pharmacodynamic modelling of the psychedelic experience induced by N,N-dimethyltryptamine - implications for dose considerations
Using data from 13 healthy volunteers given intravenous DMT, the authors developed a population PK/PD model (two‑compartment PK, high clearance ≈26 L/min, effect‑site sigmoid Emax with EC50 ≈95 nM) linking plasma concentrations to subjective psychedelic intensity. Simulations translate exposure into dose–response predictions (median maximum intensity ratings for 1–20 mg), providing a tool to guide dose selection in clinical investigations.
Being no one, being One: The role of ego-dissolution and connectedness in the therapeutic effects of psychedelic experience
This mixed-methods systematic review of 15 studies (n = 2,182) found that both ego-dissolution and connectedness predict improved outcomes after psychedelic experience, with ego-dissolution tending to trigger rapid but transient psychological change and connectedness being more sustained and linked to enduring positive therapeutic feelings. The authors suggest emphasising ego-dissolution during preparation and fostering connectedness during integration to refine models of psychedelic therapy.
Scoping Review of Experiential Measures from Psychedelic Research and Clinical Trials
This review (2022) investigates the subjective (experiential) measures that are being used in psychedelic trials and finds good correlations between mystical experiences (MEQ) and oceanic boundlessness and therapeutic/mood outcomes. Similar results (with fewer participants studied) are also found for challenging experiences, psychological insight, and emotional breakthroughs. Alas, not much comment is made about the construct validity of the measures.
Towards an understanding of psychedelic-induced neuroplasticity
This review (2022) investigates how classical psychedelics (LSD, psilocybin, ayahuasca) elicit neuroplasticity. Animal and human studies show evidence for neuroplasticity, but evidence for BDNF (protein, encoded by a gene, indicated in neuronal growth) is mixed in humans. Neuroplasticity mostly happens through the 5-HT2a receptor (but other serotonin receptors could also be involved). Most of this happens 5-HT2a rich areas in the brain (neocortex). The evidence for micro/mini-dosing on neuroplasticity is currently inconclusive. Neuroplasticity happens as fast as in a few hours, lasting up to a month.
Self-Entropic Broadening Theory: Toward a New Understanding of Self and Behavior Change Informed by Psychedelics and Psychosis
This review (2022) provides a theory of how changes due to (classical) psychedelics and psychosis have such different (positive vs negative) outcomes. This is done through the lens of self-entropic broadening theory (broader attentional scope, hyperassociative thinking), where psychedelics lead to low self-focus (awe, ego dissolution, mystical experiences), whilst psychosis leads to high self-focus (hyperreflexivity, self-referential processing).
A long trip into the universe: Psychedelics and space travel
The paper proposes that psychedelics, particularly psychedelic mushrooms, could facilitate long‑duration space travel by supporting astronauts’ physical health and psychological well‑being through promotion of neuroplasticity, immune modulation and anti‑inflammatory effects. The authors also argue these substances may help process the profound, spiritual aspects of deep‑space travel and should be considered as adjuncts to medical and psychological support for interplanetary missions.
Psychedelics and mindfulness: A systematic review and meta-analysis
This review (s=13) & meta-analysis (s=6) finds that classical psychedelics use is associated with an increase in mindfulness, specifically acceptance, non-judgement of inner experience, and non-reactivity.
Clinical Effectiveness of Intravenous Racemic Ketamine Infusions in a Large Community Sample of Patients With Treatment-Resistant Depression, Suicidal Ideation, and Generalized Anxiety Symptoms: A Retrospective Chart Review
This analysis of open-label real-world data (n=424) of patients with treatment-resistant depression (TRD) find that ketamine (10x 35mg/70kg) infusions led to a clinical response (>50% reduction in symptoms, PHQ-9) for 72% of patients and remission (>80%) in 38%. Similar positive effects were found on scores of suicidal ideation (50% reduction), and anxiety (GAD-7, 30%).
Association between Lifetime Classic Psychedelic Use and Sick Leave in a Population-Based Sample
Using representative US survey data (N = 407,717), the study found that lifetime use of classic psychedelics was significantly associated with lower sick leave in the past 30 days (B = −0.09, p < 0.01) after adjusting for sociodemographic and behavioural factors. The authors suggest psychedelics could potentially reduce sick leave and related costs, but stress that causal pathways and mechanisms need further investigation.
Neural Mechanisms and Psychology of Psychedelic Ego Dissolution
This review (2022) investigates the neural mechanisms, 5HT2A receptor agonism at the top of the cortical hierarchy, that lead to ego dissolution and long-term neural plasticity. This study uses the hierarchical predictive coding framework to understand the neural mechanisms of consciousness (and psychedelics to test the model).
Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD
This study inspects how LSD binds to the 5-HT2B (serotonin 2B) receptor (not the 2A receptor most commonly studied) to understand what signalling cascades it triggers. The researchers determined the cryo-EM structures of LSD-bound HTR2B in the transducer-free, Gq-protein-coupled, and β-arrestin-1-coupled states. The information from this study can help with the design of novel psychedelics.
International pooled patient-level meta-analysis of ketamine infusion for depression: In search of clinical moderators
This meta-analysis (n=809, s=17) finds robust effects of ketamine for relieving depression (at 24 hours and seven days). Moderators of this effect were the level of treatment resistance (i.e. more failed SSRIs) and studies that used a cross-over design (smaller placebo effect). Other moderators were found, but all were modest and clinically irrelevant (i.e. age or sex doesn't moderate treatment effect).
Effects of psilocybin versus escitalopram on rumination and thought suppression in depression
In a randomised trial of 59 patients with major depressive disorder, psilocybin (COMP360) but not escitalopram produced significant reductions in rumination and thought suppression over 6 weeks; decreased thought suppression was specific to psilocybin responders while rumination fell in responders to both treatments. Reductions in both measures in the psilocybin arm correlated with ego dissolution and session-linked psychological insight, suggesting these processes may mediate its antidepressant effects.
Microdosing psilocybin for chronic pain: a case series
In a three‑patient case series, self‑administered sub‑psychedelic (micro) doses of psilocybin produced robust analgesia and reduced reliance on conventional analgesics for chronic neuropathic pain, with minimal cognitive or somatic adverse effects. Effects were enhanced and sometimes prolonged by functional exercise, and repeated dosing suggested possible plasticity‑mediated cumulative benefit, warranting controlled investigation.
Predictors of attitudes toward psychedelics among psychologists in the USA
This survey (n=358) of psychologists finds that several factors make it more likely for psychologists to have a positive attitude towards psychedelics. These include younger age, male, more knowledge about psychedelics, not religious, (in)direct experience.
Antianhedonic effects of serial intravenous subanaesthetic ketamine in anxious versus nonanxious depression
This posthoc analysis explored the effects of six repeated ketamine infusions (0.5mg/kg) in participants with anxious depression (n = 92) and nonanxious depression (n = 43). Anxious depressed patients were associated with a relatively lower antianhedonic response (47.8 % versus 51.2 %, p > 0.05) and remission (17.4 % versus 27.9 %, p > 0.05) than their non-anxious counterparts. Across both groups, a significant reduction in anhedonic symptoms was observed from the first infusion to the last infusion and at a 2-week follow-up.
Characterizing thalamocortical (dys)connectivity following d-amphetamine, LSD, and MDMA administration
This neuroimaging study (n=28) investigated the effects of LSD, d-amphetamine and MDMA on thalamocortical intrinsic functional connectivity (iFC). Each substance elicited auditory-sensorimotor-thalamic-hyperconnectivity compared to placebo, despite predominantly distinct pharmacological actions and subjective effects. LSD produced salience (SAL) hyperactivity whereas MDMA and amphetamine produced hypoconnectivity with SAL. This range of activity is similar to that seen in patients with psychotic disorders.
Past-Year Hallucinogen Use in Relation to Psychological Distress, Depression, and Suicidality among US Adults
This study used a sample from the U.S. National Survey on Drug Use and Health (n=241,675) to assess if past-year psychedelic use is associated with reporting past-year serious psychological distress (SPD), major depressive episode (MDE), and suicidality. LSD was associated with an increased likelihood of MDE and suicidal thinking. MDMA use was associated with a decreased likelihood of SPD and suicidal thinking.