Psychedelic Research Recap October 2023
Psychedelic Research Recap October 2023
This October, we saw two significant psychedelic studies being published that were previously released as pre-prints. The first is concerned with the extended DMT trial (also see our April Recap), and the second investigates the antidepressant effects of ketamine when given to patients under anaesthesia (also see our May Recap).
Next to these studies, a good mix of surveys highlights both the potential of psychedelics and the risks involved. Acutely, many people reported feelings of shame and guilt during the trip, whilst after a trip, a third of recreational users who had a challenging experience reported extended difficulties up to a year later. Still, the use of psychedelics might enhance someone’s meditative practice.
October was another fruitful month for psychedelic research, with 26 articles (and full summaries for paying members) added to the database (nearing 2000 articles). In this recap, I also cover ego dissolution, affordability of treatments, and integration guidelines.
For all the latest papers, check out the database and those that weren’t added in our October Link Overview.
Leaving Reality Behind, Two Distinct Trials
Psychedelic research serves several different outcomes. One line of thought is concerned directly with the applicability of the research findings to clinical practice. Is it effective? Can we make it affordable? Another line investigates scientific questions, the big ‘what if’ questions (without direct regard for practical outcomes). Two studies along the second line were recently published (after being out in pre-print – before peer review – in April and May).
The first deals with the extended effects of DMT in healthy participants. It asks what will happen to them and tests the infusion protocol. On both accounts, the “Psychological and physiological effects of extended DMT” study is a success, reporting that the volunteers safely navigated the changed psychological landscape in an intense trip that lasted half an hour longer than the typical DMT trip.
Changing the paradigm from a very intense trip to none at all is the triple-masked ketamine under anaesthesia study. In this study, participants who were undergoing routine surgery were given either ketamine or a placebo whilst under general anaesthesia. The researchers argue that this was able to filter out the acute/psychological effects of ketamine and thus provide a ‘cleaner’ picture of the physiological effects alone.
Still, many researchers chimed in, and many discussions erupted on Twitter/X. One thing that stood out is the large positive effect seen in both arms (there was no difference between the placebo and ketamine arms of the study). This, once again, shows the vast role that expectancy effects play in (psychedelic) research/treatment.
Psychedelic Surveys of October 2023
Recently, there has been a heightened emphasis on the adverse effects of psychedelics. After a barrage of positive news, the balance shifts towards the other side. And this isn’t without reasons. A survey on extended difficulties finds that of those who had experienced negative effects after psychedelics (so a subsection of all users), a third of them still experienced these adverse effects a year later. Those who had experienced negative outcomes in a guided setting or with a lower dose were less likely to experience negative effects long-term.
Investigating the psychiatric risks of psychedelics, a survey of over 2800 people (of which 20% used psychedelics) finds a correlation between psychedelic use and more unusual visual experiences. Of those who used psychedelics, 1.3% had been told by a doctor that they suffered from HPPD.
A longitudinal study looked at the effects of psilocybin use on feelings of shame and guilt in a naturalistic setting. The research found that while most participants reported positive psilocybin experiences, acute feelings of shame or guilt during the trip were common, occurring in 68% of users. The ability to constructively work through these difficult emotions was linked to greater well-being after psilocybin use. On average, psilocybin resulted in a small but significant decrease in trait shame that lasted 2-3 months. However, for a substantial minority of participants (30%), trait shame increased following psilocybin use.
Another longitudinal study investigated associations between psychedelic use and meditation practices in the US and UK. The research found that psychedelic use over two months was linked to increased engagement with mindfulness meditation. Additionally, having more profound insights during a psychedelic experience was associated with greater involvement in both mindfulness and loving-kindness/compassion meditation practices. An interesting finding was that more engagement with loving-kindness/compassion meditation at baseline was connected to reduced severity of challenging experiences during subsequent psychedelic use.
Bringing these threads together, a survey of people who experienced adverse childhood experiences finds that there is a high interest in the use of psilocybin (therapy) to treat psychological distress.
The Variety of Ketamine Studies – From Affordability to Quetiapine
An open-label phase IIIb trial compared esketamine plus an antidepressant to quetiapine plus an antidepressant for treatment-resistant depression (TRD). The esketamine group had significantly higher remission rates at week 8 (27.1% vs 17.6%) and lower relapse rates through week 32 after remission. Adverse events were consistent with the known safety profiles. This suggests that esketamine may be more effective for achieving and sustaining remission in treatment-resistant depression.
A randomized pilot study looked at how ketamine affects functional connectivity between the amygdala and medial prefrontal cortex (mPFC) in people with PTSD. Contrary to expectations, ketamine did not increase connectivity but caused a transient decrease in vmPFC-amygdala connectivity. This challenges previous assumptions and indicates a need for further research into dissociative states’ neurobiological basis in PTSD.
In an open-label study of esketamine nasal spray for TRD, patients reported early improvements in depression, anhedonia, and suicidality that were sustained over three months, while clinicians noted varying improvements at different time points. This study highlights the value of patient perspectives in evaluating psychedelic therapies.
A placebo-controlled study found ketamine’s effects on negative emotional states are mediated through distinct altered states it produces. Higher depersonalization relieved negative brain activity, while dissociative amnesia exacerbated insula activation. This suggests specific dissociative states differentially impact ketamine’s antidepressant response.
An analysis of IV ketamine for TRD found later depression onset positively correlated with better treatment response, indicating earlier onset may limit ketamine efficacy due to reduced neuroplasticity. Other factors like age, sex, and dissociation did not predict response, highlighting onset timing’s significance.
Finally, an economic analysis argues systemic reforms are needed to prevent patented, costly psychedelic formulations like esketamine from dominating over generic options. Commercial incentives, public funding, and reduced regulatory barriers are essential to enable affordable access to psychedelic therapies.
All Other Psychedelic Studies of October 2023
With 26 articles added (and 60 more in our link overview), there is too much to talk about in detail, so here is a quick primer on the other studies: A systematic review of MDMA’s effects on sexual function found it increased desire but had mixed impacts on arousal and erectile function in men and women. Both genders experienced delayed but more intense orgasms.
A re-analysis of an LSD neuroimaging study found it increased functional connectivity between sensory thalamus nuclei and cortices but decreased striatal-thalamic connectivity.
Reviewing the evidence on psilocybin-assisted therapy, researchers find it significantly reduces depressive symptoms, but more research is needed on safety and optimization.
A neuroimaging study found psilocybin caused individualized changes in cerebral blood flow depending on a person’s brain state and subjective psychedelic experience.
Psilocybin microdosing and neurofeedback are combined in a feasibility study. It finds significant self-reported improvements in daily executive functions like working memory and inhibition.
New proposed guidelines offer practical insights for mental health professionals on integrating psychedelic experiences, covering theoretical foundations, models, and interventions.
A philosophical piece discusses how mystical experiences from psychedelics may align with naturalism but verification of metaphysical claims about reality remains challenging.
A review of fMRI studies on psychedelics found methodological limitations but shared findings of altered connectivity in sensorimotor and prefrontal regions.
A conceptual article focuses on psychedelics’ ego effects through regression, suggesting lasting change requires targeting core ego patterns psychodynamically.
Repeated ayahuasca use is linked to cortical structural changes correlated with 5-HT2A and receptor gene expression alterations.
An analysis found psilocybin dose and age predicted challenging trip experiences, while personality traits had minimal impact.
A preclinical study showed repeated low-dose psilocybin (akin to microdosing) imparted resilience, reduced compulsiveness, and strengthened cortical-thalamic connections in rats.
Researchers found links between ADHD symptoms and lifetime use of various psychoactive substances, including ketamine and psilocybin, in university students.
Papers Published in October 2023
25 studies from the Blossom database published this month.
Psychological and physiological effects of extended DMT
This single-blind, placebo-controlled crossover study (n=11) investigated a novel administration method for DMT involving a bolus injection followed by a constant-rate infusion to extend the experience over 30 minutes. Results demonstrate that the method was safe and maintained stable subjective effects, although the plateauing of psychological effects despite rising plasma concentrations suggests the development of acute tolerance.
Does MDMA have treatment potential in sexual dysfunction? A systematic review of outcomes across the female and male sexual response cycles
This systematic review (2023, s=14) examines the effects of MDMA on the male and female sexual response cycles. Among women, MDMA showed increased sexual desire in 4 out of 6 studies, while in men, it exhibited varied effects on desire, arousal, and erectile function. Both genders experienced delayed orgasm but increased intensity and pleasure upon achieving it. Overall, while MDMA generally increased sexual desire and intensified orgasms, it presented conflicting evidence regarding sexual arousal and potentially impaired erectile and ejaculatory function in men.
Extended difficulties following the use of psychedelic drugs: A mixed methods study
This mixed‑methods study of 608 people reporting extended difficulties after psychedelic use found common problems—anxiety and fear, existential struggle, social disconnection and depersonalisation/derealisation—with about one third affected for over a year and one sixth for more than three years. Shorter duration was associated with knowing the dose and drug type and with lower acute difficulty, while a narrower range of difficulties was linked to taking the drug in a guided setting, with implications for harm reduction.
Psychedelic use and psychiatric risks
In a US-representative sample (N=2,822), lifetime naturalistic psychedelic use was associated with more lifetime unusual visual experiences and a 1.3% self-reported rate of hallucinogen persisting perception disorder, but not with greater past-two-week psychotic symptoms overall. There was an interaction with family history: psychedelic users with a family history of psychotic or bipolar disorders reported higher recent psychotic symptoms, whereas users without such a family history reported lower symptoms.
Cellular rules underlying psychedelic control of prefrontal pyramidal neurons
Contrary to the prevailing view that psychedelics increase pyramidal cell excitability via 5‑HT2A receptors, this study shows multiple classes of psychedelics dose‑dependently suppress intrinsic excitability of prefrontal pyramidal neurons by enhancing M‑current potassium channels independently of 5‑HT2A activation, with extracellular application producing larger effects than intracellular. Machine‑learning modelling indicates M‑current activation interacts with other mechanisms to markedly reduce excitability and shorten working‑memory timespan, implying modulation of ubiquitous ion channels may drive homeostatic changes that contribute to broad therapeutic benefits.
Effects of a dissociative drug on fronto-limbic resting-state functional connectivity in individuals with posttraumatic stress disorder: a randomized controlled pilot study
This randomised controlled pilot study (n=26) investigated the effect of ketamine on resting-state functional connectivity (RSFC) between amygdala and medial prefrontal cortex (mPFC) subregions. Contrary to expectations, ketamine did not increase RSFC between these areas but instead led to a transient decrease in vmPFC-amygdala RSFC in individuals with PTSD. These results challenge prior correlations and suggest a need for further exploration and a more nuanced understanding of the neurobiological basis of dissociative phenomena in PTSD.
The Patient's Perspective on the Effects of Intranasal Esketamine in Treatment-Resistant Depression
This open-label prospective study (n=25) evaluated esketamine nasal spray (ESK-NS) treatment for treatment-resistant depression (TRD). Over three months, patients reported early and sustained improvements in depression, anhedonia, and suicidality, while clinicians detected improvements that varied at different time points.
Longitudinal associations between psychedelic use and meditation practices in the United States and the United Kingdom
In representative longitudinal samples from the US and UK, self-reported psychedelic use over a two-month period was associated with greater increases in days of mindfulness meditation, and among users the subjective experience of insight predicted increases in both mindfulness and loving‑kindness/compassion practice. Higher baseline engagement in loving‑kindness/compassion meditation was associated with less intense subjective feelings of death or dying during participants' most intense psychedelic experience, suggesting psychedelics may promote meditation uptake while some meditation practices could buffer challenging psychedelic experiences.
Ketamine's acute effects on negative brain states are mediated through distinct altered states of consciousness in humans
This placebo-controlled study (n=13) investigated the effects of ketamine (3.5-35mg/70kg) on altered states of consciousness (ASCs) and their neural mechanisms. It examined the impact of different doses of ketamine on emotional task-evoked brain activity and various components of dissociation and ASCs. The study found that ketamine-induced ASCs had differential effects on brain activity, with higher depersonalization relieving negative brain states, while dissociative amnesia exacerbated insula activity. These results may provide insights into how specific dissociative states predict the response to ketamine in individuals with depression.
Trial of Ketamine Masked by Surgical Anesthesia in Depressed Patients
This triple-masked, randomised, placebo-controlled trial (n=40) of adults with major depressive disorder (MDD) found no short-term effect on depression severity (measured by MADRS) after a single dose of intravenous ketamine (35mg/70kg) compared to placebo (saline) during anaesthesia for routine surgery.
Factors Associated with Antidepressant Effects of Ketamine: A Reanalysis of Double-Blind Randomized Placebo-Controlled Trial of Intravenous Ketamine for Treatment-Resistant Depression
Reanalysis of a placebo‑controlled double‑blind RCT of intravenous ketamine in 31 adults with treatment‑resistant depression found that later age of depression onset predicted a greater antidepressant response three days after infusion, whereas age, sex, baseline severity and dissociative scores showed no association. The authors propose that impaired glutamatergic signalling and reduced neuroplasticity in earlier‑onset cases may explain the diminished ketamine response.
Psilocybin-assisted therapy for depression: A systematic review and meta-analysis
This systematic review analyzed the effects of psilocybin on depressive symptoms in patients diagnosed with life-threatening illnesses or major depressive disorder. The review included 13 studies with a total of 686 participants, and the meta-analysis of 9 studies (596 participants) found a significant and large effect in favor of psilocybin (SMD = -0.78; p<0.001) for reducing depressive symptoms. The review suggests preliminary evidence supporting the antidepressant efficacy of psilocybin-assisted psychotherapy but calls for further studies to assess safety, efficacy, and treatment optimization.
Trait mindfulness and personality characteristics in a microdosing ADHD sample: a naturalistic prospective survey study
In a naturalistic prospective survey of adults with diagnosed or severe ADHD, four weeks of psychedelic microdosing was associated with increased trait mindfulness—specifically the describing and non‑judging facets—and decreased neuroticism, while other Big Five traits remained unchanged. These effects were not altered by concurrent ADHD medication or comorbidity, though placebo‑controlled trials are needed to confirm causality.
Psilocybin-induced changes in cerebral blood flow are associated with acute and baseline inter-individual differences
In healthy volunteers, oral psilocybin produced dose-dependent changes in cerebral blood flow (relative and absolute) that correlated with the intensity of the acute subjective psychedelic experience and with baseline psychological and neurobiological characteristics, revealing marked inter-individual heterogeneity in neural response. These associations point to candidate biomarkers linking baseline traits to psilocybin-induced brain changes and support a personalised medicine approach for psychedelic-assisted therapy.
Ensuring the affordable becomes accessible-lessons from ketamine, a new treatment for severe depression
This analysis highlights the challenges in repurposing established medicines, using ketamine as a case study for treating severe depression. Generic ketamine's efficacy was known for over two decades, but commercial disinterest and lack of support delayed its approval. Instead, a costly patented formulation, Spravato®, gained widespread acceptance despite emerging evidence of generic ketamine's similar effectiveness. Systemic reforms are essential to prevent a repeat scenario with new psychedelic-assisted psychotherapy treatments, including commercial incentives, public funding, and reduced regulatory barriers.
Back from the rabbit hole. Theoretical considerations and practical guidelines on psychedelic integration for mental health specialists
This article (2023) presents proposed comprehensive guidelines for psychedelic integration, developed through an international, bottom-up project that involved literature reviews and roundtable discussions. These guidelines aim to fill the gap in mental health specialist training, providing theoretical and practical insights into psychedelic integration. They cover topics such as the effects of psychedelics, the definition of psychedelic integration, theoretical considerations, a model for integration practice, current integration models, and specific interventions from various psychotherapeutic approaches.
Psilocybin-assisted neurofeedback for the improvement of executive functions: a semi-naturalistic-lab feasibility study
This semi-naturalistic feasibility study found that psilocybin-assisted frontal-midline theta neurofeedback is practicable without psychological support and produced a trend-level increase in frontal-midline theta alongside significant self-reported improvements in everyday executive functions (working memory, shifting, monitoring, inhibition). However, no objective task-based gains were observed, indicating the need for larger randomised trials with regular sessions and active controls to confirm efficacy and specificity.
Therapeutic Potential of Psilocybin for Treating Psychological Distress among Survivors of Adverse Childhood Experiences: Evidence on Acceptability and Potential Efficacy of Psilocybin Use
This survey (n=1,249) assessed interest in and acceptability of psilocybin use among individuals who have experienced adverse childhood experiences. The study found high interest in psilocybin, and its use was associated with reduced psychological distress among those with more severe childhood adversity, indicating its potential therapeutic benefits for this group.
Functional imaging studies of acute administration of classic psychedelics, ketamine, and MDMA: Methodological limitations and convergent results
This systematic review (s=51) examines fMRI studies on the acute effects of psychedelics like psilocybin, LSD, and ketamine on the human brain. The review highlights significant methodological inconsistencies across studies, including 54% not meeting contemporary Type I error correction or motion artefact control standards. Despite these limitations, convergent findings indicate that psilocybin and LSD affect the connectivity architecture of the sensorimotor-association cortical axis, while ketamine increases activation in the dorsomedial prefrontal cortex.
The ego in psychedelic drug action - ego defenses, ego boundaries, and the therapeutic role of regression
This review (2023) focuses on the role of the ego in psychedelic-assisted psychotherapy (PAT), particularly through a psychodynamic lens. It argues that psychedelics induce regressed states of the ego, allowing for emotional integration of early life events that have shaped a person's character and defence mechanisms. The paper posits that for lasting change, PAT must target the characterological core of the ego's habitual patterns, and it suggests that this psycholytic approach is compatible with other forms of PAT like third-wave cognitive behavioural approaches (CBT/ACT).
Cortical structural differences following repeated ayahuasca use hold molecular signatures
Using 7 T MRI and morphometric similarity networks in 24 Santo Daime members and matched controls, repeated ayahuasca use was associated with sensorimotor structural differentiation and transmodal de-differentiation across the cortex. These macroscale cortical remodellings spatially correlated with dysregulation of 5‑HT2A and other psychedelic-target genes, and with altered expression of transcription factors and immediate early genes implicated in psychedelic-induced neuroplasticity, suggesting molecular mechanisms scale up to whole-brain organisation.
Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression
This open-label Phase IIIb trial (n=676) compared the efficacy of esketamine nasal spray and extended-release quetiapine, combined with an SSRI or SNRI, in patients with treatment-resistant depression (TRD). The study found that a significantly higher percentage of patients in the esketamine group achieved remission at week 8 (27.1% vs 17.6%) and had no relapse through week 32 after remission at week 8 (21.7% vs 14.1%). Adverse events were consistent with the established safety profiles of the trial treatments.
Repeated low doses of psilocybin increase resilience to stress, lower compulsive actions, and strengthen cortical connections to the paraventricular thalamic nucleus in rats
This rat study established and validated a regimen for psilocybin microdosing, administering repeated low doses of psilocybin at a level below the psychedelic threshold. The rats tolerated the regimen well without showing signs of anhedonia, anxiety, or altered locomotor activity. Additionally, the treatment imparted resilience against stress, reduced self-grooming behaviours associated with compulsiveness, and increased 5-HT7 receptor expression and synaptic density in the paraventricular nucleus of the thalamus.
Attention deficit hyperactivity disorder symptoms and lifetime use of psychoactive substances among French university students: A cross-sectional study
This observational survey study of university students (n=13,837) explored the association between ADHD symptoms and lifetime psychoactive substance use. It finds a significant correlation between high levels of ADHD symptoms and the use of various substances, including ketamine and psilocybin mushrooms.
Predicting the Intensity of Psychedelic-Induced Mystical and Challenging Experience in a Healthy Population: An Exploratory Post-Hoc Analysis
This re-analysis of a Phase I randomised controlled trial (n=89) investigated predictors of mystical and challenging experiences in healthy volunteers receiving psilocybin. It finds that dosage was the strongest predictor of intensity for both experience types, while older age was associated with fewer challenging experiences and neuroticism correlated with challenging experiences only at the higher dose.