Psychedelic Research Recap March 2023
Psychedelic Research Recap March 2023
March reflected the blossoming of psychedelic research with 23 new articles covered. In this recap, we reflect on the new microdosing study, detailed brain measures under the influence of psychedelics, a null result with psilocybin for depression, and meditation x psychedelics.
On finding null results
If you find a significant result (p-value <0.05), you’re saying that chance alone is likely not the driver of the result. Suppose a statistically significant result isn’t found. In that case, it’s customary to say that the null hypothesis (usually meaning no difference between the two experimental groups) is true (or not rejected).
Several widelypublishedstudieshave shown a statistical difference between therapy alone and therapy plus psychedelics. But a new study of psilocybin (21mg/70kg) in 19 participants shows no statistically significant difference between the two groups, both had improved depression scores.
Though this is a small study, it might signal that the magnitude of psychedelic-assisted therapy (PAT) is less pronounced than previously believed. Participants guessed correctly when they had received psilocybin, so blinding is still an issue in this study. In the discussion, the authors also highlight that some participants believed they hadn’t done the session correctly, indicating that multiple dosings (as is employed in some ongoing studies) might be a better (but costlier) regimen.
On the note of null findings, an even smaller study with ten participants finds no significant difference between arketamine and placebo (no therapy given in the trial) in those with treatment-resistant depression (TRD).
An analysis of health outcomes of nearly 300 patients finds a trend, but again no significant effect, towards lower healthcare costs in those treated with esketamine for treatment-resistant depression.
Acute benefits of microdosing
In a positive signal for the benefits of microdosing, an at-home study of repeated microdoses of LSD (10μg) finds higher ratings on creativity, connectedness, energy, and other wellness ratings. The study started with a dosing session at the lab, but the subsequent 13 doses were taken at home (over six weeks).
A common critique of microdosing studies at the lab is that the artificial condition and convoluted tasks don’t reflect the real-world setting in which people microdose. Thinking about multiple uses of a brick (building a wall, throwing contest, etc.) and doing an April fools joke for your newsletter are two very different ways of looking at creativity.
This study combines the strength of both designs, standardizing the dose (usually guessed in at-home studies) and being taken outside the lab. Still, the study finds no enduring changes in mood and cognition outside of the dosing days.
An interview study looked specifically at the experiences of those who microdosed. It identified three themes: 1) seeking a solution: agency and rationale; 2) microdosers as scientists; 3) catalysing desirable and beneficial effects.
A case study of microdosing for Lyme disease (30.000 cases per year in the US) showed improvements in a man who microdosed with psilocybin. A possible explanation could lie in the anti-inflammatory effects that psilocybin possesses, though results from one case study need to be studied in a larger trial.
Peering into the brain on psychedelics
A star-studded team of researchers combined EEG and fMRI measures to look at the brain before, during, and after the administration of DMT. EEG is helpful as it provides good information over time (high temporal resolution) but at low display resolution. fMRI provides more details (high spatial resolution) but is less suited for observing temporal changes. By combining both techniques, researchers can gain a more complete understanding of brain activity.
The team found that DMT increased global functional connectivity (GFC), network disintegration and desegregation, and a compression of the principal cortical gradient. These changes were associated with the brain’s transmodal association pole, which is linked to species-specific psychological advancements and high expression of 5-HT2A receptors.
For an in-depth analysis of these results, see the excellent substack newsletter from Andrew Gallimore.
A pre-print article investigated the effects of psilocybin on brain activity (this time with fMRI only) and found that function connectomes (FCs) become more idiosyncratic, especially in the default-mode network (DMN). Looking specifically at the DMN, the researchers find reduced within-DMN activity and more connectivity with attentional systems.
The third psychedelic where new analyses were done is ayahuasca. A re-analysis found an increase in the average information parity in the brain networks of individuals, particularly in the limbic system and frontal cortex regions. By comparing resting-state functional brain networks of individuals before and after ingesting ayahuasca, the study utilized complex network theory and calculated pairwise information parity to quantify functional, statistical symmetries between brain region connectivity.
And a fourth analysis, now of LSD, found modifications in serotonin receptor-rich areas. The local signal amplitude and functional connectivity increased in the DMN and attention networks (rich in serotonin 2a receptors). A decrease was seen in limbic areas (with many serotonin 1a receptors).
Together, these studies help map out the changes happening in the brain under the influence of psychedelics. Findings from here can help identify what changes correlate with improvements in (mental) health outcomes and help develop novel psychedelics.
Meditation, psychological insight, and psychedelics
A large survey of over 2800 people finds a correlation between lifetime classical psychedelic use and a higher frequency of current mindfulness meditation (but not compassion meditation) practice. When analysing psychological insight (an aspect of the acute psychedelic experience), a correlation with both types of meditation was found.
Psychedelics and meditative practices share many characteristics. Two essays explore the benefit of including meditation and philosophical perspectives and PAT. The first essay argues that incorporating the Tibetan framework of view, meditation, and action may enhance the efficacy of PAT. The second essay proposes integrating metaphysical experiences from PAT with metaphysics, offering a Metaphysics Matrix and Metaphysics Matrix Questionnaire to aid in this process.
A third essay takes issue with evolutionary spirituality, a cultural frame for psychedelics in Western culture, which suggests that human evolution can be guided towards creating higher beings through techniques like psychedelics and eugenics. It identifies five ethical limitations of this tradition, including spiritual narcissism and contempt for less-evolved masses, before suggesting responses to these limitations.
A field study dives deep into the experience of ‘self’ after DMT inhalation. It’s the second analysis, whereas the first looked at the ‘other’, and reports (in great detail) on five categories of breakthrough experiences, including the onset of effects, bodily, sensorial, psychological, and emotional effects.
The other studies that came out in March
An open-label study of psilocybin (25mg) finds significant effects of psilocybin plus therapy for the treatment of body dysmorphic disorder (BDD), an obsessive preoccupation with misperceptions of appearance. Seven out of 12 participants showed a response (>30% decrease on a measure of BDD). Tworeviewsfrom last year suggested using psychedelics for BDD, and this small study provides a positive signal.
Another open-label trial, this time without psychedelics but with Psyreal, a VR experience that mimics the phenomenological components of psychedelic and mystical experiences, finds it alleviates depressive symptoms in people with mild-to-moderate depression.
A retrospective analysis, from within a larger trial, finds that patients with borderline personality disorder (BPD) comorbid with TRD had reduced symptoms of depression, borderline personality, suicidality, and anxiety after treatment with ketamine.
Another analysis of the Global Drug Survey finds a positive relationship between LSD and psilocybin used for self-treatment, and well-being outcomes, particularly insight and mood. A quarter of respondents reported adverse effects.
Mice treated with a non-hallucinogenic LSD analogue (2-bromo-LSD) showed neuronal structural plasticity and active coping behaviour. The main benefit of the analogue is that it doesn’t activate the 5-HT2B receptor associated with cardiac valvulopathy (disease of heart valves).
A review of ibogaine research details animal studies and the human use of ibogaine in stopping addiction. Studies are few and far between, and clinical trials are only now being started.
Papers Published in March 2023
20 studies from the Blossom database published this month.
On the need for metaphysics in psychedelic therapy and research
This hypothesis paper (2023) proposes integrating metaphysical experiences from psychedelic-assisted therapy with metaphysics, offering a Metaphysics Matrix and Metaphysics Matrix Questionnaire to aid in this process. By fusing philosophy with practical science, the text argues that patients may receive additional benefits during the integrative phase of therapy.
Classic Psychedelic Use and Current Meditation Practice
This survey study (n=2822) finds a correlation between lifetime classical psychedelic use (n=613) and a higher frequency of current mindfulness meditation (but not compassion meditation) practice. When analysing psychological insight (an aspect of the acute psychedelic experience), a correlation with both types of meditation was found.
View, meditation, action: A Tibetan framework to inform psychedelic-assisted therapy
This paper explores integrating Tibetan Buddhist contemplative tradition with psychedelic-assisted therapy (PAT), highlighting the absence of contemplative traditions in current psychedelic therapy discourse. By comparing phenomenological similarities between Tibetan Buddhist meditation and psychedelic experiences, the paper suggests that incorporating the Tibetan framework of view, meditation, and action may enhance the efficacy of PAT.
An encounter with the self: A thematic and content analysis of the DMT experience from a naturalistic field study
In a naturalistic field study of 36 post-DMT interviews, the authors provide a systematic thematic and content analysis of the "self" during breakthrough DMT experiences, identifying five overarching categories—onset, bodily, sensorial, psychological and emotional effects—and numerous subthemes describing intense alterations of body, senses, self-awareness and time. The paper highlights parallels with other extraordinary experiences and discusses putative neural mechanisms and the compound's therapeutic potential given its profound emotional impact.
‘More evolved than you’: Evolutionary spirituality as a cultural frame for psychedelic experiences
The essay situates evolutionary spirituality as a long-standing Western cultural frame that links psychedelics (and techniques like eugenics or genetic modification) to a belief in guided human evolution. It defines this tradition, identifies five ethical dangers—spiritual narcissism, contempt for the “less-evolved” masses, Social Darwinism and Malthusianism, spiritual eugenics, and illiberal utopian politics—and offers responses to mitigate these harms.
A Randomized Double-Blind Midazolam-Controlled Trial of Low-Dose Ketamine Infusion in Patients With Treatment-Resistant Depression and Prominent Suicidal Ideation
In this randomized double‑blind trial of 84 outpatients with treatment‑resistant depression and prominent suicidal ideation, a single low‑dose ketamine infusion (0.5 mg/kg) produced greater antidepressant effects than midazolam lasting up to 14 days and antisuicidal effects lasting about 5 days. Benefits were most evident in patients whose current episode was under 24 months or who had failed ≤4 antidepressants, and the infusion was safe and well tolerated.
Information parity increases on functional brain networks under influence of a psychedelic substance
This re-analysis (n=7) found that ingesting ayahuasca (100-120ml) led to an increase in the average information parity in the brain networks of individuals, particularly in the limbic system and frontal cortex regions. By comparing resting-state functional brain networks of individuals before and after ingesting ayahuasca, the study utilized complex network theory and calculated pairwise information parity to quantify functional, statistical symmetries between brain region connectivity.
Treatment patterns, healthcare utilization, and costs of patients with treatment-resistant depression initiated on Esketamine intranasal spray and covered by US commercial health plans
This analysis of health outcomes (n=269) of those treated with esketamine for treatment-resistant depression (TRD) finds a trend (but not significant differences) towards lower healthcare costs. Dosing intervals (of ketamine) were longer than recommended on the label.
Human brain effects of DMT assessed via EEG-fMRI
In a within-subject, placebo-controlled EEG–fMRI study of 20 volunteers, IV DMT produced robust increases in global functional connectivity, network disintegration and desegregation, and a compression of the principal cortical gradient. These imaging changes tracked subjective intensity, correlated with PET-derived 5‑HT2A receptor maps and EEG alterations, supporting a predominant action of DMT on the transmodal association cortex rich in 5‑HT2A expression.
Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial
In a within-subject, placebo-controlled fixed-order trial in moderate–severe major depressive disorder, both placebo and a single 0.3 mg/kg psilocybin dose delivered within psychotherapy produced significant improvements, but psilocybin showed larger effect sizes and high response (66.7%) and remission (46.7%) rates with benefits persisting about two months. The findings support the antidepressant promise of psilocybin while emphasising the strong influence of expectancy and psychotherapeutic context—and the need for trials that better mitigate and measure these effects.
Experiences of microdosing psychedelics in an attempt to support wellbeing and mental health
Using anonymous online semi‑structured interviews with 13 participants and Interpretive Phenomenological Analysis, this study found that users approached microdosing methodically as a self-directed attempt to support mental health and wellbeing and reported perceived cognitive, physical and social benefits, describing microdosing as a catalyst for positive change. The paper adds qualitative, experiential insight into the rationale and meaning of the microdosing phenomenon to inform future research on psychedelics and mental health.
Personal Psychedelic Use Is Common Among a Sample of Psychedelic Therapists: Implications for Research and Practice
In a survey of 32 therapists affiliated with a psilocybin trial, 88% reported personal use of at least one serotonergic psychedelic (81% had used psilocybin), indicating personal psychedelic use is common in this sample. The study — limited by a low response rate and limited diversity — is the first to document therapists' personal use and highlights the need to investigate whether such experience affects clinician competency or introduces bias in psychedelic therapy.
Ibogaine - A legacy within the current renaissance of psychedelic therapy
This review (2023) gives an overview of research into ibogaine. It details animal studies and the human use of ibogaine in stopping addiction. Studies are few and far between, and clinical trials are only now being started.
Investigation of self-treatment with lysergic acid diethylamide and psilocybin mushrooms: Findings from the Global Drug Survey 2020
Analysis of 3,364 Global Drug Survey 2020 respondents who self-treated with LSD (n=1,996) or psilocybin mushrooms (n=1,368) found broadly favourable self-reported changes across 17 wellbeing and symptom items—largest effects on insight and mood—although 22.5% reported negative effects. Higher intensity, prior advice-seeking, use of psilocybin and treating PTSD predicted better averaged outcomes, while younger age, high intensity and LSD use predicted more negative effects, suggesting potential benefit but a higher adverse-event frequency than in clinical settings and informing safer community practice and clinical research.
Association between mystical-type experiences under psychedelics and improvements in well-being or mental health - A comprehensive review of the evidence
This review (2023, s=44) synthesizes the evidence for the association between mystical-type experiences and improvements in well-being and mental health. It finds the strongest evidence in cross-sectional studies and healthy people. Some studies suggest that psychological insight and emotional breakthroughs may be similarly or more closely associated with positive changes than mystical-type experiences.
A non-hallucinogenic LSD analog with therapeutic potential for mood disorders
This mice and cell study of the non-hallucinogenic LSD analogue 2-bromo-LSD (2-Br-LSD) found it to be a partial agonist at the 5-HT2A receptor but it doesn't activate the 5-HT2B receptor associated with cardiac valvulopathy (disease of heart valves). It also does not induce tolerance and has been shown to promote neuronal structural plasticity and active coping behaviour in mice. Additionally, 2-Br-LSD reverses the effects of chronic stress. These findings suggest that 2-Br-LSD may have therapeutic potential for mood disorders and other indications.
Changes in self-rumination and self-compassion mediate the effect of psychedelic experiences on decreases in depression, anxiety, and stress
This online survey study (n=164) investigated how psychedelic-induced mystical experiences improve depression, anxiety, and stress, and found that these effects are partially mediated through decreased self-rumination and increased self-compassion.
LSD and language: Decreased structural connectivity, increased semantic similarity, changed vocabulary in healthy individuals
This double-blind cross-over study (n=24) of a low/moderate dose of LSD (50μg) on the structure of language finds simpler and semantically more similar language after LSD.
Subtypes of the psychedelic experience have reproducible and predictable effects on depression and anxiety symptoms
This re-analysis of survey data (n=985) finds three different clusters (subtypes) of the psychedelic experience. The subtypes, found with machine learning, were associated with reduced anxiety and depression symptoms and other markers of psychological well-being. The subtypes were also highly reproducible across multiple psychedelic substances.
The Effectiveness of Microdosed Psilocybin in the Treatment of Neuropsychiatric Lyme Disease: A Case Study
This case study (n=1) describes an immunocompetent male with neuropsychiatric Lyme disease who did not respond to conventional treatments. However, his symptoms improved when he started using psilocybin in sub-hallucinogenic doses. Psilocybin is both serotonergic and anti-inflammatory, which may benefit patients with mental illness secondary to autoimmune inflammation.