Psychedelics Research Review: January 2021

2021 is off to a strong start in terms of psychedelics research, with plenty of insightful papers published in January.

An RCT of repeated ketamine administration for PTSD found that, among those who responded to the drug, the median time to loss of response was less than a month (27.5 days). Ketamine was also studied in the context of treatment-resistant depression (TRD). 23 adults suffering from TRD underwent a four-day (96 hours) infusion of ketamine, which provided a “tolerated, rapid, and sustained response” to TRD.

Elsewhere, a meta-analysis of 12 studies that pitted serotonergic psychedelics against mood disorders concluded:

“Despite the concerns over unblinding and expectancy, the strength of the effect sizes, fast onset, and enduring therapeutic effects of these psychotherapeutic agents encourage further double-blind, placebo-controlled clinical trials assessing them for management of negative mood and depressive symptoms.”

There’s plenty more psychedelics research to explore this month. In our endeavour to provide you with the data necessary to track and analyse the emergent psychedelic sector, we’re working with Blossom Analysis to bring you a monthly research round-up.

Clicking the title of the paper will take you to a short summary of the work on Blossom’s website.

A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder (paper)

This first double-blind (active) placebo-controlled study (n=30) of repeated ketamine (6x, 35mg/70kg) infusions found it to be effective as a treatment for PTSD (67% clinical response), but this response faded (on average) within a month.

Authors: Adriana Feder, et al.

Published: 5 January 2021

“Objective: Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder, for which available pharmacotherapies have limited efficacy. The authors’ previous proof-of-concept randomized controlled trial of single-dose intravenous ketamine infusion in individuals with PTSD showed significant and rapid PTSD symptom reduction 24 hours postinfusion. The present study is the first randomized controlled trial to test the efficacy and safety of repeated intravenous ketamine infusions for the treatment of chronic PTSD. Methods: Individuals with chronic PTSD (N=30) were randomly assigned (1:1) to receive six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psychoactive placebo control) over 2 consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). Secondary outcome measures included the Impact of Event Scale–Revised, the Montgomery-Åsberg Depression Rating Scale (MADRS), and side effect measures. Results: The ketamine group showed a significantly greater improvement in CAPS-5 and MADRS total scores than the midazolam group from baseline to week 2. At week 2, the mean CAPS-5 total score was 11.88 points (SE=3.96) lower in the ketamine group than in the midazolam group (d=1.13, 95% CI=0.36, 1.91). Sixty-seven percent of participants in the ketamine group were treatment responders, compared with 20% in the midazolam group. Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions. Ketamine infusions were well tolerated overall, without serious adverse events. Conclusions: This randomized controlled trial provides the first evidence of efficacy of repeated ketamine infusions in reducing symptom severity in individuals with chronic PTSD. Further studies are warranted to understand ketamine’s full potential as a treatment for chronic PTSD.”

Development of the Psychological Insight Questionnaire among a sample of people who have consumed psilocybin or LSD (paper)

This survey study (n=1661) introduces and validates the Psychological Insight Questionnaire (PIQ) that shows independent (from MEQ and challenging experiences) predictive power on changes in well-being and life satisfaction.

Authors: Alan K. Davis, Frederick S. Barrett, Sara So, Natalie Gukasyan, Thomas C. Swift & Roland R. Griffiths

Published: 9 January 2021

“Background: Several measures have been developed to examine acute psychedelic effects (e.g. mystical-type and challenging experiences), but no measure assesses acute psychologically insightful experiences that may occur during psychedelic experiences. Aim: The purpose of this study was to develop and examine the psychometric properties of the Psychological Insight Questionnaire. Method: A cross-sectional survey study among psilocybin and LSD users. Respondents (n=1661; Mage=22.9, standard deviation=8.5; Caucasian/White=83%; non-Hispanic=91%; men=72%; United States resident=66%) completed an Internet-based survey. Results: The Psychological Insight Questionnaire consists of 23 items with two subscales: (a) Avoidance and Maladaptive Patterns Insights and (b) Goals and Adaptive Patterns Insights. Construct validity of the Psychological Insight Questionnaire was supported by strong correlations of the Psychological Insight Questionnaire (and Avoidance and Maladaptive Patterns Insights and Goals and Adaptive Patterns Insights subscales) scores with the insight subscale of the Session Impacts Scale, and weak-to-moderate correlations with the Mystical Experiences and Challenging Experiences Questionnaires. Furthermore, Psychological Insight Questionnaire (and Avoidance and Maladaptive Patterns Insights and Goals and Adaptive Patterns Insights subscales) scores were moderately-to-strongly correlated with retrospectively reported increases in psychological flexibility, and well-being/life satisfaction that were attributed to a memorable psychedelic experience. Lastly, incremental validity was established showing that the Psychological Insight Questionnaire (and Avoidance and Maladaptive Patterns Insights subscale) scores predict unique variance in changes in psychological flexibility, and Psychological Insight Questionnaire (and Avoidance and Maladaptive Patterns Insights and Goals and Adaptive Patterns Insights subscales) scores predict changes in well-being and life satisfaction, beyond measures of acute mystical-type and challenging effects. Conclusions: The Psychological Insight Questionnaire has the potential to extend the understanding of the acute and enduring effects of psychedelics. Further longitudinal research is necessary to determine the long-term predictive validity of the Psychological Insight Questionnaire and to examine the role of psychological insight in predicting therapeutic outcomes.”

Classic serotonergic psychedelics for mood and depressive symptoms: a meta-analysis of mood disorder patients and healthy participants (paper)

This meta-analytic review (2021, n=257) found that psychedelics provide improvements in mood for patients with mood disorders, both short (3h to 1d) and long-term (up to 60 days).

Authors: Nicole L. Galvão-Coelho, Wolfgang Marx, Maria Gonzalez, Justin Sinclair, Michael de Manincor, Daniel Perkins & Jerome Sarris

Published: 11 January 2021

“Rationale: Major depressive disorder is one of the leading global causes of disability, for which the classic serotonergic psychedelics have recently reemerged as a potential therapeutic treatment option. Objective: We present the first meta-analytic review evaluating the clinical effects of classic serotonergic psychedelics vs placebo for mood state and symptoms of depression in both healthy and clinical populations (separately). Results: Our search revealed 12 eligible studies (n = 257; 124 healthy participants, and 133 patients with mood disorders), with data from randomized controlled trials involving psilocybin (n = 8), lysergic acid diethylamide ([LSD]; n = 3), and ayahuasca (n = 1). The meta-analyses of acute mood outcomes (3 h to 1 day after treatment) for healthy volunteers and patients revealed improvements with moderate significant effect sizes in favor of psychedelics, as well as for the longer-term (16 to 60 days after treatments) mood state of patients. For patients with mood disorder, significant effect sizes were detected on the acute, medium (2-7 days after treatment), and longer-term outcomes favoring psychedelics on the reduction of depressive symptoms. Conclusion: Despite the concerns over unblinding and expectancy, the strength of the effect sizes, fast onset, and enduring therapeutic effects of these psychotherapeutic agents encourage further double-blind, placebo-controlled clinical trials assessing them for management of negative mood and depressive symptoms.”

Further analysis.

Positive expectations predict improved mental-health outcomes linked to psychedelic microdosing (paper)

This prospective survey study (n=81) found that expectancy effects were mostly predictive of microdosing outcomes on reductions in state anxiety, depressive symptoms (at 4-week endpoint), and positive outcomes (e.g. psychological resilience, -connectedness, -flexibility).

Authors: Laura S. Kaertner, Michael B. Steinborn, Hannes Kettner, Meg J. Spriggs, Leor Roseman, Tobias Buchborn, Maria Balaet, Chris Timmermann, David Erritzoe & Robin L. Carhart-Harris

Published: 21 January 2021

“Psychedelic microdosing describes the ingestion of near-threshold perceptible doses of classic psychedelic substances. Anecdotal reports and observational studies suggest that microdosing may promote positive mood and well-being, but recent placebo-controlled studies failed to find compelling evidence for this. The present study collected web-based mental health and related data using a prospective (before, during and after) design. Individuals planning a weekly microdosing regimen completed surveys at strategic timepoints, spanning a core four-week test period. Eighty-one participants completed the primary study endpoint. Results revealed increased self-reported psychological well-being, emotional stability and reductions in state anxiety and depressive symptoms at the four-week primary endpoint, plus increases in psychological resilience, social connectedness, agreeableness, nature relatedness and aspects of psychological flexibility. However, positive expectancy scores at baseline predicted subsequent improvements in well-being, suggestive of a significant placebo response. This study highlights a role for positive expectancy in predicting positive outcomes following psychedelic microdosing and cautions against zealous inferences on its putative therapeutic value.”

Further analysis.

Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression (paper)

This open-label study (n=23) found that a long (96 hours (4 days)) infusion of ketamine (10mg/70kg/h up to 42mg/70kg/h) significantly improved depressive symptoms (MADRS) for those suffering from treatment-resistant depression. This effect held up to two weeks later and the study also reported on the associated neurobiological changes.

Authors: Joshua S. Siegel, Ben J. A. Palanca, Beau M. Ances, Evan D. Kharasch, Julie A. Schweiger, Michael D. Yingling, Abraham Z. Snyder, Ginger E. Nicol, Eric J. Lenze & Nuri B. Farber

Published: 22 January 2021

“Ketamine produces a rapid antidepressant response in over 50% of adults with treatment-resistant depression. A long infusion of ketamine may provide durable remission of depressive symptoms, but the safety, efficacy, and neurobiological correlates are unknown. In this open-label, proof-of-principle study, adults with treatment-resistant depression (N = 23) underwent a 96-h infusion of intravenous ketamine (0.15 mg/kg/h titrated toward 0.6 mg/kg/h). Clonidine was co-administered to reduce psychotomimetic effects. We measured clinical response for 8 weeks post-infusion. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in patients pre- and 2 weeks post-infusion and in matched non-depressed controls (N = 27). We hypothesized that responders to therapy would demonstrate response-dependent connectivity changes while all subjects would show treatment-dependent connectivity changes. Most participants completed infusion (21/23; mean final dose 0.54 mg/kg/h, SD 0.13). The infusion was well tolerated with minimal cognitive and psychotomimetic side effects. Depressive symptoms were markedly reduced (MADRS 29 ± 4 at baseline to 9 ± 8 one day post-infusion), which was sustained at 2 weeks (13 ± 8) and 8 weeks (15 ± 8). Imaging demonstrated a response-dependent decrease in hyperconnectivity of the subgenual anterior cingulate cortex to the default mode network, and a treatment-dependent decrease in hyperconnectivity within the limbic system (hippocampus, amygdala, medial thalamus, nucleus accumbens). In exploratory analyses, connectivity was increased between the limbic system and frontal areas, and smaller right hippocampus volume at baseline predicted larger MADRS change. A single prolonged infusion of ketamine provides a tolerated, rapid, and sustained response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe.”

Psychedelic Communitas: Intersubjective experience during psychedelic group sessions predicts enduring changes in psychological wellbeing and social connectedness (paper)

This prospective survey study (n=886) of those participating in a psychedelic ceremony, validated the adapted Communitas Scale and found that positive interpersonal experiences (including personal sharing) correlated with positive outcomes (psychological wellbeing & social connectedness).

Authors: Hannes S. Kettner, Fernando Rosas, Christopher Timmermann, Laura Kärtner, Robin L. Carhart-Harris & Leor Roseman

Published: 26 January 2021

“Background. Recent years have seen a resurgence of research on the potential of psychedelic substances to treat addictive and mood disorders. Historically and contemporarily, psychedelic studies have emphasised the importance of contextual elements (‘set and setting’) in modulating acute drug effects, and ultimately, influencing long-term outcomes. Nevertheless, current small-scale clinical and laboratory studies have tended to bypass a ubiquitous contextual feature of naturalistic psychedelic use: its social dimension. This study introduces and psychometrically validates an adapted Communitas Scale, assessing acute relational experiences of perceived togetherness and shared humanity, in order to investigate psychosocial mechanisms pertinent to psychedelic ceremonies and retreats. … Results. The adapted Communitas Scale demonstrated substantial internal consistency (Cronbach’s alpha = 0.92) and construct validity in comparison with validated measures of intra-subjective (visual, mystical, challenging experiences questionnaires) and inter-subjective (perceived emotional synchrony, identity fusion) experiences. Furthermore, communitas during ceremony was significantly correlated with increases in psychological wellbeing (r = 0.22), social connectedness (r = 0.25), and other salient mental health outcomes. Path analyses revealed that the effect of ceremony-communitas on long-term outcomes was fully mediated by communitas experienced in reference to the retreat overall, and that the extent of personal sharing or ‘self-disclosure’ contributed to this process. A positive relationship between participants and facilitators, and the perceived impact of emotional support, facilitated the emergence of communitas. Conclusions. Highlighting the importance of intersubjective experience, rapport, and emotional support for long-term outcomes of psychedelic use, this first quantitative examination of psychosocial factors in guided psychedelic settings is a significant step towards evidence-based benefit-maximisation guidelines for collective psychedelic use.“

Lasting effects of a single psilocybin dose on resting-state functional connectivity in healthy individuals (paper)

This fMRI study (n=10) found that a single dose of psilocybin (14-21mg/70kg) decreased the executive control network (ECN) one week later, but didn’t elicit other lasting (neuronal) effects at that time and at 3-months follow-up.

Authors: Drummond E-W. McCulloch, Martin K. Madsen, Dea S. Stenbæk, Sara Kristiansen, Brice Ozenne, Peter S. Jensen, Gitte M. Knudsen & Patrick M. Fisher

Published (pre-print): 29 January 2021

“Background Psilocybin is a psychedelic drug that has shown lasting positive effects on clinical symptoms and self-reported well-being following a single dose. There has been little research into the long-term effects of psilocybin on brain connectivity in humans. Aims Evaluate changes in resting-state functional connectivity (RSFC) at one-week and three-months after one psilocybin dose in 10 healthy psychedelic-naïve volunteers and explore associations between change in RSFC and related measures. Methods Participants received 0.2-0.3 mg/kg psilocybin in a controlled setting. Participants completed resting-state fMRI scans at baseline, one-week and three-months post-administration and [¹¹C]Cimbi-36 PET scans at baseline and one-week. We examined changes in within-network, between-network and region-to-region RSFC. We explored associations between changes in RSFC and psilocybin-induced phenomenology as well as changes in psychological measures and neocortex serotonin 2A receptor binding. Results Psilocybin was well tolerated and produced positive changes in well-being. At one-week only, executive control network (ECN) RSFC was significantly decreased (Cohen’s d=-1.73, p_FWE=0.010). We observed no other significant changes in RSFC at one-week or three-months, nor changes in region-to-region RSFC. Exploratory analyses indicated that decreased ECN RSFC at one-week predicted increased mindfulness at three-months (r =-0.65). Conclusions These findings in a small cohort indicate that psilocybin affects ECN function within the psychedelic “afterglow” period. Our findings implicate ECN modulation as mediating psilocybin-induced, long-lasting increases in mindfulness. Although our findings implicate a neural pathway mediating lasting psilocybin effects, it is notable that changes in neuroimaging measures at three-months, when personality changes are observed, remain to be identified.“

More Psychedelic Research Papers

Use CTRL/CMD+F to quickly search if anything relevant for you has been published this month.

A Systematic Review of the MDMA Model to Address Social Impairment in Autism (review, finds trend but limited amount of human studies)
Ethical Concerns about Psilocybin Intellectual Property (concerns about not including the Mazatec communities in intellectual property filings around psilocybin)
Lectotypification of Banisteriopsis caapi and B. quitensis (Malpighiaceae), names associated with an important ingredient of Ayahuasca (taxonomy of two ingredients in ayahuasca brew)
Adverse Effects of Esketamine for the Treatment of Major Depression Disorder: Findings from Randomized Controlled Trials (“The most frequent adverse effects under treatment with esketamine were nausea, dissociation, dizziness, vertigo, hypoesthesia, sedation and paresthesia.”)
The acute effects of classic psychedelics on memory in humans (review, “Classic psychedelics dose-dependently impair memory task performance but may enhance autobiographical memory. These findings are relevant to the understanding of psychological mechanisms of action of psychedelic-assisted psychotherapy.“)
Increased sensitivity to strong perturbations in a whole-brain model of LSD (pre-print, now published, more complex brain dynamics after LSD ingestion, n=12, 75 ug LSD (see line 128 for an interesting typing omission))
Combining Ketamine, Brain Stimulation (rTMS) and Mindfulness Therapy (TIMBER) for Opioid Addiction (open-label pilot study, n=3)
Repeated subcutaneous esketamine for treatment-resistant depression: Impact of the degree of treatment resistance and anxiety comorbidity (retrospective, n=70, 35-70mg/70kg esketamine, higher treatment resistance associated with lower response to subcutaneous (under skin) esketamine)
Ketamine treatment for depression: qualitative study exploring patient views (interview study, n=14, of patients with depression but had never tired ketamine treatment)
Death due to consumption of ibogaine: case report (n=1, died after underground ibogaine treatment, also still had morphine and codeine in system)
Increased behavioral and neuronal responses to a hallucinogenic drug after adolescent toluene exposure in mice: Effects of antipsychotic treatment (in mice, “increased functionality of 5-HT_2A receptors may play a critical role in solvent-induced psychosis and recommend the antipsychotics with more selective 5-HT_2A receptor antagonism as the first-line treatment for solvent-induced psychosis“)
Narratives of the mystical among users of psychedelics (n=50, interviews, identified three narratives 1) transcendence of time and space, 2) deep euphoria, 3) being at one with ‘larger whole’)
Literature Review: Dreams, Hallucinations and Real Sensations (review, investigating the similarities and differences between dreams, psychedelics, and schizophrenia)
Does the posteromedial cortex play a primary role for the capacity for consciousness in rats? (in rats, “findings seem to support the claim that the posteromedial cortex may play a primary role for the capacity for consciousness“)
Development and validation of an LC-MS/MS method for the bioanalysis of psilocybin’s main metabolites, psilocin and 4-hydroxyindole-3-acetic acid, in human plasma (better measure the levels of psilocin (which psilocybin converts into, what is active) that could help with research, e.g. measure levels in human plasma (blood) during session)
Ketamine-induced urological toxicity: potential mechanisms and translation for adults with mood disorders receiving ketamine treatment (safety research, “Notwithstanding the evidence of [Ketamine-induced urological toxicity] in ketamine abusers, there is no evidence that ketamine and/or esketamine treatment in adults with mood disorders is associated with KIUT“)
Safety, Tolerability, and Real-World Effectiveness of Intravenous Ketamine in Older Adults With Treatment-Resistant Depression: A Case Series (found similar outcomes in older adults as earlier studies with younger populations)
Behavioral arrest and a characteristic slow waveform are hallmark responses to selective 5-HT _2A receptor activation (in mice, using 25I-NBOH – a derivative of the phenethylamine-derived hallucinogen 2C-I)
A Single Dose of Psilocybin Increases Synaptic Density and Decreases 5-HT_2A Receptor Density in the Pig Brain (in pigs, 5mg/70kg dose of psilocybin, “R density. Our findings suggest that psilocybin causes increased persistent synaptogenesis and an acute decrease in 5-HT_2AR density, which may play a role in psilocybin’s antidepressive effects“)
Pharmacological-assisted Psychotherapy for Post-Traumatic Stress Disorder: a systematic review and meta-analysis (21 studies, -1 standard deviation reduction in PTSD symptoms)
Ethical Transgressions and Boundary Violations in Ayahuasca Healing Contexts: A Mixed Methods Study (thesis, ethical transgressions (16%) and boundary violations (14%, 8% sexual) in context of ayahuasca healing)
Comparative effects of (S)-ketamine and racemic (R/S)-ketamine on psychopathology, state of consciousness and neurocognitive performance in healthy volunteers (finds (R)-ketamine to possibly be preferred to (S)-ketamine)
Is Ketamine More Effective Than Electroconvulsive Therapy for Treatment-Resistant Depression? (review, finds favorable comparison of ketamine vs ECT for TRD & MDD)
A qualitative study of patients’ experience of ketamine treatment for depression: The ‘Ketamine and me’ project (n=13, qualitative study that investigates experience of patients)
Ketamine for acute suicidality in the emergency department: A systematic review (review of three papers, there aren’t many studies directly on ketamine for suicidal ideation (SI) but could be (acutely) effective)
At baseline patients treated with esketamine have higher burden of disease than other patients with treatment resistant depression: Learnings from a population based study (finds that patients with esketamine had worse baseline characteristics than rest of treatment-resistant depression (TRD) comparison group, could have implications around regression toward the mean)
Classical Psychedelics as Therapeutics in Psychiatry – Current Clinical Evidence and Potential Therapeutic Mechanisms in Substance Use and Mood Disorders (review, we need more and larger RCT studies)
Within-treatment changes in a novel addiction treatment program using traditional Amazonian medicine (n=36, open-label, ayahuasca, helped significantly with addiction (substance use disorder, SUD))
Use of psilocybin (“mushrooms”) among US adults: 2015–2018 (estimated 10% lifetime use of psilocybin)
Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission (in mice, identifies pathways by which LSD promotes social behavior – note: used repeated administration (7 days) as 1x 30μg/kg didn’t produce effects)
Psychedelic psychiatry and the C-L psychiatrist: A primer (short review for psychiatrists)
Apnea during slow sub-anaesthetic infusion of intravenous ketamine for treatment-resistant depression (case report of apnea – cessation of breathing – with IV ketamine for TRD)
Oral S-ketamine effective after deep brain stimulation in severe treatment-resistant depression and extensive comorbidities (case report of effective, repeated dosage, treatment with es-ketamine for TRD)
Ayahuasca blocks the reinstatement of methylphenidate-induced conditioned place preference in mice: behavioral and brain Fos expression evaluations (in mice, ayahuasca vs ritalin)
Management of overdoses of salvia, kratom, and psilocybin mushrooms: a literature review (weird combination of drugs, does mention possible ‘trip stoppers’ in the final table of the paper)
Spontaneous electrical low-frequency oscillations: a possible role in Hydra and all living systems (low-frequency (spontaneous) neural oscillations, same as in DMN, in Hydra and other animals)
Use and abuse of dissociative and psychedelic drugs in adolescence (review, identifies gaps in literature with regard to adult-vs-adolescent motivations and gender differences)
Sociological investigations of human enhancement drugs: The case of microdosing psychedelics (commentary, where microdosing (research) may go in the future)
Designing an LSD Micro-Dose Transdermal Patch for Mental Illness Drug Therapy (pre-print, an interesting paper on the development of LSD-patch)
Zebrafish and Artemia Salina in Vivo Evaluation of the Recreational 25c-NBOMe Drug Demonstrates Its High Toxicity (give zebrafish a synthetic psychedelic, at very high dosages (compared to human use of 200-500µg) and they die)
New designer phenethylamines 2C-C and 2C-P have abuse potential and induce neurotoxicity in rodents (in rats, see comments on the zebrafish paper)
Sociological investigations of human enhancement drugs: The case of microdosing psychedelics (microdosing, commentary)

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