Each month I’m surprised by the large number of studies done with ketamine, especially when compared to the small number of psilocybin and MDMA studies. This month also features some of those, one comparing ketamine unfavorably to ECT. Psychedelics for anxiety disorder and psilocybin specifically for OCD are also reviewed. A small study with MDMA in Brazil is reported, and exploratory research with 5-MeO-DMT and ibogaine see extraordinary results for trauma with veterans.

Effects of serial ketamine infusions on cortico-limbic functional connectivity in major depression

Authors: Megha M. Vasavada, Joana Loureiro, Antoni Kubicki, Ashish Sahib, Benjamin Wade, Gerhard Hellemann, Randall T. Espinoza, Eliza Congdon, Katherine L. Narr & Amber Leaver

Published: 3 July 2020

One-sentence summary: Repeated administration of ketamine increased functional connectivity between limbic regions and the central executive network, decreased it between left amygdala and salience network.

“Background Ketamine is a highly effective antidepressant for patients with treatment-resistant major depressive disorder (MDD). Resting-state fMRI studies show disruptions of functional connectivity (FC) between limbic regions and resting-state networks (RSNs) including default mode (DMN), central executive (CEN), and salience networks (SN) in MDD. Here, we investigated whether serial ketamine treatments change FC between limbic structures and RSNs. Methods MDD patients (n=44) were scanned at baseline (T1), and 24 hours after the first (T2), and fourth infusion (T3) of ketamine. Healthy controls (n=50) were scanned at baseline with a subgroup (n=17) rescanned at two weeks. Limbic regions included the amygdala and hippocampus and RSNs included the DMN, CEN and SN. Results Ketamine increased right amygdala FC to the right CEN (p=0.05), decreased amygdala FC to the left CEN (p=0.005) at T2 versus T1 (p=0.015), which then increased at T3 versus T2 (p=0.002), and decreased left amygdala FC to the SN (p=0.016). Decreased left amygdala to SN FC at T2 predicted improvements in anxiety at T3 (p=0.006). Ketamine increased right hippocampus FC to left CEN (p=0.001) and this change at T2 predicted decreased anhedonia at T3 (p=0.005). Conclusions Ketamine modulates FC between limbic regions and RSNs implicated in MDD. Increases in FC between limbic regions and the CEN suggest ketamine may be involved in restoring top-down control of emotion processing. FC decreases between the left amygdala and SN suggest ketamine may restore MDD-related hyper-connectivity in these circuits. Early FC changes between limbic regions and RSNs may be predictive of clinical improvements.”

3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for victims of sexual abuse with severe post-traumatic stress disorder: an open label pilot study in Brazil (online ahead of print)

Authors: Alvaro V. Jardim, Dora V. Jardim, Bruno Rasmussen Chaves, Matheus Steglich, Marcela Ot’alora G, Michael C. Mithoefer, Dartiu X. da Silveira, Luís F. Tófoli, Sidarta Ribeiro, Rebecca Matthews, Rick Doblin & Eduardo E. Schenberg

Published: 3 July 2020

One-sentence summary: Three participants in MDMA study for PTSD in Brazil had significant (30%+) reduction on CAPS-4 scores two months after therapy (15 weeks, 3x MDMA).

“Objective: To conduct Brazil’s first clinical trial employing 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder (PTSD), given its high prevalence resulting from epidemic violence. Methods: Of 60 volunteers, four matched the inclusion & exclusion criteria. Three patients with PTSD secondary to sexual abuse (diagnosed by the Structured Clinical Interview for DSM-IV and the Clinician Administered PTSD Scale for DSMV-4 [CAPS 4]) completed enrollment and treatment, following a standardized Multidisciplinary Association for Psychedelic Studies protocol consisting of 15 weekly therapy sessions: three with orally administered MDMA with concurrent psychotherapy and music, spaced approximately 1 month apart. CAPS-4 scores two months after the final MDMA session were the primary outcome. Results: No serious adverse events occurred. The most frequent adverse events were somatic pains and anguish. CAPS-4 reductions were always greater than 25 points. The final scores were 61, 27, and 8, down from baseline scores of 90, 78, and 72, respectively. All reductions were greater than 30%, which is indicative of clinically significant improvement. Secondary outcomes included lower Beck Depressive Inventory scores and higher Post-Traumatic Growth Inventory and Global Assessment of Functioning scores. Conclusions: Considering the current limitations in safe and efficacious treatments for PTSD and recent studies abroad with larger patient samples, MDMA-assisted psychotherapy could become a viable treatment in Brazil.”

Historic Psychedelic Drug Trials and the Treatment of Anxiety Disorders

Authors: Neil M. Weston, Damian Gibbs, Catherine I. V. Bird, Aster Daniel, Luke A. Jelen, Gemma Knight, David Goldsmith, Allan H. Young & James J. Rucker

Published: 5 July 2020

One-sentence summary: A summary analysis of psychedelic drug trials for anxiety disorders found that drug administration and psychological therapy to work (but not psychedelic drugs alone).

“Introduction: In this paper, we systematically review literature from 1940 to 2000 relating to the combined use of psychological therapies and psychedelic drugs in the treatment of ICD-10 anxiety disorders. Methods: The databases Ovid MEDLINE(R), PsycINFO, and Multidisciplinary Association for Psychedelic Studies (MAPS) were searched for case reports and trials involving humans in the treatment of ICD-10 anxiety and related disorders. Twenty-four studies are described; four describe anxiety symptoms in diverse patient groups, 14 studies describe historic diagnoses that usefully correspond with ICD-10 anxiety disorders, six studies pooled results or failed to detail results specific to contemporary ICD-10 anxiety disorders. Two of the 24 studies reported are individual case reports while two of them were inadequate in terms of the reporting of outcome measures. Thus 20 studies were ultimately included in the summary analysis. Results: Three of the 20 studies reviewed described improvements in anxiety by standardized measures (p < .05) and two studies found that this effect was dose related. Of the 20 studies included in the final analysis, 94 of 145 (65%) cases of “psychoneurotic anxiety reaction” as defined by Diagnostic and Statistical Manual of Mental Disorders-I showed improvement that ranged from moderate improvement to full recovery. Despite methodological inadequacies, the results from previous studies are encouraging and should be used to guide and inform further investigation. Conclusion: The majority of studies indicate that a combination of psychedelic drug administration and psychological therapy was most beneficial. We found no study suggesting that the pharmacological action of psychedelic drugs in isolation is sufficient”

Further analysis will follow.

Psychedelic Treatment for Trauma-Related Psychological and Cognitive Impairment Among US Special Operations Forces Veterans

Authors: Alan K. Davis, Lynnette A. Averill, Nathan D. Sepeda, Joseph P. Barsuglia & Timothy Amoroso

Published: 8 July 2020

One-sentence summary: This survey study (n=51) found very large effects on mental health for special forces veterans after ibogaine and 5-MeO-DMT treatment.

“Background U.S. Special Operations Forces Veterans are at increased risk for a variety of mental health problems and cognitive impairment associated with military service. Current treatments are lacking in effectiveness and adherence. Therefore, this study examined psychedelic treatment with ibogaine and 5-methoxy-N,N-dimethyltryptamine for trauma-related psychological and cognitive impairment among U.S. Special Operations Forces Veterans. Method We conducted a survey of Veterans who completed a specific psychedelic clinical program in Mexico between 2017 and 2019. Questions probed retrospective reports of mental health and cognitive functioning during the 30 days before and 30 days after treatment. A total of 65 people completed treatment during this time frame and were eligible for contact. Of these, 51 (78%) completed the survey and were included in data analyses (mean age = 40; male = 96%; married = 55%; Caucasian/White = 92%; Operation Enduring Freedom/Operation Iraqi Freedom Service = 96%). Results Results indicated significant and very large reductions in retrospective report of suicidal ideation (p < .001; d = −1.9), cognitive impairment (p < .001; d = −2.8), and symptoms of posttraumatic stress disorder (p < .001; d = −3.6), depression (p < .001; d = −3.7), and anxiety (p < .001; d = −3.1). Results also showed a significant and large increase in retrospective report of psychological flexibility (p < .001; d = 2.9) from before-to-after the psychedelic treatment. Increases in the retrospective report of psychological flexibility were strongly associated with retrospective report of reductions in cognitive impairment, and symptoms of posttraumatic stress disorder, depression, and anxiety (rs range −0.61 to −0.75; p < .001). Additionally, most participants rated the psychedelic experiences as one of the top five personally meaningful (84%), spiritually significant (88%), and psychologically insightful (86%) experiences of their lives. Limitations: Several limitations should be considered including the retrospective, self-report, survey design of the study, and the lack of randomization and blinding, thus making these finding preliminary. Conclusion U.S. Special Operations Forces Veterans may have unique treatment needs because of the sequela of problems associated with repeated trauma exposure and the nature of the exposure. Psychedelic-assisted therapy with these under-researched psychedelics may hold unique promise for this population. However, controlled studies are needed to determine whether this treatment is efficacious in relieving mental health and cognitive impairment among U.S. Special Operations Forces Veterans.“

Further analysis

A potential role for psilocybin in the treatment of obsessive-compulsive disorder

Authors: Edward Jacobs

Published: 17 July 2020

One-sentence summary: A comprehensive (2020) review of psilocybin in the treatment for OCD. The current research is limited in scope (one trial), but points towards possible mechanisms and effectiveness.

“The recent revivification of interest in the therapeutic use of psychedelics has had a particular focus on mood disorders and addiction, although there is reason to think these drugs may be effective more widely. After outlining pertinent aspects of psilocybin and obsessive-compulsive disorder (OCD), the current review summarizes the evidence indicating that there may be a role for psilocybin in the treatment of OCD, as well as highlighting a range of potential therapeutic mechanisms that reflect the action of psilocybin on brain function. Although the current evidence is limited, that multiple signals point in directions consistent with treatment potential, alongside the psychological and physiological safety of clinically administered psilocybin, support the expansion of research, both in animal models and in further randomized controlled trials, to properly investigate this potential.”

Antidepressant effects of ketamine and ECT: A pilot comparison (online ahead of print)

Authors: Ravi K. Sharma, Gajanan Kulkarni, Channaveerachari Naveen Kumar, Shyam Sundar Arumugham, Venkataramaiah Sudhir, Urvakhsh M Mehta, Sayantanava Mitra, Milind Vijay Thanki & Jagadisha Thirthalli

Available: 18 July 2020

One-sentence summary: Electro-convulsive therapy compared favorably to ketamine in over six treatment sessions for severe (uni/bipolar) depression) (n=25).

“Background: To compare the antidepressant effects and cognitive adverse effects of intravenous ketamine infusion and Electro-convulsive therapy (ECT) in persons with severe depressive episodes. Methods: This assessor-blinded randomized control trial included 25 patients (either sex; 18-65 years) meeting ICD-10 criteria for severe depression (bipolar or unipolar). Patients received either ECT (n = 13) or intravenous infusions of ketamine hydrochloride (0.5 mg/kg over 45 min; n = 12) for six alternate day sessions over a period of two weeks. Severity of depression was assessed at baseline and on every alternate day of intervention using the Hamilton Depression Rating Scale (HDRS) and self-reported Beck Depression Inventory (BDI). Results: Baseline socio-demographic and clinical variables including HDRS (ECT: 25.15±6.58; Ketamine: 23.33±4.05, p = 0.418) and BDI (ECT: 37.07±6.58; Ketamine: 33.33±9.29; p = 0.254) were comparable. Repeated-measures analysis of variance revealed that ECT patients showed significantly greater reduction in HDRS (grouptime interaction effect; F = 4.79; p<0.001) and BDI scores (grouptime interaction effect; F = 3.83; p<0.01). ECT patients had higher response rate than ketamine patients [HDRS: ECT- 13/13(100%) vs ketamine- 8/12 (66.70%); p = 0.04]. This was true for remission as well [ECT- 12/13(92.30%) vs ketamine- 6/12(50%), p = 0.030; both HDRS and BDI]. Performance on Digit Symbol Substitution Test (as part of the Battery for ECT-Related Cognitive Deficits scale) significantly improved in ketamine patients (p = 0.02) while that in ECT patients worsened non significantly (p = 0.30). Limitations: Relatively small sample size; higher proportion of dropouts in the Ketamine arm. Conclusion: This study favoured ECT over ketamine for a better efficacy over six treatment sessions in severe depression. The results need to be replicated in larger studies.”

A proposal for a 240-person comparison was made last month.

LSD-induced increases in social adaptation to opinions similar to one’s own are associated with stimulation of serotonin receptors

Authors: Patricia Duerler, Leonhard Schilbach, Philipp Stämpfli, Franz X. Vollenweider & Katrin H. Preller

Published: 22 July 2020

One-sentence summary: LSD (100μg) increased social adaptation in a double-blind, randomized, counterbalanced, cross-over study, but only when opinions were similar to one’s own.

“Adapting one’s attitudes and behaviors to group norms is essential for successful social interaction and, thus, participation in society. Yet, despite its importance for societal and individual functioning, the underlying neuropharmacology is poorly understood. We therefore investigated its neurochemical and neural correlates in a pharmacological functional magnetic resonance imaging study. Lysergic acid diethylamide (LSD) has been shown to alter social processing and therefore provides the unique opportunity to investigate the role of the 5-HT_2A receptor in social influence processing. Twenty-four healthy human volunteers received either (1) placebo + placebo, (2) placebo + LSD (100 µg), or (3) the 5-HT_2A receptor antagonist ketanserin (40 mg) + LSD (100 µg) at three different occasions in a double-blind, randomized, counterbalanced, cross-over design. LSD increases social adaptation but only if the opinions of others are similar to the individual’s own. These increases were associated with increased activity in the medial prefrontal cortex while participants received social feedback. Furthermore, pretreatment with the 5-HT_2A antagonist ketanserin fully blocked LSD-induced changes during feedback processing, indicating a key role of the 5-HT_2A system in social feedback processing. Our results highlight the crucial role of the 5-HT-system in social influence and, thus, provide important insight into the neuropharmacological basis of social cognition and behavior.”

Modulatory effects of ayahuasca on personality structure in a traditional framework

Authors: Nige Netzband, Simon Ruffell, S. Linton, W. F. Tsang & T. Wolff

Published: 23 July 2020

One-sentence summary: Similarly to earlier findings with psilocybin, ayahuasca increased agreeableness and decreased neuroticism, which was sustained at the 6-month mark.

“Abstract Ayahuasca is a psychoactive plant brew containing dimethyltryptamine (DMT) and monoamine oxidase inhibitors (MAOIs). It originates from the Amazon basin, where it is used primarily for ceremonial purposes. Ayahuasca tourists are now entering certain communities seeking alternative physical or psychological healing, as well as spiritual growth. Rationale Recent evidence has shown that the similar acting psychedelic compound, psilocybin, facilitated long-term increases in trait openness following a single administration. Objectives This paper assesses the impact of ayahuasca on personality in a traditional framework catering for ayahuasca tourists. Method Within a mixed design, we examined the effect of ayahuasca on participants’ personality (measured by the NEO Personality Inventory 3 questionnaire) across time (pre- to post-ayahuasca administration, and 6-month follow-up), relative to a comparison group (who did not ingest ayahuasca). Results The results demonstrated significant increases in agreeableness pre- and post-ayahuasca administration and significant reductions in neuroticism in 24 participants, relative to the comparison group. Both of these changes were sustained at 6-month follow-up, and trait level increases were also observed in openness at this stage. Additionally, greater perceived mystical experience (measured using the Mystical Experience Questionnaire 30) was associated with increased reductions in neuroticism. Conclusions These findings, which indicate a positive mediating effect of ayahuasca on personality, support the growing literature suggesting potential therapeutic avenues for serotonergic psychedelics.“

The Current Status of Psychedelics in Psychiatry

Authors: David J. Nutt & Robin L. Carhart-Harris

Published: 29 July 2020

One-sentence summary: High-level overview of psychedelic research, but without punches pulled or strong opinion.

Neurocognitive impact of ketamine treatment in major depressive disorder: A review on human and animal studies

Authors: Camilla Crisanti, Paolo Enrico, Alessio Fiorentini, Giuseppe Delvecchio & Paolo Brambilla

Published: 29 July 2020

One-sentence summary: The 11 studies used in this review showed no cognitive impairment after (medical) ketamine use, and did show a normalization (reduction in impairment) in specific brain regions.

“Background: Most recent evidence support a rapid and sustained antidepressant effect of subanesthetic dose of intravenous ketamine in patients with major depressive disorder (MDD). However, clinical and animal studies investigating the effects of intravenous ketamine on specific functional domains disrupted by depression reported conflicting results. Therefore, the aim of this review is to provide an overview of the recent findings exploring the cognitive effects of ketamine in depression. Methods: After a bibliographic search on PubMed, Medline and PsycInfo, we retrieved 11 original studies meeting our research criteria, 7 in humans with MDD or Treatment Resistant Disorder and 4 using rats models for depression. Results: Overall the results showed that a) ketamine reduced activation and normalized connectivity measures of several brain regions related to depressive behaviors and reversed deficits in cognitive flexibility and coping response strategy in rats with depressive features, and b) ketamine leads to a no significant impairment on neurocognitive functions in most of the studies, with only three studies observing improvements in speed of processing, verbal learning, sustained attention and response control, verbal and working memory. Limitations: The methodological heterogeneity, in terms of neuropsychological tests used and cognitive domain explored, of the studies included. Conclusions: Most of the studies included showed no significant cognitive impairments in MDD patients after ketamine treatment. Furthermore, the results of the fMRI studies considered suggest that ketamine may have a normalizing effect on brain functions during attentional and emotional processing in MDD patients. However, further studies are needed to confirm these preliminary evidences.”