Psychedelics Research Recap June 2021
Psychedelic research in June continued the path towards making psychedelics available as medicines. From those who use mental health services to the general public, everyone has to get on board before we can get there.
This month we’ve learned about sleep quality after MDMA, microdosing leaves creativity hanging, and an exciting Phase II study with nitrous oxide is published. The debate on the mystical experience continues, fMRI studies are standing on a small foundation, and some encounter entities after smoking DMT.
You can find all the papers in our database, and the ones that weren’t added in our June Link Overview.
fabulous Mystical Research Images
What if no study uses the same methodology, can you then still generalize the results that a field produces? That is what a review of fMRI (functional magnetic resonance imaging) studies with psychedelics investigates. Although there is much value in these types of studies, and there was overlap in the different techniques, the review does provide an incentive to standardize analysis techniques.
Another way of peering into the brain can be done with EEG (electroencephalogram). Whereas fMRI has high spatial resolution (where), EEG does much better in answering when (temporal resolution). A study that combined EEG with machine learning finds that ketamine blocks access to learned predictive information. A way of interpreting this data is that ketamine also blocks access to negative predictive models/ruminations underlying depression.
Sticking with machine learning, a novel study applied it to analyze written reports of psychedelic experiences and predicted whether the participants could reduce substance abuse in response to using psychedelics with a 65% accuracy across three independently trained Natural Language Processing (NLP) models.
Finding null results
Not all studies find what the investigators have set out to find. In many cases the paper ends up in the rejection bin of a journal and is forgotten. Pre-registration and pre-print publishers (e.g. PsyArXiv) do make it easier to still access this research. Still, some make it to publication and provide valuable information.
Microdosing continues to be a hot topic and is considered in a new academic book chapter by Kim Kuypers. Double-blind studies, alas, keep turning up little to no results. A microdosing pooled analysis that investigated creativity finds a small improvement in a subscale of divergent creativity, but nothing else.
Epigenetics is the study of how your environment can have an influence on the way our genes work. This doesn’t mean that your genes are changes (as you may read in some places), but just how your body reads a DNA sequence. A six-month follow-up study found positive results after an ayahuasca retreat but no changes in epigenetics.
Ketamine keeps delivering results
This month features eight articles that discuss the results of studies conducted with ketamine. Two studies stand out because they investigate novel applications of ketamine. One study presents the first known case of successfully treating functional neurological disorder (FND) with (es)ketamine. Another study compares ketamine to lidocaine (local anesthetic) and finds it to be better at treating chronic migraines. Alas in this case the effects didn’t last after the initial treatment.
The largest meta-analysis (as far as we know) of intranasally (via the nose) administrated ketamine finds that it quickly reduces depressive (MDD & TRD) symptoms which were sustained 28 days later. And via another route of administration, intravenous (via veins) ketamine finds that it reduced suicidal thoughts (SI). In both studies, the effects were most pronounced right after infusion and dropped significantly at the follow-up a month later.
When researchers looked at cognition, they found improvements in executive functions, processing speed, and other measures of brain function. Another study finds that ketamine improves responses to rewards in the hours following administration. The improved response correlated with a variety of neurological measures.
A final ketamine study finds that giving Cognitive Behavioral Therapy (CBT) after successful ketamine treatment can improve the longer term (two weeks) outcomes of patients. Whereas much research with ketamine has lacked any therapy of note, this is a welcome study that could bring ketamine closer to how other psychedelics are combined with therapy.
Psychedelics everywhere
Not usually included in the psychedelic line-up is nitrous oxide (N20, laughing gas) is somewhat psychedelic and is commonly used as an anesthetic (as ketamine is too). A phase II clinical trial finds that 25% nitrous oxide provides the same antidepressant effects as was found earlier with a 50% mix.
Psychedelics have also found themselves in popular media again and the framing of psychedelic experiences can have a large impact on public perception of what it entails. A critical commentary examines a tendency of psychedelic research and popular media to frame subjective experiences, such as psychedelic ego dissolution, as a pharmacological outcome of using ayahuasca, rather than just one specific or desired outcome.
The framing of psychedelics is also discussed with regards to the mystical experience (MEQ) in a response to last month’s critique of the measure.
Why psychedelics work has been discussed extensively last month. A hypothesis paper by Kocarova, Horacek and Carhart-Harris dives deeper into this question and proposes that the transdiagnostic (psychedelics being effective for many mental health disorders) quality of psychedelics lies in its ability to increase neuronal and mental plasticity.
If, or when, psychedelics find their way towards users of mental health services, most are supportive of the research and over half are open to treatment with psychedelics. The respondents who were younger, less religious, or who had used psychedelics before, were the most positive.
A survey of a population that is younger and was using psychedelics by themselves (outside the lab) finds that psychedelics improve well-being. The changes were found in the subscales of ‘being well’ and ‘staying well’ but no changes were found in ‘spirituality’.
Ayahuasca encounters
We already featured one ayahuasca paper that investigated epigenetic differences. Another study, this one a placebo-controlled pilot study, finds improvements in the self-perception of speech performance. The participants in this study were suffering from social anxiety and the results suggest that ayahuasca can improve the cognitive aspects of speech performance.
An observational study of those who smoked DMT finds that all of them encountered the representations of another being and emerged into another world during their experiences.
The rest of the psychedelic studies
Two studies investigated MDMA this month. The first study analyzed the recent phase II data and finds improvements in sleep quality for those who received MDMA up to 12 months later. The second study is another follow-up that of Cognitive Behavioral Conjoint Therapy (CBCT) and finds improved scores on relational support, social intimacy, and other measures.
Investigating how group therapy for those suffering from AIDS can help is investigated in an interview study. Breaking free from ‘autopilot’ by becoming more mindful and meaning-making were two of the key themes identified.
A study in rats finds that the expression of genes (epigenetics as we just saw above) becomes less centralized and more complex under the influence of LSD.
And finally to leave you with something to think about, psychedelics alter metaphysical beliefs and shift them towards panpsychism and fatalism (away from physicalist/materialist). The level of impressionability, and the level of emotional synchrony of participants mediated these effects.
Papers Published in June 2021
35 studies from the Blossom database published this month.
Increased Entropic Brain Dynamics during DeepDream-Induced Altered Perceptual Phenomenology
EEG recordings showed that DeepDream-modified videos elicited higher entropy and lower complexity in frontal activity across time scales, together with increased undirected connectivity and greater entropy in functional connectivity networks compared with regular videos. These alterations parallel patterns reported under psychedelic drugs, suggesting DeepDream can non‑pharmacologically mimic altered perceptual brain dynamics for neuroimaging research.
Cognitive Behavioral Therapy to Sustain the Antidepressant Effects of Ketamine in Treatment-Resistant Depression: A Randomized Clinical Trial
In a proof-of-concept randomised sequential trial in treatment‑resistant depression, responders to six ketamine infusions were randomised to 14 weeks of CBT versus treatment‑as‑usual and CBT showed a significant group-by-time advantage on self-report depressive symptoms (QIDS; moderate-to-large Cohen d ≈ 0.71), while the primary clinician-rated outcome (MADRS) showed a non-significant moderate effect (d = 0.65). A subset analysis also found improved accuracy on an emotional N‑back task among ketamine responders.
Real-world effectiveness of repeated ketamine infusions for treatment resistant depression during the COVID-19 pandemic
This open-label study (n=267) investigated if Covid had any impact on the effectiveness of ketamine treatments (iv, 4x 35-53mg/70kg) for depression (TRD). Patients in both groups experience significant and comparable improvements in depressive symptoms, suicidal ideation (SI), and anxiety.
Sustained, multifaceted improvements in mental well-being following psychedelic experiences in a prospective opportunity sample
In a prospective naturalistic study of volunteers intending to take psychedelics (N=654 at baseline), 14 well‑being measures clustered into three factors labelled “Being well”, “Staying well” and “Spirituality”. The study found robust, selective increases in Being well and Staying well (but not Spirituality) following the psychedelic experience that remained statistically significant up to two years' follow‑up, despite high attrition.
Relational and Growth Outcomes Following Couples Therapy With MDMA for PTSD
In a pilot trial of Cognitive Behavioural Conjoint Therapy for PTSD combined with two MDMA‑assisted psychotherapy sessions in six romantic dyads, both partners reported sustained improvements in post‑traumatic growth, relational support and social intimacy, reduced behavioural accommodation and conflict, and patients reported improved psychosocial functioning and empathic concern that were maintained through 6‑month follow‑up. These findings suggest dyadic CBCT with MDMA can produce durable relational and growth benefits alongside symptom-focused PTSD treatment.
The chemical induction of synaesthesia
Surveying recreational users and developmental synaesthetes for 28 psychoactive drugs, the study found that serotonergic compounds—especially tryptamines and LSD—most frequently induce synaesthesia (commonly sound–colour), with induction rates clustering by drug class and similar patterns in controls and synaesthetes. The results support a serotonergic contribution to chemically induced synaesthesia, while also indicating individual susceptibility and possible involvement of non-serotonergic pathways.
Ketamine's effect on inflammation and kynurenine pathway in depression: A systematic review
This literature review (2021) explores ketamine's anti-inflammatory properties and tryptophan-kynurenine (KYN) pathway in patients with unipolar and bipolar depression as well as in animal models of depression. It found that ketamine induces anti-inflammatory effects in at least a proportion of patients with depression and decreased activation of the KYN pathway's neurotoxic arm.
Pharmacodynamic interactions between ketamine and psychiatric medications used in the treatment of depression: a systematic review
This systematic review (2021) examines the pharmacodynamic interactions between ketamine and generally prescribed psychiatric drugs based on published evidence and found that lamotrigine and benzodiazepines attenuate and shorten ketamine’s antidepressant effects. There are also indications for interactions between ketamine and antipsychotic drugs, such as haloperidol, risperidone and clozapine (but not olanzapine), although further research is necessary to understand their side effects.
Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo
This cell study shows that brain cells, specifically the layer five pyramidal neurons in mice, grew by 10% after the introduction of psilocybin. The effects were still present 30 days later, providing more evidence for brain plasticity as an underlying mechanism of psychedelic-assisted therapies' long-lasting effects.
Psychedelics alter metaphysical beliefs
Using large prospective online samples and an independent controlled trial, the authors show that psychedelic use shifts metaphysical beliefs away from physicalist/materialist views and towards panpsychism and fatalism, with changes detectable up to six months. These shifts correlated with greater past use and improved mental-health outcomes, were moderated by baseline impressionability and mediated by perceived emotional synchrony during the experience, implying a causal influence of psychedelics on metaphysical belief.
Psilocybin as a Novel Pharmacotherapy for Treatment-Refractory Anorexia Nervosa
This review (2021) appraises psilocybin as a novel pharmacotherapy for treatment-resistant anorexia nervosa (AN). It observes that classic psychedelics like LSD, 5-MeO-DMT, DMT, and psilocybin show a significant decrease in anxiety and depression-like symptoms, and lasting improvement in mental health. The review suggests that classic psychedelics, psilocybin in particular, show promise in normalizing dysfunctional neurobiological systems in AN and point towards a novel treatment intervention for treatment-resistant patients.
Ayahuasca Improves Self-perception of Speech Performance in Subjects With Social Anxiety Disorder: A Pilot, Proof-of-Concept, Randomized, Placebo-Controlled Trial
In a pilot randomised, placebo‑controlled trial of 17 individuals with social anxiety disorder, a single dose of ayahuasca significantly improved self‑perceived speech performance during a public‑speaking test versus placebo. This cognitive benefit occurred independently of task‑related anxiety or emotion‑recognition changes; ayahuasca increased somatic symptoms (nausea, gastrointestinal discomfort, vomiting) but was otherwise well tolerated.
LSD induces increased signalling entropy in rats' prefrontal cortex
Analysing RNA-seq from the rat prefrontal cortex after chronic LSD, the authors show that LSD rewires gene co‑expression networks to become less centralised but more complex, producing an overall increase in signalling entropy consistent with heightened molecular plasticity. This molecular increase in entropy parallels human neuroimaging reports of greater brain entropy and, via network topology, the study nominates candidate transcriptional regulators and implicates specific cell types in psychedelic action.
Psychedelics as a Training Experience for Psychedelic Therapists: Drawing on History to Inform Current Practice
This article reviews archival Spring Grove (later Maryland Psychiatric Research Center) training data and explores psychedelics as a training program for psychedelic therapists to inform current practice.
Ketamine and Attentional Bias Toward Emotional Faces: Dynamic Causal Modeling of Magnetoencephalographic Connectivity in Treatment-Resistant Depression
In a double-blind crossover MEG study using dynamic causal modelling during an emotional-face attentional task, a single ketamine infusion rapidly reduced symptoms in treatment-resistant depression and produced region-specific changes in glutamatergic and GABAergic transmission (faster GABA and NMDA in early visual cortex, faster NMDA in fusiform, slower NMDA in amygdala) with altered local inhibition in early visual and inferior frontal cortices. Symptom improvement correlated with faster AMPA transmission and increased gain of spiny stellate cells in early visual cortex, supporting GABA/NMDA inhibition–disinhibition models and emphasising AMPA throughput as a key mediator of ketamine's antidepressant effects.
Microdosing Psychedelics as a Promising New Pharmacotherapeutic
This book chapter (2021) discusses the state of the art regarding microdosing psychedelics. Microdosing is well tolerated and produces subtle effects that can be beneficial in specific domains. But studies are currently only done with very small sample sizes and healthy volunteers. Double-blind studies with patient populations (including those with ADHD) are needed.
Cross-sectional associations between lifetime use of psychedelic drugs and psychometric measures during the COVID-19 confinement: A transcultural study
In a cross‑sectional online survey of 2,974 English, Portuguese and Spanish speakers during the first COVID‑19 lockdown, regular lifetime users of psychedelic drugs reported lower psychological distress and peritraumatic stress and greater perceived social support than occasional users and non‑users. They also scored higher on novelty‑seeking and self‑transcendence and lower on cooperativeness, suggesting either a protective effect of psychedelics or pre‑existing personality differences that predispose to regular use.
Do sleep changes mediate the anti-depressive and anti-suicidal response of intravenous ketamine in treatment-resistant depression?
In 323 patients with treatment‑resistant depression, self‑reported improvements in insomnia, night‑time restlessness, early morning waking and overall sleep partially mediated the antidepressant and anti‑suicidal effects of four IV ketamine infusions. Except for hypersomnia, better sleep was also linked to higher likelihood of response/remission — each one‑point improvement in total sleep score tripled the odds of responder/remitter status (OR 3.29, 95% CI 2.00–5.41).
Improvement of functional neurological disorder after administration of esketamine nasal spray: a case report
This case report describes a patient with treatment‑resistant depression and functional neurological disorder (mixed sensory‑motor paralysis of the left arm) who achieved remission of both conditions after treatment with esketamine nasal spray. It is, to the authors' knowledge, the first reported instance of functional neurological symptoms improving with esketamine, suggesting a potential therapeutic role that requires further study.
A draft reference assembly of the Psilocybe cubensis genome
Using high-fidelity single-molecule sequencing, the authors produced a 46.6 Mb draft genome assembly of Psilocybe cubensis in 32 contigs (46% GC, N50 3.3 Mb) with 97.6% BUSCO completeness. The psilocybin biosynthesis cluster resides on a single 3.2 Mb contig and the dataset is available from NCBI BioProject PRJNA687911 and PRJNA700437.
Migraine prevalence in visual snow with prior illicit drug use (Hallucinogen Persisting Perception Disorder) versus without
In this case‑control study, none of 24 patients with HPPD manifesting as visual snow after illicit drug use had lifetime migraine, versus 20 of 37 (54%) visual snow controls without prior drug use, while symptom severity (VHI) was similar between groups. The authors infer that HPPD‑related visual snow and non‑drug visual snow may have partly distinct pathophysiological mechanisms and warn that ecstasy and other hallucinogens can precipitate persistent visual snow.
Psychedelic perceptions: mental health service user attitudes to psilocybin therapy
A survey of 99 mental health service users found that most supported further research into psilocybin (72%) and its medical use (59%), with 55% saying they would accept it if recommended by a doctor; favourable attitudes were more common in younger people, those with prior psychedelic experience, and non‑religious individuals. Nonetheless, significant reservations remained—around one fifth viewed psychedelics as addictive or unsafe and concerns included adverse effects, illegality and relapse risk, while a small minority with psychosis/bipolar still considered it useful despite potential harm.
Psilocybin and MDMA for the treatment of trauma-related psychopathology
This review (2021) investigates the therapeutic rationale behind the use of psilocybin and MDMA in the treatment of PTSD and depression. Both compounds and the possible treatment modalities (the combination with talk therapy) are discussed. A combination of first MDMA-assisted therapy, followed by psilocybin-assisted therapy is also presented.
Participant Reports of Mindfulness, Posttraumatic Growth, and Social Connectedness in Psilocybin-Assisted Group Therapy: An Interpretive Phenomenological Analysis
In an interpretive phenomenological analysis of nine gay cisgender men with long-term HIV and clinically significant trauma, psilocybin-assisted group therapy shifted participants from habitual evaluative processing to mindful experiential processing, enabling release of disowned emotions, access to prosocial and self‑transcendent feelings, meaning‑making and posttraumatic growth. These results provide the first empirical indication that adjunctive group‑delivered psilocybin may enhance trauma processing by reinforcing social cohesion, safety and belonging.
An Encounter with the Other: A Thematic Analysis of Accounts of DMT Experiences from a Naturalistic Field Study
In the first naturalistic field study using immediate micro-phenomenological interviews, thematic analysis of 36 breakthrough DMT experiences found near-universal encounters with other “beings” (94%) and immersive other “worlds” (100%), characterised by consistent themes of role, appearance, demeanour, communication and interaction. The authors relate these entity encounters to alien-abduction, shamanic and near-death phenomena and discuss possible neural mechanisms and implications for psychotherapy.
Sleep Quality Improvements After MDMA-Assisted Psychotherapy for the Treatment of Posttraumatic Stress Disorder
In four randomised, double‑blind Phase 2 trials (n=63), 2–3 sessions of MDMA‑assisted psychotherapy significantly improved self‑reported sleep quality and produced larger reductions in PTSD symptoms than low‑dose/control MDMA, with sleep gains maintained at 12 months. At the primary endpoint CAPS‑IV scores fell by −34.0 versus −12.4 and PSQI total score changed by −3.5 versus +0.6 for active versus control (p = .003 for both).
A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression
In a phase 2 trial, inhaled nitrous oxide at 25% concentration improved symptoms of treatment‑resistant major depression and produced fewer adverse effects than the 50% concentration.
Ceremonial Ayahuasca in Amazonian Retreats-Mental Health and Epigenetic Outcomes From a Six-Month Naturalistic Study
In a prospective naturalistic study of 63 self-selected participants attending ayahuasca ceremonies at a Peruvian Amazon retreat, significant reductions in depression, anxiety and general distress and increases in self‑compassion were observed post‑retreat and were largely sustained or further improved at six months. Epigenetic findings were inconclusive but pointed to candidate targets such as SIGMAR1, supporting further mechanistic and clinical investigation.
Psychedelic medicalization, public discourse, and the morality of ego dissolution
This critical commentary (2021) examines a tendency of psychedelic research and popular media to frame subjective experiences, such as psychedelic ego dissolution, as a pharmacological outcome of using ayahuasca, rather than just one specific or desired outcome for certain societies, cultures, and individuals. This highlights the pitfalls of naturalizing socially constrained orientations towards psychedelics as amoral and objective criteria that conceptualize mental health as an individualized process.
Reconciling Mystical Experiences with Naturalistic Psychedelic Science: Reply to Sanders and Zijlmans
This commentary (2021) offers a rebuttal to the opinion piece on Moving Past Mysticism in Psychedelic Science by Sanders and Zijlmans and argues against the notion of demystifying psychedelic experiences or dismissing mystical experiences from the scope of empirical inquiry. Given that all experiences are ineffable by the nature of their subjectivity, it is argued that the epistemic gap between subjective and objective viewpoints of consciousness is a question of philosophy and that it is not the role of science to decide whether metaphysical insights related to mystical experiences are compatible with their particular worldview.
Predicting changes in substance use following psychedelic experiences: natural language processing of psychedelic session narratives
This quantitative interview study (n=1141) applied a machine learning tool to analyze written reports of psychedelic experiences and predicted whether the participants could reduce substance abuse in response to using psychedelics with a 65% accuracy across three independently trained Natural Language Processing models.
The effect of single administration of intravenous ketamine augmentation on suicidal ideation in treatment-resistant unipolar depression: Results from a randomized double-blind study
This randomised double-blind placebo-controlled study (n=56) found that a single dose of ketamine significantly reduced the level of suicidal ideation (SI). Still, in both groups, there was a high level of suicidal ideation, and the study showed diminishing results rapidly over the 30 days of the study (the effects being the largest at 3 days post-infusion).
Catalysts for change: the cellular neurobiology of psychedelics
This Perspective argues that classical psychedelics act as catalysts of neural plasticity by engaging diverse cellular and subcellular signalling pathways — interacting with stress and inflammation — which likely underpin their therapeutic effects. The authors contend that this mechanistic complexity both mirrors the heterogeneity of psychiatric disorders and reshapes our understanding of mood, behaviour and consciousness.
Intranasal Ketamine for Depression in Adults: A Systematic Review and Meta-Analysis of Randomized, Double-Blind, Placebo-Controlled Trials
This meta-analysis (s=6, n=858) found that (es)ketamine administrated intranasally (via the nose) led to quick antidepressant effects for those suffering from depression (MDD & TRD). Although the effect was most pronounced in the first 24 hours after administration (MADRS decreased by 9.96 points), the effects held up at 28 days (4.09).
Predictive value of heart rate in treatment of major depression with ketamine in two controlled trials
This open-label study (n=51) found that a large increase in heart rate (HR) and -variability (HRV) predicted better outcomes for those suffering from depression (MDD) after administration of ketamine.