Psychedelic Research Recap January 2024
Psychedelic Research Recap January 2024
This January we were treated to a mix of novel psychedelic trials and an unusually large amount of re-analyses of earlier studies.
In the former category, ibogaine was researched for traumatic brain injury (TBI) in veterans, DMT was researched in two separate trials, and psilocybin for chronic cluster headaches (CCHs) was put to the test.
The re-analyses investigated the effects of psychedelics in the brain, the role of the therapeutic relationship in MDMA-assisted therapy, and the effects of visual information during an LSD trip.
Other studies examined the relationship between SSRIs and psychedelics, the role of expectancy, and the effects of microdosing on the heart.
This month’s recap is made possible by our supporting members.
Check out the research link overview for all the studies we didn’t add to the database.
Ibogaine Beyond Addiction & Other Trials
An observational trial in veterans (SOF) got a lot of press, including being published in Nature Medicine (usually reserved for controlled trials). The factors behind the high-profile nature of the study? A combination of a stellar research team, a novel indication (TBI), immense results, and a population (veterans) that are currently not receiving the help they need.
The study investigated the effects of a high dose of ibogaine (up to 1g) in 30 veterans with mild traumatic brain injury (mTBI). mTBI refers to a head trauma where unconsciousness was limited to 30 minutes or shorter, although the long-term effects in this population were anything but mild. Many participants also suffered from PTSD, depression, and anxiety.
At the end of the treatment, at a well-known Mexico-based center, the disability score (WHODAS) went down from 30 (mild-to-moderate disability) to 20 immediately following treatment, and to 5 (no disability) a month later. Even more dramatic responses were seen in the PTSD (CAPS-5), depression (MADRS), and anxiety (HAM-A) scores, each reducing by 81-88%, and achieving a remission rate of 83-86%.
One final note on the study, it used a protocol where magnesium was administrated at the start and during treatment (MISTIC protocol). This has been used in treatment centres for quite a while, but this marks the first research study that investigates this more formally. As ibogaine treatment (especially with powdered iboga root with varying purity/strength) has been associated with several deaths, this may be a way to protect the heart and pave the way for ibogaine to become a medicine.
For more on possible mechanisms on psychedelics for brain injury, see this recently published review.
Same Participants, New Findings
In just about any study, more than one thing is being measured. As we saw with the ibogaine study, at least four different mental health/well-being measures were examined. And there is just a certain amount you can fit in one research article, or sometimes two very different things are being measured (e.g. brain measures and behavioural outcomes). So many studies are re-analysed through a different. Here are those studies from the last month.
A re-analysis of the psilocybin versus escitalopram (SSRI) data finds that expectancy effects played a role in the SSRI, but not in the psilocybin treatment arm. The expectancy effect measures the role of expectancy in participants (that a treatment will work) in the final outcome. For those who expected the SSRI to work, it worked better than for those who didn’t think it would help them (similar effects have been found where more side-effects also lead to more efficacy – ‘something is happening, so it must work’). Conversely, negative expectations for escitalopram may also be seen as a “know-cebo” effect, knowing you didn’t receive psilocybin and being disappointed in being assigned this treatment arm (participants were randomized in the two arms).
A lack of expectancy effect may be a positive sign for psychedelic treatments, providing a signal that it might work for those outside of controlled trials (with motivated patients). Still, this article did find an effect of suggestibility on outcomes.
What the study didn’t look at, was the therapeutic relationship, that is the topic of the next re-analysis.
Looking back, all the way to the early MAPS trials in 2014, the role of therapeutic alliance in MDMA-assisted psychotherapy is examined. The data from 22 participants provides a signal that the therapeutic alliance in the mid and late (4th and 9th session) significantly predicts the self-reported and clinician-assessed PTSD severity after treatment. Still, as a relatively recent review argued, there is little research on what therapeutic method works best in these treatments.
Two other studies analysed data from MDMA trials, one looked at the effect on self-expience, the other examined the response to social feedback.
The first of these two studies examined 90 participants in the Phase IIIa study of MDMA (plus therapy) for PTSD. It found that participants reported improvements in self-experience (e.g. alexithymia – the inability to identify & describe emotions experienced by oneself). The change in scores of self-experience correlated with recovery from PTSD. I also covered this study as a pre-print back in January 2023.
The second wanted to know how people respond to social feedback under the influence of different stimulants (MDMA and methamphetamine; meth). The study concludes that the higher dose of MDMA increases positive affective responses to social feedback, suggesting a potential mechanism by which MDMA may enhance social connection. Surprisingly, to the researchers, MDMA had no influence on feelings of rejection (i.e. not reducing the impact). Meth had no impact on social feedback.
But those weren’t the only re-analyses, so here is the rest in a whirlwind: A pre-print examines the destabilisation of whole-brain dynamics under the influence of DMT (20mg; iv), showing a peak at 5 minutes in.
Only a micro/mini-dose (13-26µg) of LSD increased neural complexity when compared to THC and meth.
On a moderately high dose of LSD (70µg), there is more brain entropy when the eyes are closed versus open.
An fMRI analysis finds that psilocybin (15mg/70kg) led to a pattern of decreased top-down connectivity between different brain networks.
Reviews: Microdosing, Older Adults, and Number Needed to Treat
Starting with a brief analysis of the psychedelic trials, a review investigated the prevalence of older adults that were included. Of the 36 studies they looked at, with over 1400 participants, only 19 participants were 65 years or older. The data from ten of these participants (all that were available) didn’t immediately show anything out of the ordinary, but also represent a very small population on which there is clinical data available.
A meta-analysis of six trials took another look at the effectiveness of ketamine for PTSD. The study finds that there was an initial reduction within the first 24 hours, but (as we often see with ketamine studies for depression) the results became murkier in the days and weeks after that.
Microdosing has become increasingly popular over the last 5 years. Still, we don’t know to what extend psychedelics influence the heart (as some ‘serotonin’ receptors also live here). As with the ibogaine research, it’s important to also protect the downside, especially when doing something more chronically. Still, the review finds no smoking gun, but argues there need to be more long-term studies into the possibility of inducing cardiac fibrosis (leading to heart failure).
Looking at the short-term effects of microdosing, a systematic review brings together results from 14 double-blind studies. It reports that acute low doses of LSD affect blood pressure, sleep, neural connectivity, mood, social cognition, and perceptions of pain and time, with noticeable effects at 10-20μg but not at 5μg. While no serious adverse effects were noted, repeated microdosing didn’t significantly change mood or cognition.
Finally, a review of studies looking at psilocybin and esketamine (Spravato)examines at a commonly used metric of the effectiveness called ‘Number Needed to Treat’ (NNT). The metric tries to capture how many people would need to receive the treatment before you are (statistically) helping one person. Psilocybin came out favourably in the study (NNT of 5 vs 7), but noted should be that the results were measured only weeks after treatment, with data coming from different studies (not head-to-head).
The Other Psychedelic Studies From January 2024
A prospective survey looked at the interactions between psychedelics and serotonergic antidepressants (SRI; SSRIs & SNRIs). The researchers wanted to know if taking an SRI would have an influence on the mood and well-being outcomes of psychedelics. It found no such effect, but did find that the acute trips of those on SRIs were less intense.
Another survey dove deep into the coping mechanisms people used after challenging psychedelic experiences. Predominant individual coping strategies included meditation and prayer, along with self-educational activities like reading and journaling. Social coping methods were commonly seeking support from friends or family, and obtaining assistance from a therapist or coach, with reported benefits including feeling heard, accepted, and sharing similar experiences.
A final survey reported on real-world impacts of ketamine on suicidality. The researchers split up the participants based on initial severity and treatment response, providing some insights into who might benefit (or not) from this type of treatment.
Two studies (of note) looked at novel psychedelics and the effects they had on cells and mice.
The first investigated MDMA-like compounds(5/6-MABB) and looked specifically at the left and right-handed isomers, finding the left-handed variation exhibiting efficacy as releasing agents for serotonin, norepinephrine, and dopamine transporters.
The second examined DOI-like compounds (R-DOTFM/DOI) for inflammation in a mice asthma model. R-DOTFM didn’t prevent inflammation, but the right-handed version of DOI did, suggesting distinct anti-inflammatory mechanisms associated with certain psychedelics.
And for the last study we covered this month, a qualitative study explored the roles and competencies of spiritual health practitioners in psychedelic-assisted therapy (PAT). The findings reveal seven themes, categorizing unique contributions like competency with spiritual material and awareness of power dynamics, as well as general contributions such as utilizing a therapeutic repertoire and fostering interdisciplinary collaboration. The study emphasizes the importance of delineating the roles and qualifications of spiritual health practitioners to enhance the quality and standards of care in PAT teams.
Papers Published in January 2024
25 studies from the Blossom database published this month.
Neural complexity is increased after low doses of LSD, but not moderate to high doses of oral THC or methamphetamine
This re-analysis (n=73) investigates the effects of low doses of LSD (13-26µg; n=21), THC (7.5-15mg), and methamphetamine (MA; 10-20mg) on neural complexity in healthy volunteers without inducing altered states of consciousness. Utilizing a within-subjects design over three laboratory visits, the study records resting state EEG data to measure Lempel-Ziv complexity and spectral power. Results demonstrate that only LSD, not THC or MA, dose-dependently increases neural complexity and reduces delta and theta power, while THC and MA respectively decrease and increase alpha power, primarily in frontal regions.
Interactions between classic psychedelics and serotonergic antidepressants: Effects on the acute psychedelic subjective experience, well-being and depressive symptoms from a prospective survey study
This prospective survey study found that people on serotonergic antidepressants reported significantly reduced acute subjective psychedelic effects—especially mystical, challenging and emotional breakthrough experiences—compared with unmedicated participants, yet both groups showed similar improvements in well‑being and depressive symptoms. The authors conclude SRIs may blunt subjective effects without diminishing short‑term antidepressant benefit, warranting controlled investigation.
MDMA enhances positive affective responses to social feedback
In a double-blind, placebo-controlled crossover trial in 36 healthy adults, the high dose of MDMA (1.5 mg/kg) — but not the lower dose — increased positive affective responses to personalised social feedback compared with placebo and methamphetamine. This suggests a potential mechanism by which MDMA may enhance social connection and support its use as a psychotherapy adjunct.
Microdosing psychedelics: Current evidence from controlled studies
This systematic review (s=14) compiles double-blind, placebo-controlled studies on microdosing LSD (5-20μg) under laboratory conditions. It reports that acute low doses of LSD affect blood pressure, sleep, neural connectivity, mood, social cognition, and perceptions of pain and time, with noticeable effects at 10-20 μg but not at 5μg. While no serious adverse effects were noted, repeated microdosing did not significantly change mood or cognition.
Novel Benzofuran Derivatives Induce Monoamine Release and Substitute for the Discriminative Stimulus Effects of 3,4-Methylenedioxymethamphetamine
This in vitro and in vivo study investigates novel analogues of the designer drug 5-(2-methylaminopropyl) benzofuran (5-MAPB) as potential MDMA-like monoamine releasers. The research reveals that the S isomers of 5- and 6-(2-methylaminobutyl)benzofuran (5-MABB and 6-MABB) exhibit efficacy as releasing agents for serotonin, norepinephrine, and dopamine transporters. In contrast, the R isomers show reduced potency in inducing behavioural effects, suggesting the aminoalkyl benzofuran scaffold is a potential template for developing compounds with MDMA-like properties.
Assessing expectancy and suggestibility in a trial of escitalopram v. psilocybin for depression
In a double-blind randomised trial (n=55) comparing escitalopram and COMP360 psilocybin for major depressive disorder, pre-treatment expectancy predicted response to escitalopram but not to psilocybin, whereas baseline trait suggestibility was associated with response to psilocybin only. These findings suggest psychedelic therapy may be less vulnerable to expectancy biases but could be particularly effective in highly suggestible individuals.
Older adults in psychedelic-assisted therapy trials: A systematic review
This systematic review (n=1400; s=36) aimed to assess the prevalence of older adults in psychedelic clinical trials and explore safety data. Only 19 participants aged 65 or older were identified, constituting less than 1.4% of all trial participants. Detailed safety data for 10 of these older adults revealed no serious adverse events, with only transient mild-to-moderate adverse events related to anxiety, gastrointestinal upset, and hypertension during psychedelic dosing sessions.
CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity
In a small open‑label trial of 10 patients with chronic cluster headache, three oral doses of psilocybin (0.14 mg/kg) were well tolerated and produced a mean 31 per cent reduction in attack frequency, with one patient achieving 21 weeks' remission. Changes in hypothalamic–diencephalic functional connectivity on fMRI correlated strongly with attack reduction (R = −0.81), implicating hypothalamic circuits in the therapeutic response and supporting further clinical study.
So how special is special K? A systematic review and meta-analysis of ketamine for PTSD RCTs
This systematic review & meta-analysis (2024; s=6; n=221) of randomised control trials (RCTs) on ketamine interventions for PTSD finds a small advantage for ketamine over control conditions in reducing PTSD symptoms at 24 hours post-initial infusion, but bias and heterogeneity pose concerns, indicating that blind penetration and the placebo effect might contribute to reported therapeutic effects.
Effects of external stimulation on psychedelic state neurodynamics
This further analysis of data from a single-blind, placebo-controlled study (n=20) on the effects of LSD (75µg) finds that the context (eyes closed/open, silence/music/video) modulates the level of brain entropy. The study finds that eyes-closed elicited the biggest response, and that video (external stimuli) disrupts the correlation between brain entropy and subjective ratings of the experience.
Microdosing psychedelics and the risk of cardiac fibrosis and valvulopathy: Comparison to known cardiotoxins
This review (2023) assesses the potential long-term impact of microdosing psychedelics on cardiac health, particularly focusing on LSD and psilocybin. Despite the increasing popularity of microdosing, concerns arise due to structural similarities between these substances and medications associated with cardiac fibrosis and valvulopathy. The review emphasizes the need for future studies to evaluate the safety of prolonged microdosing and discusses the relationship between drug-induced cardiac fibrosis and the 5-HT2B receptor.
Serotonin-2 Receptor Agonists Produce Anti-inflammatory Effects through Functionally Selective Mechanisms That Involve the Suppression of Disease-Induced Arginase 1 Expression
This in vitro study examines functional selectivity between two 5-HT2A receptor agonists, (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] and (R)-2,5-dimethoxy-4-trifluoromethylamphetamine [(R)-DOTFM], in the context of their impact on inflammation and airway hyperresponsiveness (AHR) in a murine asthma model. Despite similar in vitro activity and behavioral potency, (R)-DOTFM does not prevent inflammation or elevated AHR, in contrast to (R)-DOI, suggesting distinct anti-inflammatory mechanisms associated with certain psychedelics.
Safety, tolerability, pharmacodynamic and wellbeing effects of SPL026 (dimethyltryptamine fumarate) in healthy participants: a randomized, placebo-controlled phase 1 trial
In a randomized, placebo‑controlled Phase 1 trial in psychedelic‑naïve healthy volunteers, single escalating IV doses of SPL026 (DMT fumarate) were well tolerated with an acceptable safety profile and showed dose‑related increases in acute psychometric intensity that correlated with plasma concentrations; based on safety, PK and pharmacodynamic data a 21.5 mg two‑phase 10‑minute infusion was selected for the subsequent Phase 2a study.
Effects of MDMA-assisted therapy for PTSD on self-experience
This re-analysis of an RCT of MDMA-assisted therapy for PTSD finds that study participants (n=90) had significant improvements in the measures of self-experience (e.g. alexithymia -; the inability to identify & describe emotions experienced by oneself). The change in scores of self-experience correlates with recovery from PTSD.
Potential therapeutic effects of an ayahuasca-inspired N,N-DMT and harmine formulation: a controlled trial in healthy subjects
In a crossover RCT of 31 healthy male volunteers, an ayahuasca‑inspired formulation combining intranasal N,N‑DMT (up to 100 mg) with an orodispersible 100 mg harmine tablet produced robust, phenomenologically rich psychedelic experiences characterised by psychological insights and emotional breakthroughs, low challenging effects, and mainly positive persisting effects at 1 and 4 months. The compound showed good psychological safety and tolerability with no increases in psychopathology or changes in trait measures, indicating potential to support psychotherapeutic applications.
Magnesium-ibogaine therapy in veterans with traumatic brain injuries
This observational study (n=30) evaluates ibogaine (up to 980mg/70kg) in combination with magnesium (1-2 hours before and 12 hours later) in male Special Operations Forces veterans with predominantly mild traumatic brain injury (mTBI). The study assessed changes in disability, PTSD, depression, and anxiety immediately and one month after treatment using various scales. Results show significant improvements in functioning and psychological symptoms with no serious adverse events.
Preliminary evidence for the importance of therapeutic alliance in MDMA-assisted psychotherapy for posttraumatic stress disorder
This analysis of a clinical trial (n=22) examines the role of therapeutic alliance in MDMA-assisted psychotherapy (MDMA-AP) for treating chronic PTSD. It reports that after controlling for baseline PTSD severity, a strong therapeutic alliance at the mid and late stages of treatment (sessions 4 and 9) significantly predicts lower clinician-assessed and self-reported PTSD severity post-treatment.
Psychedelics for acquired brain injury: a review of molecular mechanisms and therapeutic potential
This review (2023) explores the potential of psychedelics as a therapeutic intervention for acquired brain injury (ABI), such as traumatic brain injury (TBI) and stroke. It highlights the challenge in managing ABI despite medical advancements and suggests psychedelics may improve neurobehavioral outcomes due to their impact on serotonin receptors, sigma-1 receptors, and neurotrophic signalling.
The antidepressant effects of vaporized N,N-Dimethyltryptamine: a preliminary report in treatment-resistant depression
This Phase 2a open‑label, dose‑escalation study in six patients with treatment‑resistant depression found that a single‑day session of vapourised N,N‑dimethyltryptamine produced rapid and sustained reductions in depressive symptoms (mean MADRS change −22 at Day 7 and −17 at one month), with 83.3% response and 66.7% remission at Day 7 and 66.7% response and 50% remission at one month. The authors highlight the non‑invasive, short‑acting delivery as a practical advantage that could improve accessibility of psychedelic-assisted interventional psychiatry.
Spiritual health practitioners’ contributions to psychedelic assisted therapy: A qualitative analysis
Interviews with 15 spiritual health practitioners identified seven themes—five unique contributions (competence with spiritual material, awareness of power dynamics, familiarity with non‑ordinary states, holding space, and a counterbalance to biomedical perspectives) and two general contributions (therapeutic repertoire and interdisciplinary collaboration)—showing they offer distinctive expertise to psychedelic‑assisted therapy. The authors conclude that teams may benefit from including spiritual health practitioners, but standardised role definitions, qualifications and training are needed to ensure quality and safety.
Anti-suicidal effects of IV ketamine in a real-world setting
This community-based study (n=295) examined the impact of intravenous ketamine treatment on suicidality. Using growth mixture modelling, three trajectory groups were identified: one with moderate baseline scores showing gradual improvement (n=170, 57.6%), another with severe baseline scores showing no improvement (n=63, 21%), and a third with rapid improvement (n=62, 21%). Among clinical and demographic variables, only higher scores on active thoughts of death and/or plan predicted a lack of benefit from treatment for those with severe baseline CHRT-SR scores. The findings support ketamine's potential effectiveness in addressing suicidality in a proportion of patients.
Conflict monitoring and emotional processing in 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine users - A comparative neurophysiological study
This comparative study (n=38 METH users, n=42 MDMA users, n=83 controls) examines the impact of chronic METH and MDMA use on conflict control processes in social-affective contexts. Both METH and MDMA users exhibit reduced behavioral effects in cognitive-emotional conflict processing, particularly regarding anger content. These effects are associated with stronger P3 event-related potential modulations, suggesting altered decision-making and stimulus-response mapping, potentially linked to noradrenergic dysfunctions. Understanding the role of noradrenaline in chronic users of substituted amphetamines represents a significant direction for future research in this area.
Navigating Groundlessness: An interview study on dealing with ontological shock and existential distress following psychedelic experiences
This qualitative study (n=26) explored existential distress following psychedelic experiences, finding persistent preoccupation with sense-making and confusion about existence and purpose. Participants reported cognitive, emotional, social, bodily, and functional impacts. They managed distress through embodiment practices and social/cognitive normalization.
Shared functional connectome fingerprints following ritualistic ayahuasca intake
This fMRI study (n=21) of people who regularly use ayahuasca within the Santo Daime church finds that during the experience, changes in functional connectivity (FC, how brain areas communicate) indicate on the scans more similarity between them (so less 'unique' FC). The authors use an analogy that each person still has their own hairstyle, but instead of wearing different coloured t-shirts, all are now wearing the same shirt.
Safety pharmacology of acute psilocybin administration in healthy participants
This pooled analysis (n=85; doses=113) of three randomised crossover studies evaluates the safety pharmacology of psilocybin (15-30mg). Psilocybin induced stronger effects at higher doses, with 25 mg and 30 mg doses showing increased anxiety. However, overall, psilocybin was found to be safe in terms of acute psychological and physical harm, with no serious adverse reactions reported, suggesting its potential safety for controlled research settings.