Psychedelic Research Recap December 2023
Psychedelic Research Recap December 2023
A Phase II trial affirmed the safety and efficacy of psilocybin-assisted therapy in a group setting, with a majority experiencing sustained response and remission from depressive symptoms. A qualitative analysis of these participants underscored the acceptability of psilocybin-assisted group therapy in patients with cancer and major depressive disorder, highlighting the therapy’s positive impact on patient connectivity and belonging.
These studies, along with others examining psychedelics’ impact on alcohol use disorder, the correlation between esketamine and specific adverse events, and personality changes associated with psychedelic use, collectively contributed to the expanding database of over 2000 articles with comprehensive summaries, ensuring a well-rounded understanding of the field’s progress.
This month’s recap will delve into these findings, emphasizing their implications across health economics, safety and tolerability, and personality outcomes. Check out the monthly link overview for all studies we didn’t add to the database.
Group Therapy Shows Promise
A Phase II open-label trialdelves into the efficacy of psilocybin-assisted therapy for cancer patients suffering from major depressive disorder (MDD). Administering 25mg of psilocybin to groups of 3-4 participants, the study combines individual and group therapeutic support. Remarkably, 80% of participants displayed a sustained response, while 50% achieved complete remission of depressive symptoms by week 1, maintained through week 8. The trial stands out for its dual approach, merging individualized attention within a group setting, and demonstrates a significant reduction in depression severity.
A qualitative analysis of 28 of the 30 participants explores the acceptability of psilocybin-assisted group therapy among cancer patients with MDD. Data gathered from semi-structured interviews with trial participants reveal an overwhelmingly positive response. The study underscores the crucial role of group therapy in fostering a sense of safety, preparedness, and belonging. It highlights the intricate balance of individual and group dynamics, revealing the nuanced impact of group size and interaction structures on therapeutic outcomes. The findings illuminate the multifaceted nature of psychedelic therapy, emphasizing the importance of a supportive therapeutic framework and the synergistic value of combining individual sessions with group experiences.
An economic analysis offers a compelling case for the adoption of group psychedelic therapy models. By examining two trials – one utilizing MDMA for PTSD and the psilocybin for MDD we just discussed – the study presents a detailed comparison of clinician time, costs, and patient access between group and individual therapy formats. The results are striking: group therapy achieves substantial cost savings of 50.9% for MDMA-PTSD and 34.7% for psilocybin-MDD treatments. This approach could potentially alleviate the need for thousands of full-time equivalent clinicians, translating into projected savings of billions over a decade. This analysis highlights the economic benefits and suggests a pragmatic solution to the clinician shortage, ultimately improving access to these innovative therapies.
While group therapy models for psychedelic-assisted treatments, such as those involving psilocybin and MDMA, demonstrate promising results in terms of efficacy, cost savings, and improved patient access, there are potential downsides and other benefits worth considering. On the downside, group settings might inadvertently create a sense of comparison or competition among participants, potentially impacting the individual’s experience and therapeutic outcomes. The dynamics of group therapy could also lead to less personalized attention from therapists, which might be crucial for patients with complex emotional or psychological needs. Moreover, the group setting might not suit all individuals, particularly those who have difficulty opening up in a shared environment or have a history of trauma that makes group interactions challenging.
Conversely, group therapy offers additional benefits beyond cost-effectiveness and access. It can foster a sense of community and shared experience, which is particularly valuable in dealing with isolation often associated with conditions like depression and PTSD. The shared journey can lead to mutual support and empathy among participants, enhancing the therapeutic process. Furthermore, witnessing the experiences and progress of others can be inspiring and reassuring, potentially contributing to a more profound and meaningful therapeutic experience. These communal aspects might also lead to long-term support networks post-therapy, aiding in sustained recovery and well-being. Therefore, while group therapy presents certain challenges, its potential to create a supportive and empathetic community offers a unique and valuable dimension to psychedelic-assisted treatments.
Evidence for Microdosing?
A randomized controlled trial (RCT) investigates the effects of a low dose of LSD (26µg) on individuals with mild depression. The study involved 39 participants, divided into two groups based on their Beck Depression Inventory-II (BDI-II) scores: one with mild depression (BDI-II≥17) and the other comprising non-depressed controls. The mildly depressed group experienced greater positive mood enhancements, stimulant-like effects, and psychedelic experiences compared to the control group. Additionally, this group reported a more pronounced decrease in self-rated depression scores 48 hours post-LSD administration.
The trial’s findings suggest that low-dose (26µg sits above the usual microdose range of 5-20µg) LSD holds potential therapeutic value for treating depression, especially considering both groups exhibited the anticipated physiological and subjective drug effects without significant adverse events. This study is among the first to demonstrate the efficacy of microdosingLSD in a controlled setting, providing a promising avenue for future research and potential clinical applications in mental health treatments.
Exploring the Relationship Between Psychedelic Use, Personality, and Emotional Perception
A cross-sectional study of 400 Swedish psychedelic users, compared with a matched group of non-users, revealed intriguing insights into the mental health and personalitycharacteristics associated with psychedelic experiences. The study showed that psychedelic users had lower levels of depression and higher levels of drug use, with a notable difference in the personality trait of openness. This finding suggests that certain personality traits, particularly openness, might influence not only the likelihood of using psychedelics but also the effects these substances have on mental health, specifically depression.
Expanding on the theme of personality and psychedelic use, another survey (n=426) delved deeper into the perception of psychedelic-mediated personality changes. The study identified 52 unique themes and eight factors, such as Unitive Spiritual and Emotional Stability, indicating that psychedelic users are more open, extraverted, and less neurotic compared to non-users. This research proposes a model linking personality to psychedelic use and its subsequent impact on personality traits. Like the previous study, this one highlights the significant role of personality traits in shaping psychedelic experiences and their long-term effects, emphasizing the need for holistic measures in psychedelic-assisted therapies.
A cross-sectional analysis involving 111 participants investigated the neural markers of emotional reactivity in individuals with extensive naturalistic psychedelic use (15 or more lifetime experiences) compared to non-users. The study found that experienced psychedelic users exhibited significantly lower N200 amplitudes in response to fearful faces, suggesting a reduced reactivity to negative emotional stimuli at early processing stages. This finding aligns with the previous studies, as it demonstrates how psychedelic use can influence emotional and cognitive processes, potentially mediated by personality traits and individual differences in emotional perception.
Advancements in Ketamine and Esketamine Treatments for Depression
In a post-hoc analysis combining two cohorts (n=311), researchers compared the effectiveness of intravenous ketamine (KET-IV) and intranasal esketamine (ESK-NS) for treating Treatment-Resistant Depression (TRD). The study revealed that KET-IV exhibited larger effect sizes and higher response rates than ESK-NS. Both treatments significantly reduced depressive symptoms, albeit KET-IV was associated with more side effects. However, the discontinuation rate due to adverse events was comparable between KET-IV and ESK-NS. This analysis suggests a potential preference for KET-IV (which is generally much cheaper) in terms of short-term antidepressant effectiveness, though both treatments were generally well-tolerated.
Widening the scope to safety, a retrospective analysis of FAERS data on esketamine (compassing over 500 participants) revealed 117 distinct adverse reactions. This study identified new potential adverse event signals such as flashback, tachyphylaxis, and autoscopy, in addition to known side effects. Notably, instances of suicidal ideation and attempts were relatively high, highlighting the critical need for vigilant monitoring. This study, like the previous one, emphasizes the importance of careful consideration of esketamine’s adverse effects, particularly for patients susceptible to mental health fluctuations or those requiring nasal administration.
Transitioning to a more focused approach, the KADS study, a Phase III RCT (n=174), evaluated the efficacy and safety of a 4-week course of subcutaneous ketamine injections for TRD. The study found that ketamine was more effective than midazolam in the flexible-dose cohort, with a remission rate of 19.6% versus 2.0%. This indicates that adequately dosed subcutaneous racemic ketamine is both effective and safe for treating TRD over four weeks.
From my perspective, the high costs associated with esketamine (Spravato) present a significant concern, especially when juxtaposed with the potential effectiveness of racemic ketamine, a more economical alternative. The studies reviewed underscore a crucial point: despite esketamine’s high cost, there is no substantial evidence suggesting it is more effective than the cheaper racemic ketamine. In fact, some data indicate that racemic ketamine might be equally, if not more, effective in treating depression, especially in the short term.
However, it’s important to note that while both treatments demonstrate efficacy in the initial month, long-term relief from depression remains elusive with ketamine-based therapies. This transient nature of symptom alleviation necessitates a critical evaluation of cost versus benefit, particularly regarding esketamine’s pricing. The financial burden on patients and healthcare systems could be significantly reduced by opting for racemic ketamine, provided its effectiveness and safety profile are upheld in broader, long-term studies.
The Other Psychedelic Studies From December 2024
Next to the group therapy study and the ketamine studies, six other human studies (experiments and observational studies) were published in December, offering fresh perspectives in the field of psychedelic research.
An open-label clinical trial involving 27 participants explored the safety of inhaled DMT. Varying doses (5-60mg) were administered to healthy volunteers, resulting in dose-dependent increases in intensity and perceptual ratings. Crucially, the study reported no significant safety concerns, positioning inhaled DMT as a promising and safe method for psychedelic administration.
In another open-label trial, this time with 15 patients suffering from Bipolar II disorder, a single dose of synthetic psilocybin (25 mg) was combined with psychotherapy. The results were significant, with marked improvements in depression scores three weeks post-treatment. This study suggests the potential of psilocybin as a safe and effective treatment option for Bipolar II depression, mirroring the therapeutic promise seen in other psychedelic substances.
A safety-feasibility trial involving two adults explored the interaction between psilocybin and buprenorphine in treating opioid use disorder (OUD). The study confirmed the safe coadministration of these substances, with no adverse events or significant changes in opioid craving. This trial underscores the expanding scope of psychedelic therapy, potentially including treatments for substance use disorders.
A mixed-methods case series evaluated the impact of a 3-day ayahuasca intervention on military veterans with PTSD. The results were encouraging, with a majority of participants showing significant improvements in PTSD symptoms post-treatment and maintaining these changes at the 3-month follow-up. The study highlights ayahuasca’s potential in addressing complex mental health conditions like PTSD, particularly in populations with high trauma exposure.
An fMRI study of 21 regular ayahuasca users within the Santo Daime church revealed that during the ayahuasca experience, there were more similarities in functional connectivity among participants, suggesting a “shared” functional space. This study adds a neuroscientific dimension to our understanding of ayahuasca’s impact on the brain, complementing the clinical findings of its therapeutic potential.
A study compared the effects of a new psychoactive substance, 5,6-methylenedioxy-2-aminoindane (MDAI), with MDMA. Involving six volunteers, MDAI was found to be well-tolerated, eliciting subjective effects similar to MDMA but without significant increases in heart rate or body temperature. This study broadens the scope of research on psychedelic substances, exploring alternatives to well-known compounds like MDMA.
Papers Published in December 2023
19 studies from the Blossom database published this month.
Outcomes and physiologic responses associated with ketamine administration after traumatic brain injury in the United States and Canada: a retrospective analysis
Ketamine administration after traumatic brain injury was not associated with increased mortality or greater disability despite being given to more severely injured patients. Ketamine exposure correlated with fewer episodes of elevated intracranial pressure and smaller rises in TBI protein biomarkers, but a higher incidence of seizures and, in the intracranial haemorrhage subgroup, more cardiac events.
The rapid antidepressant effectiveness of repeated dose of intravenous ketamine and intranasal esketamine: A post-hoc analysis of pooled real-world data
This combined analysis of two cohorts (n=311) compared intravenous ketamine (KET-IV) and intranasal esketamine (ESK-NS) in the treatment of Treatment-Resistant Depression (TRD). The study found that KET-IV (n=171) had larger effect sizes and higher response rates than ESK-NS (n=140), although both significantly reduced depressive symptoms. Despite KET-IV having more reported side effects, its discontinuation rate due to adverse events was not significantly higher than ESK-NS.
Set and setting predict psychopathology, wellbeing and meaningfulness of psychedelic experiences: a correlational study
This survey (n=1022) investigated the correlation between set and setting variables in psychedelic therapy with psychopathology, well-being, and personality. Findings suggest that growth motivations, natural settings, and the presence of significant others predict positive outcomes. In contrast, problematic motivations are associated with greater psychopathology and lower well-being.
Ayahuasca-induced personal death experiences: prevalence, characteristics, and impact on attitudes toward death, life, and the environment
This cross-sectional research on ayahuasca-induced Personal Death (APD) experiences involves two studies. Study 1 (n=54) reveals that over half of participants in ayahuasca ceremonies report APDs, which are intense and transformative, leading to an increased sense of transcending death and certainty in consciousness continuation. Study 2 (n=306) supports these findings, showing no demographic or psychopathology associations with APDs but linking them to heightened environmental concern, improved coping abilities, and a greater sense of fulfilment in life. Overall, the studies suggest that APDs during ayahuasca ceremonies may contribute to long-term positive effects in non-clinical populations.
Acceptability of psilocybin-assisted group therapy in patients with cancer and major depressive disorder: Qualitative analysis
In interviews with 28 cancer patients with major depressive disorder, a combined model of psilocybin‑assisted simultaneous individual and group therapy was generally judged acceptable and was felt to enhance perceived safety, preparedness, connection and opportunities for self‑transcendence and compassion. Participants emphasised the therapeutic framework, the complementary value of individual sessions, and careful attention to group size and interaction structure as key factors influencing acceptability and scalability in cancer care.
Psilocybin-assisted group therapy in patients with cancer diagnosed with a major depressive disorder
In a phase 2 open‑label trial, a single 25 mg dose of psilocybin given in a group therapy setting with one‑to‑one therapist support was safe and feasible in 30 patients with cancer and major depressive disorder, with no psilocybin‑related serious adverse events. The treatment produced a large reduction in depressive symptoms (mean 19.1‑point decrease; 80% sustained response; 50% remission at week 1 maintained through 8 weeks), suggesting clinical efficacy warranting further study.
The impact of psychedelics on patients with alcohol use disorder: a systematic review with meta-analysis
This systematic review and meta-analysis (s=6; 2023) assessed the role of psychedelics in treating alcoholism (AUD). LSD and any psychedelic therapy showed enhanced odds of achieving abstinence or reducing alcohol consumption in randomised, double-blind, placebo-controlled trials. However, the study highlights methodological weaknesses in the literature. It suggests that while promising, definitive statements about the value of psychedelics in treating AUD are precluded, emphasizing the need for future trials with greater rigour.
The correlation of Esketamine with specific adverse events: a deep dive into the FAERS database
This retrospective analysis (n=5061) of FAERS data on esketamine from 2019 to 2023 reveals 117 adverse reactions. In addition to known adverse events, new signals like flashback, tachyphylaxis, and autoscopy were identified. Suicidal ideation and attempts were relatively high, emphasizing the need for vigilance, while issues related to nasal administration, such as monitoring procedure errors and discomfort, were highlighted.
Perceptions of psychedelic personality change, determinants of use, setting and drug moderation: Toward a holistic model
Analysing free-text reports from psychedelic users and survey data from users and non‑users, the study identified 52 distinct perceived personality‑change themes that aggregated into eight higher‑order factors and showed that openness, extraversion and neuroticism predict interest in and outcomes of psychedelic use. These results support a tentative holistic model in which baseline personality, drug type and setting interact to produce diverse, clinically relevant personality changes, and they point to directions for prospective research and psychedelic‑assisted therapies.
5-MeO-DMT: An atypical psychedelic with unique pharmacology, phenomenology & risk?
This review (2023) of 5-MeO-DMT, a tryptamine with unique antidepressant potential, notes its distinct effects compared to typical psychedelics. It draws parallels between 5-MeO-DMT's effects and epileptiform activity, particularly through 5-HT1A receptor interactions, suggesting its therapeutic action may resemble electroconvulsive therapy (ECT).
The relation between naturalistic use of psychedelics and perception of emotional stimuli: An event-related potential study comparing non-users and experienced users of classic psychedelics
This EEG study compared non-users and individuals with extensive naturalistic psychedelic use (≥15 lifetime experiences) during presentation of emotional facial expressions. Experienced users showed reduced early ERP responses (N170/N200) to fearful faces—suggesting diminished automatic reactivity to negative stimuli—whereas later attention-related components (P200/P300) did not differ between groups.
Ayahuasca in the treatment of posttraumatic stress disorder: Mixed-methods case series evaluation in military combat veterans
This mixed-methods case series study (n=8) investigated the impact of a 3-day ayahuasca intervention on military veterans with PTSD. Results indicate that 87.5% of participants demonstrated clinically significant improvements in PTSD symptoms post-treatment, with 70% maintaining these changes at a 3-month follow-up. Veterans also reported significant improvements in momentary PTSD symptoms and daily life affect, citing deep positive emotions, decentering/acceptance, and purpose in life as perceived benefits.
Acute psychotropic, autonomic, and endocrine effects of 5,6-methylenedioxy-2-aminoindane (MDAI) compared with 3,4-methylenedioxymethamphetamine (MDMA) in human volunteers: A self-administration study
In a non‑blinded study of six healthy volunteers, 5,6‑methylenedioxy‑2‑aminoindane (MDAI) produced subjective effects comparable with 125 mg MDMA and raised blood pressure and endocrine markers (cortisol, prolactin) but, unlike MDMA, did not increase heart rate or body temperature. MDAI was well tolerated and remained detectable in serum and urine for several days, warranting further clinical investigation of potential medicinal properties.
Group psychedelic therapy: empirical estimates of cost-savings and improved access
Analysing 2023 data from MDMA-assisted PTSD and psilocybin-assisted MDD trials, the authors show that group therapy markedly reduces clinician time and costs while expanding potential patient access. Group protocols cut clinician costs by 50.9% for MDMA‑PTSD (≈$3,467 per patient) and 34.7% for psilocybin‑MDD (≈$981), potentially freeing 6,711 and 1,159 FTE clinicians respectively and saving up to $10.3 billion and $2.0 billion in the US over 10 years (3% annual discount).
Psilocybin for Opioid Use Disorder in Two Adults Stabilized on Buprenorphine: A Technical Report on Study Modifications and Preliminary Findings
This safety-feasibility trial (n=2) explored the interaction between psilocybin and buprenorphine in adults with opioid use disorder (OUD). The study found that coadministration of psilocybin and buprenorphine was safely tolerated, with no serious adverse events or significant changes in opioid craving or withdrawal measures. Feasibility challenges led to modifications in the study population and eligibility criteria, emphasizing the need for improved accessibility and overall generalizability.
Greater subjective effects of a low dose of LSD in participants with depressed mood
This double-blind, randomised, placebo-controlled, crossover trial (n=39) finds a low dose of LSD (26μg) to produce greater positive mood, stimulant-like, and psychedelic effects in people with mild depression (BDI-II≥17) compared to non-depressed controls. Self-rated depression scores decreased more 48 hours after LSD for the mildly depressed group. Both groups showed expected physiological and subjective drug effects. This suggests low-dose LSD may have therapeutic potential for depression.
Double-Blind Comparison of the Two Hallucinogens Dextromethorphan and Psilocybin: Experience-Dependent and Enduring Psychological Effects in Healthy Volunteers
This double-blind experimental study (n=20) compares the effects of high-dose dextromethorphan (DXM; 400mg/70kg) to psilocybin (10, 20, 30mg/70kg) under conditions typical of therapeutic psychedelic trials. DXM and psilocybin showed increases over placebo in ratings of experiences predictive of psychological benefit at 1 week. However, psilocybin's effects were dose-dependent and more favourable, while DXM had poorer physical tolerability.
LSD-induced changes in the functional connectivity of distinct thalamic nuclei
This re-analysis study (n=20) investigated the impact of acute LSD (75μg) administration on thalamocortical connectivity in healthy volunteers. The study utilized structural and resting-state fMRI to examine the thalamus at the nucleus-specific level. LSD intake was found to increase functional connectivity between the thalamus's ventral complex, pulvinar, and non-specific nuclei, particularly with sensory cortices such as somatosensory and auditory networks, as well as parts of the associative cortex dense in serotonin type 2A receptors. The study also reported decreased connectivity between the striatum and thalamus.
The Bodily Self from Psychosis to Psychedelics
Using the Moving Rubber Hand Illusion in patients with psychosis, people with substantial psychedelic experience, and controls (N = 75), the study found that patients with psychosis showed reduced body ownership and sense of agency during volitional action, whereas the psychedelic group—despite reporting enduring subjective changes to selfhood—did not differ from controls on measures of the bodily self. This suggests that psychedelic-induced alterations in self-experience are not reflected in bodily self-processing, while psychosis involves specific disruption of action-related bodily self-processing.