Psychedelic Research Recap November 2024
Psychedelic Research Recap November 2024
Welcome back to our monthly update on psychedelic research!
In November, psychedelic research spans from clinical applications to fundamental neuroscience. Studies provide new insights into how psilocybin, MDMA, and ketamine can affect mental health conditions such as depression, PTSD, OCD, and fibromyalgia. Researchers are also examining the safety profiles of substances like mescaline and 3-MMC.
Several studies examine the mechanisms behind psychedelics’ therapeutic effects, focusing on neuroplasticity and neuronal pathways. From exploring how psychedelics (don’t) influence brain-derived neurotrophic factor (BDNF) levels to understanding their impact on specific pyramidal cells in the cortex, these findings shed light on how these substances may promote lasting psychological benefits.
The research this month places special emphasis on user experiences during psychedelic sessions and how they relate to therapeutic outcomes. Studies investigate major life changes following psychedelic use, strategies for navigating challenging experiences, and the effects of psychedelics on memory and self-related thought processes.
We also see important findings regarding safety and adverse effects, including reevaluations of the incidence of psychedelic-induced psychosis and new insights into MDMA-induced hyponatremia. Additionally, a cost-effectiveness analysis of MDMA-assisted therapy for PTSD suggests promising economic viability for these treatments.
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.
Psychedelics’ Effects on Brain Plasticity
Recent studies are shedding light on how psychedelics influence brain plasticity, which may help explain their potential benefits for mental health.
A comprehensive review by an all-star team looked at how classic psychedelics like LSD and psilocybin, as well as substances like ketamine and MDMA, affect brain plasticity. Drawing from animal and human studies, it discussed how these drugs might reopen periods when the brain is more adaptable. Translating these findings from animals to humans is tough, but new imaging tools offer promise for future research.
A meta-analysis examined whether psychedelics and similar substances raise levels of BDNF, a protein linked to brain plasticity, in humans. The study found no significant changes in BDNF levels after administering these drugs, suggesting that blood BDNF might not be a reliable marker of brain changes in people. The authors suggest using brain imaging or other methods in future studies.
Another review highlighted animal research showing that ketamine and psychedelics can promote the growth of connections in brain cells, boosting plasticity. It compared the lasting effects of different drugs and discussed gaps in our understanding, especially how these findings apply to humans.
A mouse study investigated how psilocybin affects different brain cells in a region involved in decision-making. The research found that psilocybin increased the number of connections in certain brain cells and that these changes were key to its stress-reducing effects. These effects depended on activating a specific serotonin receptor.
While animal studies show that psychedelics can enhance brain plasticity by increasing connections between neurons, human studies have not found significant changes in blood levels of BDNF. This suggests that results from animal studies might not directly translate to humans, or that blood BDNF isn’t a good indicator of brain changes. Future research may need to focus on other ways (e.g. PET radioligands and multimodal approaches) to measure plasticity in people.
Expanding Therapeutic Uses of Psychedelics
A recent cost-effectiveness analysis compared MDMA-assisted therapy (MDMA-AT) to placebo with therapy for treating chronic PTSD over five years. The study found that MDMA-AT, despite higher upfront costs due to the therapy sessions and MDMA administration, was cost-effective. It provided better health outcomes and reduced the need for other healthcare services. The incremental cost-effectiveness ratio was below the willingness-to-pay threshold, suggesting that MDMA-AT could be a valuable option for patients with severe PTSD.
In addition to PTSD, psychedelics are being explored for other challenging conditions. A small study investigated ketamine for treatment-resistant obsessive-compulsive disorder (OCD). Twelve patients received intramuscular ketamine or a control substance in a double-blind, randomized design. The results showed that ketamine led to dose-dependent reductions in OCD symptoms, with effects lasting up to a week. Some participants experienced dissociative effects, highlighting the need for careful dosing and monitoring.
Another pilot study looked at psilocybin-assisted therapy for fibromyalgia, a chronic pain condition with limited treatment options. Five participants received psilocybin in conjunction with psychotherapy. The treatment was well-tolerated, with only temporary side effects like mild headaches. Participants reported meaningful improvements in pain, sleep, and overall symptoms one month after treatment. While preliminary, these findings suggest that psilocybin could offer relief for fibromyalgia patients.
Finally, a subgroup analysis from a trial on treatment-resistant depression evaluated psilocybin in individuals with Bipolar II disorder. Four participants received psilocybin-assisted psychotherapy. The results showed a decrease in depression scores without triggering mania or psychosis. This suggests that psilocybin might be safe and potentially effective for depressive episodes in Bipolar II disorder (see more on safety in the next section).
Safety and Adverse Effects
Recent studies have focused on understanding the safety profiles and potential adverse effects of various psychedelics to inform their therapeutic use.
A systematic review and meta-analysis investigated the incidence of psychedelic-induced psychosis, particularly in individuals with schizophrenia. The analysis found that the occurrence of psychosis was very low in the general population and in clinical trials. In uncontrolled trials that included participants with schizophrenia, a small percentage developed lasting psychotic symptoms. The study suggests that while caution is necessary, schizophrenia might not be an absolute exclusion criterion for psychedelic research.
Another study examined the safety of mescaline in healthy participants. In a pooled analysis of two trials, participants received varying doses of mescaline. Positive subjective effects increased with higher doses, while adverse effects like nausea were dose-dependent. There were no significant changes in liver or kidney function, and “flashbacks” were rare. The study concluded that single doses up to 800 mg are safe in a controlled setting, although nausea may limit tolerability at higher doses.
A reanalysis of four clinical trials explored the causes of hyponatremia (low blood sodium levels) after MDMA use. The study found that hyponatremia occurred in a significant number of participants who were not fluid-restricted but did not occur in those with limited fluid intake. Interestingly, the condition was associated with increased oxytocin levels rather than vasopressin, suggesting that oxytocin may play a role in MDMA-induced hyponatremia.
A first-of-its-kind trial assessed the safety and cognitive effects of 3-MMC, a synthetic cathinone and popular ‘research chemical’ or designer drug. Participants received escalating doses, and the study found dose-dependent increases in heart rate and blood pressure, but these were not clinically significant. Cognitive performance improved in some tasks, and mild psychedelic effects were noted. Participants also reported decreased appetite and transient increases in drug liking. The study concluded that low to moderate doses were well-tolerated, but higher doses and repeated use might carry risks.
While these studies generally indicate that psychedelics can be safe under controlled conditions, they also underscore the need for careful monitoring of potential adverse effects. Differences in individual responses and specific substance effects highlight the importance of tailored approaches in research and therapeutic settings.
User Experiences and Behaviors
A recent survey explored major life changes reported by people who use psychedelics in natural settings. Out of 581 participants, over 80% noted significant changes in at least one area of their lives after using psychedelics. Common areas included personal goals, values, and spirituality. These changes were generally viewed positively. The study also found that those who used psychedelics more frequently reported more life changes, while higher education levels were linked to fewer reported changes.
Another large survey examined global trends in psychedelic microdosing. Among over 6,000 respondents, those who only microdosed were typically older, more likely to be female, and had used fewer other substances compared to those who also took larger doses. Psilocybin and LSD were the most commonly used substances for microdosing, with many users aiming to improve general well-being. The study highlighted that most users did not test their substances, raising safety concerns.
An observational study looked at how ayahuasca affects memory in experienced users (averaging at over 500 ceremonies attended). Participants showed improved memory accuracy and recall after consuming ayahuasca, without an increase in false memories. This suggests that ayahuasca might enhance certain memory processes (again, in very experienced users), possibly due to compounds in the brew that affect the brain differently than other psychedelics.
A comparative study investigated how experienced psychedelic users and non-users process self-related thoughts. Using EEG measurements, the study found differences in brain activity between the two groups during tasks involving self-reflection. However, a follow-up analysis did not replicate these findings, possibly due to limitations in sample size. This indicates that more research is needed to understand the long-term effects of psychedelic use on self-perception.
Another study focused on strategies people use to handle challenging psychedelic experiences. By analyzing accounts from participants at psilocybin retreats and an online survey, researchers identified three main coping strategies: accepting and reinterpreting the experience, engaging with sensory inputs or physical activities, and seeking social support. Strategies involving acceptance and social support were linked to positive emotional breakthroughs.
Lastly, a small controlled trial examined how psilocybin affects visual perception. Participants who took psilocybin showed increased visual surround suppression, meaning they perceived central images as having less contrast when surrounded by other visuals. This effect was stronger in those who reported more intense visual experiences under psilocybin. The study adds to our understanding of how psychedelics alter sensory processing and may have implications for conditions like depression, where visual perception is affected.
These studies highlight the diverse ways in which psychedelics can influence user experiences and behaviours. While some findings point to potential benefits, such as personal growth and improved memory, others underscore the importance of safety considerations and the need for further research to understand these complex effects fully.
Papers Published in November 2024
16 studies from the Blossom database published this month.
Ayahuasca enhances the formation of hippocampal-dependent episodic memory without impacting false memory susceptibility in experienced ayahuasca users: An observational study
This observational study (n=24) examines the acute effects of ayahuasca on memory in experienced Santo Daime members (>500 lifetime uses). Findings show ayahuasca enhances memory accuracy and recollection while not impacting familiarity or false memory, suggesting β-carboline activity may drive selective improvements in hippocampal-dependent processes.
Effects of psychoplastogens on blood levels of brain-derived neurotrophic factor (BDNF) in humans: a systematic review and meta-analysis
This meta-analysis (s=29) examines the effects of psychedelics (including ketamine and MDMA) and two other 'psychoplastogens' on peripheral BDNF levels in humans. It finds no significant changes in BDNF levels post-administration (SMD=0.024, p=0.64), regardless of drug, dose, participant age, or psychiatric condition. Studies with better-controlled designs report smaller effect sizes, and later timepoints show minimal increases in BDNF. The authors conclude that peripheral BDNF is likely not a reliable marker of rapid neuroplasticity and recommend neuroimaging or stimulation-based methods for future research.
Neuroplasticity and Psychedelics: a comprehensive examination of classic and non-classic compounds in pre and clinical models
This review (2024) examines the effects of classic psychedelics (e.g., LSD, psilocybin, DMT) and non-classic psychedelics (e.g., ketamine, MDMA) on neuroplasticity. Drawing on preclinical and clinical studies, it discusses molecular, structural, and functional changes induced by these agents, highlighting their potential to re-open developmental windows (hyper-plasticity) and increase nervous system sensitivity to stimuli (meta-plasticity). Translating findings to humans remains challenging, but emerging tools like PET radioligands and multimodal approaches offer promise for future research.
Ketamine for treatment-resistant obsessive-compulsive disorder: Double-blind active-controlled crossover study
In a randomised double‑blind active‑controlled crossover study of 12 patients with severe treatment‑resistant OCD, intramuscular racemic ketamine (0.5 and 1.0 mg/kg) produced greater, dose‑related reductions in Y‑BOCS scores than IM fentanyl that were maximal at 1–2 hours and showed separation out to 168 hours. Ketamine was associated with short‑term dissociative and cardiovascular effects and two dropouts for poor tolerability, and the authors conclude IM ketamine shows preliminary efficacy but requires further work to define optimal dosing and longer‑term use.
Reconsidering evidence for psychedelic-induced psychosis: an overview of reviews, a systematic review, and meta-analysis of human studies
This systematic review (2024) and meta-analysis (s=131) examines the incidence of psychedelic-induced psychosis, focusing on individuals with schizophrenia. It finds an incidence of 0.002% in population studies, 0.2% in UCTs, and 0.6% in RCTs, with 3.8% of UCT participants with schizophrenia developing long-lasting psychotic symptoms. It also reports that 13.1% of those with psychedelic-induced psychosis later developed schizophrenia.
MDMA pharmacokinetics: A population and physiologically based pharmacokinetics model-informed analysis
Using clinical, published and in vitro data, the authors developed and verified population and physiologically based pharmacokinetic models for MDMA which show that a high‑fat meal delays Tmax without changing overall exposure and that split dosing (2 h apart) lowers early AUC and delays Tmax compared with a single dose. The models further indicate MDMA is a potent CYP2D6 inhibitor but is unlikely to cause clinically meaningful drug–drug interactions via renal transporters, supporting model‑informed predictions of clinically relevant dosing regimens.
Major life changes following psychedelic use: A retrospective survey among people using psychedelics naturalistically
This survey (n=581) evaluates the Psychedelic-related Major Life Changes Questionnaire (P-MLCQ) in people reporting naturalistic psychedelic use. It finds that 82.96% of participants reported major life changes in at least one domain, including goals (53.7%), values (53.53%), and spirituality (49.05%), with changes rated highly positively (M = 4.64/5). Frequency of use correlated with more changes (r = 0.34), while education level was negatively associated with the number of changes (β = -0.137).
Safety pharmacology of acute mescaline administration in healthy participants
Pooled analysis of two double‑blind, randomized, placebo‑controlled studies (48 participants, 96 administrations) found that single oral doses of mescaline 100–800 mg produced dose‑dependent increases in positive subjective effects with only moderate autonomic changes and no clinically significant liver, kidney or haematological abnormalities. Although nausea was dose‑limiting and small proportions experienced transient diastolic hypertension, tachycardia, fever or “flashbacks”, single doses up to 800 mg were considered safe with respect to acute psychological and physical harm in healthy participants in a controlled clinical setting.
Strategies for resolving challenging psychedelic experiences: insights from a mixed-methods study
Using mixed methods and a new Responses to Challenging Psychedelic Experiences Inventory (ReCiPE), the study identified three response strategies—Acceptance and Reappraisal; Sensory Regulation and Physical Interaction; and Social Support and Disclosure. Acceptance and Reappraisal and Social Support were positively associated with emotional breakthrough, whereas fear-related challenges were linked to lower breakthrough and fewer adaptive coping strategies.
Structural neural plasticity evoked by rapid-acting antidepressant interventions
This review (2024) highlights preclinical research from the past 15 years showing that ketamine and psychedelics trigger dendritic spine growth in cortical pyramidal neurons, enhancing neural plasticity. It compares the longitudinal effects of psychoactive drugs, emphasizing rapid-onset and sustained structural plasticity as key features of rapid-acting antidepressants, and discusses gaps in understanding and prospects for other interventions like rTMS.
Oxytocin and the Role of Fluid Restriction in MDMA-Induced Hyponatremia: A Secondary Analysis of 4 Randomized Clinical Trials
Pooled analysis of 96 participants in four randomised trials found that a single dose of MDMA produced acute hyponatraemia in about 31% (37% with unrestricted fluids) while no cases occurred with fluid restriction, indicating fluid management can mitigate risk. Hyponatraemia correlated with large acute rises in oxytocin but not copeptin, suggesting oxytocin‑mediated renal antidiuresis rather than direct vasopressin release.
Cost-effectiveness of midomafetamine-assisted therapy (MDMA-AT) in chronic and treatment-resistant post-traumatic stress disorder of moderate or higher severity: A health-economic model
Using a health state-transition model, midomafetamine-assisted therapy for chronic, moderate-or-higher PTSD produced a 0.377 QALY gain over five years at an incremental cost of $31,613, yielding an ICER of $83,845 per QALY. These results indicate MDMA-AT is likely cost-effective versus placebo with therapy at a $150,000 willingness-to-pay threshold (assuming a $12,000 per-session drug price).
Global Trends in Psychedelic Microdosing: Demographics, Substance Testing Behavior, and Patterns of Use
This online survey (n=6,193; 2,488 microdosers) examines differences between exclusive microdosers and those who use both micro and macrodoses of psychedelics. The study finds exclusive microdosers were typically older, more likely to be female and non-Caucasian, with psilocybin (74.5%) and LSD (34.4%) being the most commonly used substances, primarily for general wellbeing (73.0%).
Enhanced visual contrast suppression during peak psilocybin effects: Psychophysical results from a pilot randomized controlled trial
This placebo-controlled study (n=6) investigates how psilocybin (25mg) affects visual surround suppression compared to placebo (100mg niacin). The study finds increased surround suppression effects under psilocybin, with stronger suppression correlating with more intense subjective visual effects.
Preliminary safety and effectiveness of psilocybin-assisted therapy in adults with fibromyalgia: An open-label, proof-of-concept clinical trial
In an open-label proof-of-concept trial (N=5), psilocybin-assisted therapy was well tolerated in adults with fibromyalgia, producing only transient elevations in blood pressure/heart rate and non-serious post-dose headaches. Participants showed clinically meaningful improvements in pain severity, pain interference and sleep disturbance one month after treatment, supporting progression to larger randomised controlled trials.
The conceptual framework for the therapeutic approach used in phase 3 trials of MDMA-assisted therapy for PTSD
This paper articulates the conceptual framework behind the inner‑directed, relational and trauma‑informed psychotherapeutic approach used in Phase 3 MDMA‑assisted therapy trials for PTSD, centring the participant’s "inner healing intelligence", a non‑pathologising stance, therapist attunement, and integration of top‑down and bottom‑up processes. It notes that MDMA plus therapy outperformed placebo plus therapy on symptom reduction, while substantial improvement in control groups underscores the psychotherapy model’s independent efficacy and the need to identify which elements drive clinical benefit.