Psychedelic Research Papers

This pre-print, based on predictive processing and an energy-based model of cortical dynamics, explores the therapeutic mechanism of serotonergic psychedelics. It suggests that a combination of 5-HT2a and 5-HT1a agonism leads to a more psychologically tolerable acute experience and better therapeutic efficacy compared to pure agonists. This finding supports the clinical success of mixed serotonin agonists like LSD, psilocybin, and DMT, and suggests potential for the development of even more effective and tolerable psychotherapeutic agents, such as biased 5-HT1a agonist psychedelics like 5-MeO-DMT.

This re-analysis of an RCT (n=59) examines the concept of an 'inner healer' effect associated with psilocybin. Participants receiving a high dose of psilocybin (25mg, 2x) reported higher inner healer scores compared to those receiving a placebo (escitalopram). Furthermore, higher inner healer scores in the high-dose group correlated with improved depressive symptoms two weeks post-dosing, suggesting a potential therapeutic mechanism.

This review (2024) examines the potential therapeutic mechanisms of action for alcoholism (AUD) treatment using 5-MeO-DMT. It highlights that 5-MeO-DMT can induce mystical experiences and ego-dissolution, leading to increased psychological flexibility and mindfulness, which may alleviate AUD symptoms. Additionally, preliminary evidence suggests that 5-MeO-DMT modulates neural oscillations and exhibits neuroplasticity and anti-inflammatory properties, indicating its potential clinical implications for AUD and related psychiatric comorbidities.

This cross-sectional study (n=113) compared experienced psychedelic users (n=56) to nonusers (n=57) regarding neural responses to Self-name stimuli, known for activating self-representation. While no difference in P300 amplitude was found between users and nonusers for Self- or Target-names, users exhibited increased P300 amplitude for Other-names. Additionally, users showed a smaller increase in P300 amplitude for task-relevant stimuli compared to nonusers, suggesting potential alterations in attentional resource allocation rather than prolonged changes in self-representation due to psychedelic use.

This double-blind, placebo-controlled study (n=10) assesses the safety and efficacy of repeated pulse administration of psilocybin (10mg/70kg, 3x in 15 days) in cluster headache patients. Following the initial trial, eligible participants received a psilocybin pulse at least 6 months later and kept headache diaries for 8 weeks. Results indicate a significant reduction in cluster attack frequency following the psilocybin pulse, suggesting potential therapeutic benefits.

This double-blind, randomized study (n=27) assessed the antidepressant effects of a novel oral prolonged-release formulation of racemic ketamine (KET01) in TRD patients as add-on therapy. Patients received either 160 mg/day or 240 mg/day KET01 or placebo for 14 days, with the primary endpoint being the change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to day 15. Results suggest a positive trend towards antidepressant efficacy with 240 mg/day KET01.

This prospective cohort study (n=124, 62 older adults) investigates the effects of a guided psychedelic group session on well-being in older adults (OA) compared to younger adults (YA). Mixed linear regression analyses show significant improvements in well-being in both groups, particularly amplified in OA with a history of psychiatric diagnosis. Acute subjective psychedelic effects were attenuated in OA compared to YA, but a psychosocial measure of Communitas emerged as a predictor in OA, indicating the potential value of relational components in psychedelic group settings for OA.

This placebo-controlled study (n=36) investigated fMRI data from experienced meditators undergoing focused attention and open monitoring meditation before and after a five-day psilocybin-assisted (22mg/70kg on day 4) meditation retreat. Psilocybin-induced positive derealization, coupled with enhanced open-monitoring meditation, correlated with the optimal transport distance between open monitoring and resting state. This suggests that enhanced meta-awareness through meditation combined with psilocybin may mediate insightfulness, offering potential novel brain markers for positive synergistic effects between mindfulness practices and psychedelics.

This meta-analysis (n=1100; s=14) of clinical trials on patients with depression (MDD) receiving ketamine or esketamine reveals a substantial placebo response, accounting for up to 72% of the overall treatment response. The study emphasizes the importance of considering the placebo response in clinical practice to maximize the benefit to patients.

This pre-print single-blind study (n=14) used multimodal neuroimaging techniques (fMRI + EKG) to investigate brain activity and autonomic physiology during DMT (20mg) altered state of consciousness. Results reveal unique brain activity substates, with increased superior temporal lobe activity and hippocampal deactivation under DMT, correlating with auditory distortions and meaningfulness of the experience, respectively. Moreover, increased heart rate under DMT correlates with hippocampal and medial parietal deactivation, suggesting a potential link between sympathetic regulation and positive mental health outcomes following psychedelic administration.

This reanalysis of a trial (n=59) investigates the mechanisms underlying the efficacy of Psilocybin Therapy (PAT) versus Escitalopram Treatment in patients with depression (MDD) over a 6-week trial period. Acute psychological experiences such as "mystical experience" and "ego dissolution" were found to mediate the effect of treatment condition on depressive response, suggesting a mechanistic role of these experiences in the treatment of depression via PAT.

This cell & mice study explores the psychopharmacological profile of amino-substituted 5-MeO-tryptamines, focusing on their interactions with serotonin receptors and transporters, as well as their psychoactive and thermoregulatory properties. The study demonstrates selectivity for 5-HT1AR over 5-HT2AR among examined compounds using radioligand binding methodologies and computational docking analyses, and 5-MeO-pyr-T was identified as the most potent partial 5-HT releaser.

This observational study (n=16.255) investigates the association between naturalistic psychedelic use and self-reported psychotic or manic symptoms in adolescents, utilizing a genetically informative design. Results suggest that psychedelic use may be associated with reduced psychotic symptoms after adjusting for other drug use, while associations with manic symptoms seem to be linked to genetic vulnerability to schizophrenia or bipolar I disorder.

This randomized, waiting list-controlled clinical trial (n=24) for depression (MDD) assessed the therapeutic alliance between participants and intervention facilitators in psilocybin-assisted therapy (PAT). Therapeutic alliance significantly increased from the final preparation session to one-week post-intervention, with a stronger alliance predicting depression scores at various post-intervention time points. Stronger alliances were correlated with peak ratings of mystical experiences and psychological insight, which in turn were correlated with depression scores.

This pooled analysis (n=85; doses=113) of three randomized 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.

This pre-print (n=13) investigates the subjective experiences of individuals engaging in psilocybin microdosing in their daily lives. Combining momentary ecological assessments and retrospective interviews, participants reported varied effects, including loosening of mental structures, increased salience of external stimuli, flexible cognition, and ego-dystonic contents.

This longitudinal study (n=71) examines five years of real-world clinical data on the use of IV low-dose ketamine alongside standard care for outpatients with depression (MDD & TRD). Results indicate a significant reduction in depressive symptoms and suicide ideation by treatment endpoint, with 55% of patients responding to treatment. Side effects were transient and mild for 78% of patients, with a dropout rate of 11%. Multivariate analysis suggests that demographic variables did not impact treatment efficacy or tolerability.

This pharmacokinetic study (n=14) on ibogaine (700mg/70kg) for opioid use disorder (OUD) finds significant variability in ibogaine clearance, strongly correlated with CYP2D6 genotype. Ibogaine plasma concentrations correlate with QTc prolongation and cerebellar effects, while neither ibogaine nor noribogaine correlate with the severity of opioid withdrawal symptoms.

This observational study (n=231) examines the relationship between childhood trauma, challenging experiences during acute ayahuasca effects, and posttraumatic growth. Results show that individuals with histories of childhood trauma were not at higher risk of adverse experiences during ayahuasca use, nor did they exhibit different levels of posttraumatic growth compared to those without such histories. Additionally, experiencing more challenges during acute ayahuasca effects did not correlate with increased posttraumatic growth.

This post hoc analysis of a recent clinical trial comparing psilocybin to escitalopram with psychological support for depression (MDD) found that discontinuing SSRIs/SNRIs prior to psilocybin treatment led to reduced treatment effects on depression severity measures. However, there were no observed effects on the acute psychedelic experience. The study suggests that discontinuation of SSRIs/SNRIs before psilocybin treatment might impact treatment response.

This randomized placebo-controlled trial (n=111) investigated the efficacy, safety, and tolerability of fixed low-dose oral esketamine (3x p/d 42d; 30-90mg; oral) in patients with treatment-resistant depression (TRD). Results indicate that fixed low-dose oral esketamine did not show benefit on depressive symptom severity compared to placebo, but individually titrated higher doses in the open-label extension phase demonstrated potential antidepressant properties.

This survey (n=185) of an international Jewish sample with psychedelic experience explores the association between attachment-related variables and psychedelic experiences. Findings suggest that perceptions of an insecure attachment history are positively linked to various measures of psychedelic phenomenology, while adult attachment orientations show no significant relationship. Moreover, psychedelic experiences do not typically moderate the association between perceived insecure attachment history and present attachment insecurity.

This retrospective analysis (n=431) of at-home ketamine treatments (1x p/w, 50-400mg lozenges) for depression, generalized anxiety, and social anxiety found statistically significant improvements in symptoms measured via PHQ-9, GAD-7, and SAD-D-10 at all follow-up time points (1-2-3 months). Minor side effects were reported by 18.8% of patients, resolving within 24 hours, and the majority concluded treatment within ≤ 6 months. No significant differences were observed between treatment-resistant and non-resistant depression outcomes.

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.

This hypothesis paper proposes that psychedelic agents like LSD and psilocybin induce altered states of consciousness by activating the 5-HT2A receptor system, leading to a state of "synthetic surprise." This concept is based on recent understandings of serotonin's role in signaling surprise and is framed within the predictive coding framework, where surprise is seen as a mismatch between expectations and sensory input. The paper suggests that psychedelics disrupt maladaptive patterns by dynamically interacting with top-down expectations and sensory data, with implications for their clinical use, particularly emphasizing their ability to induce surprise to promote therapeutic effects.

This machine learning study (n=16) examines baseline resting-state functional connectivity (FC) measured with fMRI as a predictor of symptom severity in psilocybin-assisted therapy for treatment-resistant depression (TRD). Results show that FC of visual, default mode, and executive networks predicted early symptom improvement, with the salience network predicting responders up to 24 weeks after treatment.

This computational study investigates the membrane permeability of 12 selected tryptamines, aiming to elucidate the impact of various structural modifications on their permeation behaviour. Using classical molecular dynamics simulations and umbrella sampling techniques, the study finds that dimethylation of the primary amine group and methoxy substitution at position 5 increase permeability, while positional substitutions on the indole groups and protonation decrease permeability.

This review (2024) explores the impact of participant expectations on psychedelic clinical trials. It highlights the challenge of maintaining blinding as doses increase and discusses the potential bias introduced by positive expectancy. The review covers expectancy effects in both micro- and macrodose trials, suggesting that understanding and managing expectancy could enhance trial rigour and treatment outcomes in future psychedelic research.

This double-blind, randomized, controlled cross-over study (n=13) explores MDMA's (30-70mg) impact on tinnitus through behavioural and rs-fMRI assessments. No notable effects were observed at the lower dose. However, the 70 mg dose significantly reduced tinnitus annoyance and ignore ratings post-administration. Neurophysiological analysis revealed decreased connectivity in emotion and memory-related brain regions (hippocampal and amygdala) and increased connectivity in sensory processing and attention areas (right post-central gyrus, posterior and superior temporal gyrus, thalamus, and frontoparietal network) with MDMA versus placebo.

This open-label waitlist trial (n=30) assessed the feasibility of psilocybin-assisted psychotherapy (PAP/PAT) in a complex population with treatment-resistant depression (TRD), including major depressive and bipolar II disorders, baseline suicidality, and significant comorbidity. Participants received one, two, or three sessions of PAP with psilocybin (25mg), accompanied by preparation and integration psychotherapy sessions. Immediate treatment showed greater reductions in depression severity (MADRS) compared to the waitlist period, with a large effect size (g = 1.07, p < 0.01). Repeated doses were associated with further reductions in depression severity. Adverse events were transient, and the study demonstrated feasibility, preliminary antidepressant efficacy, safety, and tolerability in this population.