Background: Psilocybin-assisted therapy (PAT) has emerged as a promising intervention for alcohol use disorder (AUD), yet contemporary clinical evidence has not been systematically synthesized to validate its clinical utility and safety profile. Methods: Contemporary clinical trials of PAT for AUD were identified systematically from PubMed, PsycINFO, and Scopus by two independent reviewers....
Tobacco use remains a leading preventable cause of morbidity and mortality. Although several pharmacotherapies and behavioral treatments for tobacco use disorder (TUD) exist, their overall efficacy is modest, underscoring the need for innovative treatment approaches. Ketamine, a rapid-acting glutamate receptor antagonist with neuroplasticity-enhancing properties, has shown promise in the...
BACKGROUND: Psychoactive serotonin 5-HT2A receptor agonists are potent modulators of awareness. Influential theories propose that psychedelics alter whole-brain dynamics by increasing neural signal diversity and dynamic flexibility. Beyond temporal variability, it is an open question whether psychedelics impact the characteristics of transient neural state sequences themselves. AIMS: Our goal...
Extant literature indicates mitochondrial dysfunction may contribute to the pathophysiology of depressive disorders. Preclinical data indicate that anesthetic doses of ketamine are associated with deficits in mitochondrial viability and function. Ketamine and esketamine have demonstrated rapid antidepressant effects in persons with difficult-to-treat depressive disorders. Herein, we aim to...
Common wisdom in the psychedelic literature suggests that early controlled trials of psychedelic therapy were methodologically flawed. In this review we challenge this view and discuss 11 controlled studies that were conducted in the United States and Canada between 1965 and 1977 to evaluate psychedelic (peak) therapy for individuals suffering from alcohol and opioid use disorder and...
Background: Psilocybin’s therapeutic potential is neurophysiologically characterized by acute alpha power reductions and increased entropy. However, the systematic time-course of these changes from administration through the 24-hour sub-acute phase remains poorly characterized. Methods: In a double-blind, placebo-controlled, crossover trial ( N = 20, 10 females), healthy participants received a...
Serotonergic psychedelics, such as N,N-dimethyltryptamine (DMT), have shown therapeutic potential in various psychiatric disorders. However, DMT demonstrates pharmacokinetic (PK) variability and a short half-life. This exploratory study investigated the PK, pharmacodynamic (PD), and safety profile of CYB004, a deuterated DMT analogue, following intravenous administration in healthy volunteers....
BACKGROUND: -dimethyltryptamine (DMT) might have therapeutic effects in various psychiatric disorders. AIMS: Prior to exploring this clinical potential, it is essential to determine an optimal administration regimen for DMT, explore the relationship between its pharmacokinetics (PK) and pharmacodynamics and identify potential sources of pharmacokinetic variability. METHODS: Therefore, DMT was...
Fentanyl is the leading cause of fatal overdoses worldwide, and repeated use may lead to substance use disorder (SUD). In SUD, drug-associated contexts can trigger reward-related behavior even in the absence of the drug. Psychedelic compounds may weaken context-drug associations, reducing reward-related behavior to fentanyl. We evaluated the effects of the psychedelic psilocin and its...
BACKGROUND Psilocybin, a serotonergic psychedelic found in hallucinogenic mushrooms, is metabolized to psilocin, the compound responsible for its psychoactive effects. Psilocybin has demonstrated therapeutic potential for neuropsychiatric conditions. While recent trials have primarily used orally administered synthetic psilocybin, alternative formulations and delivery methods may offer...
, is a highly selective κ-opioid receptor agonist and a rare example of a κ-opioid receptor-mediated psychedelic drug. Preclinical work of salvinorin A has shown promising effects in neuropsychiatric animal models. However, human studies remain heterogeneous and fragmented, highlighting the need for synthesis. Thus, we conducted a systematic review to synthesize available human studies of...
Psychedelics have emerged as promising pharmacological agents for treating a range of neuropsychiatric disorders. While preclinical studies have provided valuable insight into the neural mechanisms underlying their effects, systematic characterization of psychedelic effects on inherent spontaneous behaviors in animal models remains limited. In the current study, male and female Sprague-Dawley...
Background: Psychedelic-assisted psychotherapy (PAP) shows promise for substance use disorders (SUDs), yet the respective contributions of pharmacological, experiential, psychotherapeutic, and contextual factors remain insufficiently understood. Objective: To synthesize contemporary clinical evidence on PAP for SUDs, with particular attention to therapeutic frameworks, dosing strategies,...
The re-emergence of serotonergic psychedelics has introduced rapid-acting antidepressant effects and has been widely described as a paradigmatic shift in depression treatment. Recently, there has been intense debate about whether the acute subjective effects of psychedelics are necessary for their therapeutic efficacy or merely byproducts of underlying neuroplastic processes. Recent...
Background: The potential safety and efficacy of the psychedelic 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) for post-traumatic stress disorder (PTSD) has been researched in phase 2 and phase 3 clinical trials. We examined the occurrence and role of mystical experiences in MDMA-AT. Methods: Data were sourced from two phase 2 randomized trials of MDMA-AT for chronic PTSD, in...
BACKGROUND: Cannabidiol (CBD) has emerged as a potential antipsychotic treatment, acting as a negative allosteric modulator of cannabinoid type-1 (CB1) receptors within the endocannabinoid system. Although previous neuroimaging studies have shown that CBD induces changes in aberrant brain activity and functional connectivity (FC) in psychosis, they have not directly integrated information about...
Background: When administered alongside monitoring and support, psilocybin has shown promise in the treatment of multiple psychiatric conditions. However, the contribution and nature of participant support in the context of psychedelic trials are much debated. Aims: We sought to further illustrate the structure and format of the monitoring and support used in Compass Pathfinder Ltd (Compass)...
BACKGROUND Cannabidiol (CBD) is widely consumed in low-dose products. However, evidence for its psychotropic effects at non-clinical doses is sparse and inconsistent. AIMS To characterise the acute behavioural effects of low-dose synthetic CBD in healthy volunteers. We hypothesised that 200 mg of CBD would produce a greater peak pleasant drug effect than a placebo. METHODS In a triple-blind,...
The occupancy-driven pharmacology model in psychopharmacology has guided drug discovery and development for decades, whereby the goal is stable receptor occupancy over an extended period with a direct relationship of drug exposure to pharmacodynamic and therapeutic response. Event-driven pharmacology (EDP) is a concept where the acute pharmacodynamic actions of a plastogen, a transient binding...
BACKGROUND: -dimethyltryptamine (DMT); however, long-term effects, including broader well-being dimensions, are sparsely explored across populations. AIMS: Investigating whether DMT produces sustained improvements in anxiety, life satisfaction, and quality of life, in both healthy individuals and patients with treatment-resistant depression (TRD). METHODS: In 2 open-label clinical trials, 27...
BACKGROUND: Posttraumatic stress disorder (PTSD) and major depressive disorder are often comorbid in humans. Psilocybin reportedly has beneficial therapeutic effects on depression, possibly by promoting neuroplasticity. PTSD is associated with the dysregulation of neuroplasticity in the hippocampus and medial prefrontal cortex (mPFC). We hypothesized that psilocybin might reduce fear memory by...
Background: Psychedelic microdosing—repeated sub-perceptual doses of lysergic acid diethylamide (LSD) or psilocybin—has attracted scientific interest as a potential mood and cognitive intervention. The evidence base remains methodologically heterogeneous and vulnerable to expectancy bias. Methods: We conducted an umbrella review with narrative synthesis following Joanna Briggs Institute...
With growing research on the use of psychedelics to treat mental health conditions, greater attention to the psychosocial procedures accompanying substance administration is warranted. This scoping review aims to categorize psychosocial protocols used in research involving psychedelics as psychiatric treatment according to their purpose, denomination, format, therapeutic orientation,...
Oral S-ketamine (S-KETPO) is being explored as an alternative to intravenous maintenance treatment (S-KETIV) in treatment-resistant depression (TRD). However, the first-pass effect with S-KETPO significantly alters S-ketamine's bioavailability and the systemic exposure of its active metabolites, raising potential safety and efficacy concerns. This study characterized the pharmacodynamic and...