Psychoactives

Ketamine and esketamine are two closely related compounds with fast-acting antidepressant properties that have reshaped the treatment landscape for individuals with treatment-resistant depression (TRD). Originally developed as anesthetic agents, both have since demonstrated rapid and robust antidepressant effects in patients who have not responded to conventional treatments such as selective serotonin reuptake inhibitors (SSRIs) or cognitive behavioral therapy. This narrative review synthesizes evidence on their pharmacology, mechanisms of action, clinical efficacy, safety profiles, and regulatory considerations, with a particular focus on their neuroplastic effects. While ketamine is a racemic mixture composed of equal parts R- and S-enantiomers, esketamine consists solely of the S-enantiomer and has been approved for intranasal use by the FDA and EMA for TRD. These agents have been shown to produce symptom relief within hours of administration—an unprecedented effect in psychiatric pharmacology. This rapid onset is particularly valuable in managing suicidal ideation, offering potential lifesaving benefits in acute settings. Furthermore, ketamine and esketamine’s influence on synaptic plasticity, brain-derived neurotrophic factor (BDNF), and glutamate transmission provides insights into novel therapeutic targets beyond monoaminergic systems. This review incorporates recent real-world findings and peer-reviewed literature to contextualize the clinical use of these agents in modern psychiatry, bridging experimental research with practical application. Full article

Food can help release and promote neurotransmitters. As a result, the food’s effect in this regard is of great interest to individuals who have experienced dysregulation of the brain reward circuit due to addiction to drugs or other substances. This is one of the chief reasons why dietary choices can influence the success of drug addiction programs. While the general importance of nutrition was known previously—although it has been applied on few occasions—this review provides new knowledge that has emerged in recent years, which reinforces earlier findings regarding food’s importance in overcoming addiction. In the last 15 years, there has been great progress in the understanding of the human intestinal microbiota, its importance for health, and its connections with the brain. However, since this area of nutrition is such a new field of study, it has rarely been applied to or considered in treatment programs. At the same time, it is important to avoid a diet based on ultra-processed foods, which deteriorate the microbiome and consequently harm the restoration of the natural reward system. Although ongoing research will undoubtedly provide a wealth of information in the coming years, the knowledge currently available is enough to confirm the importance of diet in a person’s addiction recovery process. For this reason, it is important for patients and programs to follow a diet that regulates the brain’s natural neurotransmitters through the microbiota and restores the natural functioning of the reward circuit, helping to overcome cravings. Full article

Chronic pain is a prevalent public health concern in the United States, frequently managed with over-the-counter (OTC) painkillers without professional medical supervision. This study investigates household-level patterns of over-the-counter painkiller use utilizing a nationally representative dataset from NielsenIQ, focusing on how reported health conditions, whether self-identified or professionally diagnosed, affect purchasing behaviors. By linking consumer purchase data with self-reported ailment information, this study analyzed painkiller expenditures across different ailment types and demographic groups. Results show that over-the-counter painkiller purchases were highly symptom-driven, particularly for headache-related products, which were the most frequently purchased category across all household types. Nearly one-third of single-member households purchased over-the-counter painkillers for headaches, regardless of diagnosis type, indicating a strong role of perceived need in driving behavior. Females and older individuals more frequently reported ailments, with consistently higher proportions across both pain-related and other conditions. Nonetheless, a notable share of households reported over-the-counter painkiller use without any reported ailments. The findings suggest that diagnostic status plays a limited role in determining over-the-counter painkiller usage, emphasizing the need for improved public health messaging around safe self-medication. These insights can inform targeted education, labeling regulations, and policy interventions to support safer and more equitable pain management practices at the population level. Full article

Introduction: Cannabis use disorder (CUD) is being increasingly diagnosed in the United States, but access to treatment remains unequal, particularly in New York. Identifying the factors that contribute to disparities in receiving treatment for CUD among different population groups is essential for ensuring effective and targeted interventions. This study explores the sociodemographic factors influencing treatment utilization for CUD in New York. Methods: Data for this study were retrieved from the 2018 Treatment Episode Data Set—Discharges (TEDS-D) of the U.S. Substance Abuse and Mental Health Services Administration (SAMHSA). Sample size for the study is 422,319 people with CUD. Logistic regression analysis was performed to examine the odds of receiving treatment for CUD based on demographic and socioeconomic factors, as well as the type of treatment setting. Results: The results revealed significant disparities in treatment utilization. Asians/Pacific Islanders and Hawaiian Natives had lower odds of receiving treatment compared to African Americans (OR = 0.367, 95% CI 0.341–0.394). Similarly, Caucasians had the lowest odds of receiving treatment (OR = 0.270, 95% CI 0.266–0.275). Females were less likely to receive treatment compared to males (OR = 0.756, 95% CI 0.744–0.768). Those with higher educational attainment (over four years of college) had the lowest odds of receiving treatment, while individuals with 9–11th grade education had the highest odds. Employment status also influenced treatment access, with the unemployed having the highest odds, and full-time employees having the lowest. Additionally, individuals with no source of income had significantly lower odds of receiving treatment. Conclusions: This study highlights significant disparities in the provision of treatment for CUD in New York, influenced by sociodemographic factors such as race, gender, age, education, and employment status. These findings emphasize the need for targeted interventions to reduce these disparities and improve treatment access for underserved populations. Full article

Obsessive–compulsive disorder (OCD) has an estimated prevalence between 1 and 2.3%. Existing treatments may not be suitable or effective for all people with OCD, and there is increasing interest in whether these individuals may benefit from the use of cannabis-based medical products (CBMPs). We document the characteristics of 257 people reporting a diagnosis of OCD within Project T21, a study of medical cannabis patients, and examined whether the use of prescribed cannabinoids improves quality of life. Individuals with OCD were prescribed an average of 2.2 CBMPs, with most products classified as THC-dominant flowers (73.7%). Three months after initiating treatment, there were substantial improvements in quality of life (Cohen’s d = 0.48; 95% CI = 0.29–0.65), general health (Cohen’s d = 0.43; 95% CI = 0.26–0.61), mood/depression (Cohen’s d = 0.85; 95% CI = 0.65–1.04), and sleep (Cohen’s d = 0.61; 95% CI = 0.43–0.79). There was a corresponding reduction in anxiety symptoms among the subsample who completed the GAD-7 (Cohen’s d = 1.14; 95% CI = 0.84–1.44). Eight individuals (5.7%) reported a total of 14 adverse effects, with the majority of these (57%) being described as mild. Given emerging evidence that those with OCD can benefit from CBMPs, coupled with the increased availability of these unlicensed products internationally, there is a need for more research, including clinical trials, to identify those who may benefit most from the use of these medicines. Full article

Psychedelic plants and fungi have been traditionally used in many cultures as part of ritual ceremonies and ancient medicinal treatments. In some regions, these psychoactive plants have already entered mainstream discourse through popular literature and art. Today, numerous academic and medical institutions are establishing dedicated departments to examine the benefits and risks of psychedelic-assisted treatments. Entheogens in healing practices and herbal medicine are part of Slavic cultural heritage. However, due to the predominantly oral transmission of this knowledge, there is a significant lack of written sources and a profound gap in documentation regarding entheogen use on the Balkan Peninsula, where many psychoactive plants and mushrooms grow in their natural habitat. Our work aims to bridge indigenous knowledge systems with contemporary therapeutic discourse, while advocating for sustainable, inclusive, and culturally respectful research practices. This review manuscript presents information on Slavic ancient entheogens, and calls for further multidisciplinary, integrative approaches in researching psychoactive plants and mushrooms of the Balkans. Our paper includes the ethnobotanical uses of native Balkan entheogens, outlines the pharmacological mechanisms of their main active compounds, and discusses their impacts on social behavior, mental health, and overall well-being. We also examine their therapeutic potential and risks, contributing to the contemporary understanding of psychoactive and psychedelic use in mental health treatment and beyond, as tools for life enhancement to improve quality of life and well-being. Full article

While research on psychedelic-assisted therapy (PAT) continues to show promise, challenges in its clinical application persist. One relevant domain includes how supervision might enhance both client and trainee outcomes. Current data suggest that, despite supervisor reports and the enthusiasm of trainees, supervision accounts for extraordinarily little variance in treatment outcome. We propose that as supervisors model relevant skills, these skills can also improve in the therapist, which should lead to enhanced alliances and improved self-care for the client, trainee, and supervisor. Thus, we propose a model of supervision that rests on key Motivational Interviewing (MI) principles and supports the integration process—a pivotal phase of PAT where clients translate psychedelic-induced insights into meaningful behavioral change. This Motivational-Interviewing-Enhanced Integration Supervision (MIE-IS) model bridges the gap between psychedelic experiences and personal growth by ensuring supervisors can effectively encourage trainees to support their clients through this crucial integration process. Supervisors would model the use of MI with trainees in supervision, who would, in turn, apply those same MI technical and relational skills to support clients’ integration experiences. Beyond enhancing client outcomes, this supervisory model could also increase each trainee’s motivation to personally engage with wellness-promoting integration behaviors, potentially enhancing professional development and minimizing burnout. By reinforcing a culture of self-care and reflective practice, this model might inspire better self-care in supervisors as well. By fostering an MI-informed supervisory relationship, the model promotes a culture of continuous learning and skill development, benefiting clients through the effective and meaningful integration of their psychedelic experiences. Full article

Both Type 2 Diabetes Mellitus (T2DM) and depression are leading causes of disability despite T2DM being largely preventable and depression being among the most treatable mental health conditions. Diabetes and depression have a bidirectional association, with each condition worsening the development and progression of the other. Depression in patients with diabetes is linked with poor glycemic control, reduced treatment adherence, and increased risk of diabetes complications. On the other hand, chronic hyperglycemia, systemic inflammation, insulin resistance, and neuroendocrine dysregulation are involved in the pathophysiology of depression. Antidepressants are often used to treat depression in diabetic patients, but their metabolic impact is still a matter of concern. While some antidepressants like fluoxetine and escitalopram increase insulin sensitivity and improve glycemic parameters, others such as especially tricyclic antidepressants (TCAs) and certain selective serotonin reuptake inhibitors (SSRIs) have been associated with an increased risk of diabetes, weight gain, and poor cardiometabolic outcomes. Considering such complexities, the prescribing of antidepressants must be done carefully. This review underscores the need for evidence-based and patient-centric pharmacological management. Further, the inclusion of psychiatry in multidisciplinary diabetes care teams has the potential to maximize both metabolic and psychological health benefits, as well as reduce the complications of T2DM. Full article

Psychoactive substances, including illicit drugs, prescription medications, and novel psychoactive compounds, are frequently analyzed in biological and in non-biological samples. Interpreting results is paramount for ensuring proper medical treatments and judicial decisions. However, false-positive results—where a sample is incorrectly identified as containing a psychoactive substance—remain a persistent issue. In other words, it is important to invest in understanding the meaning of toxicological results. Cross-reactivity in immunoassays, sample contamination, analytical interference with certain endogenous and exogenous substances, inadvertent and accidental exposure due to environmental contamination, second-hand smoke inhalation, or unintentional dermal or mucosal contact with drug residues are some of the major issues to consider. This perspective highlights major sources of artifacts in interpreting amphetamine analytical results in order to provide proper toxicological interpretations. Full article

Psychedelic substances have recently emerged as a promising method for treating mental health conditions, despite a history of stigmatization and restriction in use. The present review synthesizes existing literature on the therapeutic potential of psychedelics such as LSD, psilocybin, and MDMA in addressing specific mental health conditions like depression, anxiety, and addiction. On reviewing the existing literature, it became apparent that when administered in controlled settings with psychological support, psychedelics can induce profound psychological insights, leading to long-lasting and positive changes in mood, cognition, and behaviour. This review discusses the ethical, social, and regulatory challenges linked to using psychedelics within the mental health sector across different countries, and how these might influence societal beliefs towards their efficacy and use. Further research would be beneficial for eliciting a deeper understanding of the use of psychedelics in the field of mental health, leading to the development of standardized administration protocols and a thorough appreciation of societal implications and long-term outcomes. This review discusses the potential for psychedelics to revolutionize mental health treatment while underlining the urgent need for rigorous scientific inquiry on this topic and the ethical considerations surrounding the use of psychedelics for therapeutic purposes. Full article

The history of cannabis research spans centuries, with a focus on isolating and understanding its active compounds. Although plants like opium and coca yielded active alkaloids relatively early, cannabis posed unique challenges due to its active substances existing in oily mixtures that were difficult to isolate. Early studies in the 19th century, such as Ferdinand Tscheppe’s 1821 research, debunked claims of opioid-like substances in hemp, setting the stage for further exploration. In the late 19th and early 20th centuries, key figures like Sir William Brooke O’Shaughnessy and Robert Sidney Cahn made significant contributions to the understanding of cannabis’s chemical components, though major breakthroughs were delayed due to technical limitations. In the 1940s, Ghosh and Adams independently elucidated the structure of cannabinol, marking the first cannabinoid identified from cannabis. Subsequent work, including Šantavý’s 1964 and Mechoulam and Gaoni’s 1964 identification of ∆⁹-THC, confirmed the psychoactive compound’s structure and absolute configuration. This article traces these incremental advancements, highlighting the critical role of each researcher’s contributions in piecing together the puzzle of cannabinoid chemistry. It underscores that scientific progress thrives on collaboration and shared knowledge. Full article

Objective: To provide a state of the art on the use, role, and function of music during psychedelic-assisted therapy (PAT) with ayahuasca. Introduction: Ayahuasca is a medicinal brew with psychoactive qualities used by indigenous communities throughout the Amazon region, and music is deemed crucial during ayahuasca experiences. In PAT, music forms part of the set and setting, but it lacks systematization and is poorly explored in the scientific literature. Inclusion criteria: Published literature in English, Spanish, and Portuguese, focusing on conceptualizing, defining, or describing the use, role, and/or function of music in PAT sessions with ayahuasca. Methods: This review follows the JBI methodology for scoping reviews. We will search Web of Science, Scopus, Google Scholar, and PubMed databases without year restrictions, and a hand search of articles will be performed. Two reviewers will assess titles/abstracts, followed by independent reviews of included full texts. An Excel data extraction sheet will be used to tabulate the information. The findings will be presented narratively, including respective tables or figures. If feasible, a potential theoretical framework for the use, role, and function of music during PAT with ayahuasca will be outlined, including implications for future research and clinical practice. Full article

Since its origins, the debate on the interaction between religions and psychoactives has been strongly influenced, both positively and negatively, by prejudices, policies, fashions and trends that had little to do with scientific research. Stigma and exaltation in different historical moments have equally characterized the study of the presence and use of so-called entheogens in the different declinations of the shamanic phenomenon around the world. This article attempts to shed light on the various trends regarding the state of the art, providing new epistemological elements on the basis of an ethnographic investigation among some Indigenous peoples of India. The production of alcoholic beverages (fermented and distilled, but sometimes in combination with other psychoactive or hallucinogens among the starters) is a fundamental trait of the aboriginal (ādivāsī) cultures of the Indian subcontinent. Not immune from an attempt at political instrumentalization, which occurred both in the colonial period and in the contemporary era, the discourse on the natural production of these sacred substances is today the key to understanding indigenous ontology and its traditional idea of sustainability. Far beyond the mere documentation of the induction of altered states of consciousness, this investigation involves the discovery of local pharmacopeias, as well as principles of fermentation and food preservation. Full article

Accumulating psychedelic research has demonstrated a potential for improving mental health and wellbeing, yet studies in the context of eating disorders (EDs) are limited. This study aims to explore the subjective effects of psychedelic experiences to gain insight into the benefits and risks for people with EDs. Semi-structured interviews were conducted with eight adults aged 25–54 (mean age = 36.9), reporting to have had experiences with EDs and psychedelics in both naturalistic and clinical settings. Participants had multiple diagnoses and suffered chronic EDs, (mean age of onset = 13), diagnosed (N = 7) and undiagnosed (N = 1). Reports of cessation or the reduction of ED symptoms were unanimous and long-lasting for seven, with two participants reporting recovery attributed to psychedelic use. Two participants reported relapsing, attributed to environmental factors in the months following. Thematic analysis resulted in two superordinate themes, each comprising three subordinate themes. The first superordinate theme, ‘Exploring’ via the ‘gateway to healing’, illustrates mental, emotional, and transcendental elements of psychedelic experiences. The second superordinate theme, ‘Transformation’ and being ‘able to do the work’, illustrates cognitive and behavioural outcomes, with retrospective safety perceptions. These findings may provide more in-depth information on what benefits and experiences people with EDs can obtain from the use of psychedelic drugs and may inform more robust investigations of psychedelic-assisted therapy for the treatment of EDs. Full article

Depression is common among patients suffering from cancer, but is often challenging to diagnose due to the overlap of symptoms with cancer and its treatments. Additionally, treating depression in cancer patients is challenging because of the confusion between the adverse effects of antidepressants, cancer treatments, and cancer symptoms. This study aims to evaluate the safety and adverse effects of pharmacological interventions, focusing on antidepressants and psychedelics, in the treatment of depression in cancer patients. The review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, and includes studies published up to July 2024. We searched PubMed, Scielo, and Lilacs databases, and included randomized, double-blinded, controlled clinical trials involving cancer patients with depressive symptoms. A total of 1764 articles were identified, with 21 randomized controlled trials meeting the inclusion criteria. All studies involved cancer patients with depressive symptoms, and only one study included patients with other life-threatening conditions. Serious adverse events related to antidepressant treatment were reported in only two studies, indicating an acceptable safety profile. Most other adverse effects were mild to moderate, and generally well-tolerated. Serious adverse events were infrequent; however, the small sample sizes underscore the necessity of larger, placebo-controlled trials assessing the safety of antidepressants and psychedelics in cancer patients. Full article

Several authors have advanced the idea that psychedelics such as psilocybin might be effective means for achieving moral bioenhancement (MBE). Here, I discuss some reservations on this assertion from both neuropharmacological and bioethical perspectives, and surmised that there is little, if any, good justification for such a claim. The indication of psychedelics for MBE is undermined by their hallucinogenic properties and the risk of adverse psychosis. There is also a lack of sound bioethical basis for using psychedelics to enhance morality. Based on our current understanding, the use of psychedelics specifically for MBE in healthy individuals would violate the ethical principle of non-maleficence. Unless there is unequivocal demonstration that psychedelics could enhance morality, or that new non-hallucinogenic derivatives become available, an indication for psychedelics in MBE would be untenable. Full article

The author surveyed researchers about United States federal grant applications for therapeutic psychedelic research and their funding success. An anonymous survey was sent to corresponding authors of the 50 most-cited psychedelic research articles published after 2000 and also disseminated on Twitter. Ten researchers responded, reporting on 24 National Institutes of Health (NIH) grant applications for psilocybin, ibogaine, lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), and other psychedelics, dating back to the early 1990s. Grant applications increased noticeably after 2006. Of the applications assessed, 16.7% were funded, below the NIH’s 23.4% average funding rate for R01-equivalent grants from 1998 to 2023. While no applications submitted before 2006–2010 were funded, the funding rate since then (19.05–22.2%) aligns with the NIH’s 20.6 ± 1.9% annual average for R01-equivalent grants from 2006 to 2023. Respondents generally perceived funding for psychedelic research as more difficult to obtain than for other areas, though recent improvements were noted. If the analyzed applications represent only a small subset of total submissions of applications proposing to study therapeutic applications of psychedelics, the findings may have limited generalizability and larger-scale validation studies would be required. However, this is difficult to determine since detailed data on unfunded NIH applications are not publicly available. Full article

Dexamphetamine (DEX) is widely used in treatments, but concerns persist about its potential for addiction. This review aimed to assess the risks of DEX addiction by examining the existing literature. Originally planned as a systematic review, it was adjusted to a narrative review due to a lack of qualifying studies. A search of the literature on addiction to DEX was conducted on three databases including PubMed, Scopus, and Embase. Seven articles consisting of three reviews and four papers with original data were identified and reviewed. In total, four poorly documented cases of possible DEX addiction were found. The commonly cited papers on prescription DEX addiction did not hold up to scrutiny. Overall, the evidence that DEX is addictive is limited and inconclusive, highlighting the need for more rigorous research to clarify its true addiction risk. Full article

Background: To estimate the prevalence of co-occurring obsessive–compulsive disorder (OCD) with substance use disorder (SUD) in the general population. Methods: A comprehensive literature search was conducted on the prevalence of comorbid OCD and SUD in the general population using MEDLINE, PsycINFO, EMBASE and CINAHL. Using the keywords, relevant studies published between 1993 and 2021 were identified. These studies were analysed using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and the guidelines for Meta-analysis for Observational Studies in Epidemiology. Results: Fourteen studies met the inclusion criteria and had a total combined sample size of 47,850 participants. The lifetime prevalence of any identified SUD in patients with OCD ranged between 4.3% and 62.4%. Among co-occurring OCD with AUD, prevalence ranged between 14.1% and 35.9%; cannabis use disorder and OCD, between 11.5% and 24.4%; and tobacco use disorder and OCD, between 15% and 23.1%. Alcohol was the commonest psychoactive substance used in most of the studies reviewed and the prevalence of co-occurring substance use was highest in males. Conclusions: In conclusion, this review highlights the variable prevalence of co-occurring SUDs in individuals with OCD, emphasizing that the association differs based on the type of substance. Overall, the prevalence rate of co-occurring OCD and SUDs underscores the need for further research on the relationship between these conditions and the development of effective treatment strategies that address both disorders concurrently. Full article