Psychoactives

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

Adolescence is a phase characterized by reckless and risky behaviors, including the initiation and use of various illicit substances such as cannabis and alcohol. When ingested or administered, these substances affect mental processes by delivering pleasure, inner peace, and satisfaction. The aim of this study was to determine the prevalence and associated factors of psychoactive substance (PAS) use among adolescents. A cross-sectional study was conducted, including 300 participants surveyed using a structured questionnaire. Data were collected using the Mediterranean School Survey Project on Alcohol and Other Drugs (MedSPAD) to assess substance use, the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) to diagnose substance use disorders (SUDs), and the Early Trauma Inventory Self-Report Short Form (ETISR-SF) to identify childhood maltreatment, as well as socio-demographic characteristics. During the study period, 300 secondary school students participated. Their mean age was 17.92 ± 1.40 years, ranging from 15 to 22. There were slightly more males (56.7%) than females. A total of 40.67% of participants admitted to using at least one PAS at least once, while the prevalence of current use was 26%. Tobacco was the most commonly used substance (22.1%), followed by cannabis (7.33%). According to the DSM-5, 40.2% of users met the criteria for severe addiction. Factors associated with PAS use included the father’s level of education; place of use (e.g., home); poor relationships with parents, siblings, and teachers; and childhood maltreatment. Psychoactive substance use was found to be prevalent among adolescents in this study. Full article

In post-mortem (PM) investigations, forensic toxicologists attempt to identify legal or illegal substances present before death and determine how they contributed to the cause of death. A critical challenge is ensuring that PM sample concentrations accurately reflect those at the time of death, as postmortem redistribution (PMR) can alter these levels due to anatomical and physiological changes. The PMR phenomenon is called a ‘toxicological nightmare’. PMR significantly affects post-mortem drug concentrations, particularly for lipophilic drugs and those with a high volume of distribution. The emergence of new psychoactive substances (NPSs) has led to a growing recognition of their role as a significant public health concern, frequently associated with fatalities related to polydrug use. These substances are renowned for their ability to induce intoxication at low doses, which has led to the continuous updating of toxicological and forensic methods to improve detection and adopt new analytical standards. The comprehensive detection of NPS metabolites, some of which are still undiscovered, presents an additional analytical challenge, as do their metabolic pathways. This complicates their identification in fatal cases using standard analytical methods, potentially leading to an underestimation of their actual prevalence in toxicological results. Furthermore, the interpretation of analytical results is hindered by the absence of data on PM blood levels and the specific contributions of NPS to causes of death, exacerbated by the lack of knowledge of whether the PMR phenomenon influences them. This paper presents a comprehensive review of the literature on post-mortem cases involving various NPS, categorized according to classifications by the United Nations Office on Drugs and Crime (UNODC) and the European Union Drugs Agency (EUDA). These categories include cathinones, phenylethylamines, arylalkylamines, phencyclidine-type substances, phenmetrazines, piperazines, phenidates, aminoindanes, LSD-like NPSs, tryptamines, fentanyl analogs, designer benzodiazepines, synthetic cannabinoids, and nitazenes. This review covers not only postmortem blood levels but also the stability of the substances studied, the methods of analysis, and attempts to shed some light on the PMR phenomenon. This review used various key terms, such as PMR, NPS, and the names of previously categorized substances and drug analyses across multiple peer-reviewed journals and databases, including Scopus, Google Schoolar, Springer, PubMed, and Wiley Online Library. In addition, references from retrieved articles were examined to identify additional relevant research. Interpreting post-mortem toxicological results is complex and lacks definitive guidelines, requiring a nuanced understanding of its challenges and potential pitfalls. As a result, post-mortem toxicology is often regarded as an art. The primary aim of this review is to provide forensic toxicologists with a comprehensive framework to assist in the evaluation and interpretation of NPS analysis. This guide is intended to complement the existing knowledge and practices applied in forensic laboratories within the toxicological analysis of post-mortem cases. Full article

Psychoactive drugs are compounds that alter the function of the central nervous system, resulting in changes in perception, mood, cognition, and behavior. A subclass of psychoactive drugs, psychedelics, are hallucinogenic drugs that can trigger psychedelic experiences and possible changes in mental perception. The potential use of psychedelics as a therapeutic has led to an increase in clinical research focusing on the treatment of mental disorders including anxiety and depression. There are numerous species belonging to Psychotria and Banisteriopsis which have been reported to contain psychedelic and psychoactive compounds; however, there is a lack of validated analytical methods for raw plant material, which is crucial if these plants are to be commercially cultivated for medicines. This study provides a fully validated method using ultra-high performance liquid chromatography (UHPLC) coupled to mass spectrometry (MS) for the following six compounds: tryptamine, N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), tetrahydroharmine (THH), harmaline, and harmine. The validated method was used to determine the psychoactive concentrations in Psychotria viridis, Psychotria carthagenensis, Banisteriopsis caapi, and Alicia anisopetala. Validation parameters were established; linearity (R² = 0.988–0.999), limit of detection (LOD) (0.06–0.11 ng/mL), limit of quantitation (LOQ) (0.18–0.34 ng/mL), accuracy, precision, extraction efficiency (>98%), recovery (74.1–111.6%), and matrix effect (70.6–109%) were all evaluated. All six compounds eluted within nine minutes, with a total analysis time of 20 min including column equilibration. This method establishes a high-throughput method for the robust analysis of psychedelics which may see future use in agricultural research and industry. Full article

Treatment-resistant depression (TRD) is a substantial public health burden with limited treatment options. Recent evidence suggests that single and repeated-dose ketamine infusions have rapid and significant antidepressant effects on individuals with TRD. Few studies have compared single or repeated (6) ketamine infusions past 14 days post-treatment. This retrospective chart review study investigated the long-term effects of single (n = 9) and repeated (6) (n = 5) high-dose (1 mg/kg) intravenous ketamine infusions on TRD 30 days post-infusion(s) (N = 14). Changes in depressive symptoms were measured by comparing Beck Depression Inventory (BDI-II) scores pre- and 30 days post-treatment for an understanding of long-term efficacy in clinical practice. Results indicated that ketamine has the potential to be an effective and enduring intervention for TRD, adding treatment and management options that are currently limited. Full article

Δ⁹-Tetrahydrocannabiphorol (Δ⁹-THCP, THCP) a psychoactive cannabinoid recently found in Cannabis sativa L., is widely used as a legal marijuana substitute. THCP is encountered in sprayed Cannabis, edibles, and vape liquids. The distributors of such products claim that the THCP in use originates from a natural source. The legal status of this substance varies from country to country. THCP and similar cannabinoids with a dibenzoyprane structure have been banned in Switzerland since October 2023. A vape liquid, which contains 90% THCP and 10% terpenes according to the distributor, was analyzed by gas chromatography coupled with mass spectrometry (GC-MS). Besides CBP, CBDP, Δ⁹-THCP and Δ⁸-THCP and some terpenes, other compounds were found which probably result from a synthetic procedure. This sample contained 5-heptylresorcinol, the heptyl homologue of olivetol, a common precursor for the synthesis of tetrahydrocannabinol (THC). Bisalkylated compounds (m/z 476) were found as a result of the reaction of one equivalent of 5-heptylresorcinol with two equivalents of (+)-p-mentha-1,8-dien-4-ol or another precursor. Similar bisalkylated compounds are known as undesired side products of the synthesis of THC. The sample contained unidentified isomers of Δ⁹-THCP, presumably abnormal cannabinoids (abn-Δ⁹-THCP; abn-Δ⁸-THCP) and iso-cannabinoids (iso-THCP). Chiral derivatization with Mosher acid chlorides revealed that the Δ⁹-THCP in the sample was enantiopure. Full article

Background: There is ongoing research into the potential use of psychedelics and 3,4-methylenedioxy-methamphetamine (MDMA) as alternatives to commonly used medications for treating major depressive and anxiety disorders. Aims: We aimed to assess the efficacy of psychedelics and MDMA in managing depressive and anxiety symptoms and evaluate their safety profiles. Methods: We searched five databases for randomized controlled trials of psychedelics and MDMA targeting depressive and anxiety symptoms and conducted a meta-analysis using a random effects model when possible. The review protocol is registered in PROSPERO under CRD42022341325. Results: Psilocybin induced a rapid and sustained reduction in depressive and anxiety symptoms in patients with major depressive disorder and in patients with life-threatening cancer. MDMA induced a decrease in depressive symptoms in patients with life-threatening cancer, autism spectrum disorder, and post-traumatic stress disorder. MDMA’s effect size was either negligible or negative in reducing generalized anxiety symptoms, but MDMA reduced social anxiety symptoms. Ayahuasca induced a reduction in depressive symptoms in individuals with treatment-resistant major depressive and personality disorders. Lysergic acid diethylamide (LSD) induced a decrease in anxiety symptoms in individuals with life-threatening cancer. Psilocybin’s adverse effects were noticeable for elevated blood pressure, headaches, and panic attacks. For MDMA, elevated blood pressure, headaches, panic attacks, and feeling cold were noticeable. Conclusions: Psychedelics (psilocybin, ayahuasca, and LSD) and MDMA have the potential to induce a reduction in depressive and anxiety symptoms. Adverse effects are noticed. Rigorous randomized controlled studies with larger sample sizes utilizing instruments with better reliability and validity are warranted. Full article