Psychoactives

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

Adolescents and young adults are particularly susceptible to substance abuse. They have yet to solidify their sense of self to the degree necessary to effectively resist temptations from negative peer pressure. It is vital for mental health counselors to understand the factors affecting substance abuse in adolescents/young adults and to comprehend the effectiveness of common intervention strategies fully. This paper produces a narrative literature review of 27 international journal publications from 2004 through June 2024 related to causal factors and interventions effective for treating substance abuse in adolescents and young adults. The results indicate that adolescents who idolize antisocial peers and lack a strong sense of self, family attachment, parental monitoring, and role models are more likely to suffer from substance abuse. Successful interventions include those that help strengthen the adolescent’s sense of self, a mental-health-friendly school environment staffed with professional mental health counselors, and interactive programs that engage students in positive behaviors. Positive family and peer role models can also assist in helping adolescents/young adults build a strong self-image and resist substance use. Positive peer influence is another critical factor, but more work must be undertaken to fully assess its effectiveness as an intervention. Full article

Synthetic opioids such as fentanyl are key drivers of the opioid crisis, contributing to approximately 68% of the nearly 108,000 deaths linked to drug overdose in 2022 (CDC). Though fentanyl is a μ opioid receptor agonist, it demonstrates enhanced lipophilicity, heightened potency to induce respiratory depression, and more rapid central nervous system entry compared to certain other opioids, i.e., morphine. However, there are relatively few biodistribution comparison studies of fentanyl and classical opioids like morphine in mice, despite the use of mice as preclinical models of opioid effects, i.e., respiratory depression. Therefore, the current study compared acute fentanyl (0.3 mg/kg) and morphine (30 mg/kg) biodistribution in blood and 12 tissues at doses causing respiratory depression in male Swiss Webster mice. Whole-body plethysmography was used to select fentanyl and morphine doses producing comparable respiratory depression, and an LC/MS-MS protocol was developed to quantify fentanyl, morphine, and metabolites in diverse tissue samples. Drug distribution time courses varied by tissue, with fentanyl and morphine displaying similar time courses in the lung, stomach, and small intestine, but differing in the brain and spleen. Fentanyl exhibited greater distribution out of the blood and into the brain, liver, lung, and heart than morphine early after administration and out of the blood into fat at later time points after administration. The ratios of total drug distribution (area under the curve) in tissue–blood over time suggest that fentanyl accumulation in tissue relative to blood in several areas, such as lung, heart, kidney, spleen, fat, and small intestine, is greater than morphine. These findings indicate that fentanyl administration may affect several organs to a larger degree than morphine. Full article

This narrative review explores the utilization of psychedelic states in therapeutic contexts, deliberately shifting the focus from psychedelic substances back to the experiential phenomena which they induce, in alignment with the original meaning of the term “mind-manifesting”. This review provides an overview of various psychedelic substances used in modern therapeutic settings and ritualistic indigenous contexts, as well as non-pharmacological methods that can arguably induce psychedelic states, including breathwork, meditation, and sensory deprivation. While the occurrence of mystical experiences in psychedelic states seems to be the strongest predictor of positive outcomes, the literature of this field yields several other psychological processes, such as awe, perspective shifts, insight, emotional breakthrough, acceptance, the re-experiencing of memories, and certain aspects of challenging experiences, that are significantly associated with positive change. Additionally, we discuss in detail mystical experience-related changes in metaphysical as well as self-related beliefs and their respective contributions to observed outcomes. We conclude that a purely medical and neurobiological perspective on psychological health is reductive and should not overshadow the significance of phenomenological experiences in understanding and treating psychological issues that manifest in the subjective realities of human individuals. Full article

Alkyl nitrites (“poppers”) are a diverse class of volatile chemical compounds with a varied legal and medical history. Though once commonly prescribed to treat angina, popper use is now almost exclusively recreational. Currently, poppers are widely available and sold legally under labels like “solvent cleaner”, despite marketing suggesting they are meant to be consumed. As a result, there is little incentive for producers to implement robust quality controls to protect users. In this study, nine common popper brands were analyzed using hydrogen-1 and carbon-13 nuclear magnetic resonance spectroscopy to assess the presence of impurities. Physical labels on all nine samples indicated the contents were “pure” isobutyl nitrite, despite contradictory online marketing in several cases. Spectral results showed isobutyl nitrite was present in all popper samples. However, there was evidence that various unlabeled compounds were also present in all samples. The identity and concentration of these contaminants were not clear, but the seemingly ubiquitous presence of impurities and lack of consistency in the tested samples are concerning and may represent a threat to users’ health. We hope the results of this study draw attention to the potential dangers of recreational popper use and the need to reassess how these compounds are regulated. Full article

Research on the use of cannabis rectal suppositories for analgesia is limited. Few trials have evaluated the combined use of mindfulness and cannabis suppositories for anodyspareunia in men who have sex with men (MSM). This preliminary study, including a randomised control trial (RCT) and content analysis, assessed the effectiveness of an online mindful-compassion and cannabis suppository intervention among 52 British MSM (aged 18–50) who predominantly identified as bottoms (recipients of anal sex). Participants were randomly allocated to one of four groups based on whether they were using cannabis suppositories: adjunct cannabis suppository and mindful-compassion (CSMF), cannabis suppository only (CS), mindful compassion only (MF) and care as usual/control (CAU). Assessments measuring mindful compassion, sexual functioning, sexual self-efficacy, well-being, and anodyspareunia levels were completed at weeks 0, 4, and 12. Anodyspareunia levels were lower in the CSMF group compared to the other groups (CS/MF/CAU), p = 0.031. Feedback revealed that participants felt mindful compassion potentiated the effects of cannabis suppositories during sexual intimacy, reducing pain and enhancing sexual self-efficacy, sexual functioning, and well-being. This preliminary study warrants larger-scale investigation to establish the role of cannabis suppositories and mindful compassion in reducing anodyspareunia. Full article

Synthetic cannabinoids are a rapidly evolving, diverse class of new psychoactive substances. Synthetic cannabinoid use results in a higher likelihood of adverse events and hospitalization when compared to cannabis use. The mechanisms behind synthetic cannabinoid toxicity remain elusive. Furthermore, poly-substance use may be a significant contributing factor in many cases. This scoping review aimed to identify the key characteristics of synthetic cannabinoid co-exposure cases and discuss the potential implications of poly-substance use in humans. There were 278 human cases involving 64 different synthetic cannabinoids extracted from the databases. Cases involved a total of 840 individual co-exposures, with an average of four substances involved in each case. The most common co-exposures were alcohol (11.4%), opioids (11.2%), and cannabis (11.1%). When analyzed by case outcome, co-exposure to either antipsychotics/antidepressants, alcohol, or tobacco were significantly associated with mortality as an outcome (p < 0.05). Drug-use history (63.4%), mental illness (23.7%), and hypertensive and atherosclerotic cardiovascular disease (20.1%) were prevalent patient histories in the case cohort. There are several potential pharmacodynamic and pharmacokinetic interactions between co-exposure drugs and synthetic cannabinoids that could worsen clinical presentation and toxicity in synthetic cannabinoid users. Individuals with substance-use disorders or psychiatric illness would be especially vulnerable to these multi-drug interactions. Further research into these complex exposures is needed for the successful prevention and treatment of synthetic cannabinoid-related harms. Full article

Psychedelics, combined with talk therapy, indicate promise with challenging clients, such as those struggling with PTSD. Furthermore, groupwork, with the emphasis on social connections, can be an effective modality. There appears, however, little movement with integrating psychedelics with professional counseling and even less in groupwork. Societal perceptions of psychedelics and the concern of practicing outside one’s scope may cause practitioners to hesitate. This article provides a brief overview for the lack of progression in implementing psychedelics in group counseling. I explain what potentially inhibits the utilization of psychedelics, then offer a resolution to these issues by advocating for a psychedelic-assisted groupwork (PAG) model. The argument is that psychedelic approaches can be an innovative and transformative method for group facilitators. I conclude with an overview depicting what a PAG with an interdisciplinary team could entail, including recruitment, screening, selection, therapeutic processes, and termination. Full article

Substance use/abuse and suicide are two closely related phenomena, mostly due to neurobiological, psychological, and social impairments. In the present narrative review, the relationship between suicidal behavior (SB) and the use and abuse of common recreational drugs, such as alcohol, cannabis, cocaine, methamphetamine, heroin, nicotine, ketamine, psilocybin, MDMA, and LSD, has been explored. Furthermore, potential mechanisms linking the two have also been examined. According to current research, all substances appear to have a deleterious effect on SB except for ketamine and psilocybin, which could potentially confer a protective effect. Further studies are needed to understand the relationship between MDMA, LSD, and suicide. Full article

Methamphetamine use disorder (MuD) is a global health problem, with no FDA-approved medications. Our prior work demonstrated that repeated methamphetamine exposure alters the gut microbiota in male rats and results in depressive-like behaviors. In this study, we extend our findings to females and determine whether probiotics block these effects. Male and female rats were administered methamphetamine (2 mg/kg; SC) or saline twice daily with either a combination of two probiotics (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) or placebo solution for 14 days. Fecal samples were collected at baseline and other days after treatment cessation. Tests of anxiety- and depressive-like behaviors were conducted using open-field and forced-swim assays. Methamphetamine induced anxiety-like behavior in females and anxiety-like and depressive-like behaviors in males. Probiotics blocked the depressive-like effect in males but did not alter anxiety-like effects in either sex. Methamphetamine exposure decreased levels of alpha diversity in both sexes, but sex differences were seen in the ability of probiotics or methamphetamine to alter levels of various bacteria. These findings support the role of the gut–brain microbiome in the depressive effects of repeated methamphetamine exposure in males, suggesting that probiotics may be a viable treatment option for MuD. Full article

Because psychedelics have been found to increase psychological traits like openness, mental flexibility, and interpersonal perceptiveness, some researchers believe that psychedelics could help individuals cope with the psychological effects of discrimination. However, it is still unclear whether psychedelic use can help manage the internalized stigma that deters formal mental health treatment. This study investigates the impact of six measures of psychedelic use (MDMA, psilocybin, DMT, ayahuasca, peyote/mescaline, and LSD) on psychological distress (Kessler Psychological Distress Scale) and internalized stigma. The study used data from the National Survey of Drug Use and Health (NSDUH) from 2008 to 2019, with a sample size of 458,372 participants. Ordinary least square regression models were conducted using Stata 18. Gender analysis found that among men, ayahuasca use was linked to reduced stigma perception associated with higher distress. For women, DMT use was linked to reduced stigma perceptions when experiencing higher distress. However, results find that individuals who have used MDMA and psilocybin reported heightened perceptions of stigma associated with increased psychological distress. Among women, MDMA and psilocybin use was associated with a higher perception of stigma when they experienced distress. These findings suggest that, overall, psychedelics may not reduce the impact of distress on the perception of stigma, especially for women. Full article

Drug abuse represents a significant public health problem with a growing tendency. As a way of circumventing the strict national and international control of psychoactive substances by regulatory agencies, there is a market release of new substances with psychoactive activity, called New Psychoactive Substances (NPSs). This group of substances encompasses a diverse range of synthetic compounds designed to mimic the effects of traditional illicit substances. As NPSs show stronger psychoactive effects than classical drugs, they pose unique challenges to public health and regulatory frameworks. Additionally, some substances are considered NPSs in some countries but not in others. Therefore, based on a given legal definition, manufacturers can create an NPS that does not fall under that definition and thus is not prohibited. This review critically explores the multifaceted dimensions of the criminal and legal contexts associated with NPSs. It examines the trends of abuse, the intricate network of criminal and legal aspects surrounding these substances, and the crucial warning signs that indicate their emergence, highlighting the health risks posed by these substances. In conclusion, this manuscript addresses the intricate interplay between the pharmacology, risks, and regulatory responses. These multifaceted challenges associated with NPSs will likely provide valuable insights for future research. Full article

Novel psychoactive substances (NPSs) are compounds plotted to modify the chemical structures of prohibited substances, offering alternatives for consumption and evading legislation. The prompt emergence of these substances presents challenges in health concerns and forensic assessment because of the lack of analytical standards. A viable alternative for establishing these standards involves leveraging in silico methods to acquire spectroscopic data. This study assesses the efficacy of utilizing infrared spectroscopy (IRS) data derived from density functional theory (DFT) for analyzing NPSs. Various functionals were employed to generate infrared spectra for five distinct NPS categories including the following: amphetamines, benzodiazepines, synthetic cannabinoids, cathinones, and fentanyls. PRISMA software was conceived to rationalize data management. Unsupervised learning techniques, including Hierarchical Cluster Analysis (HCA), Principal Component Analysis (PCA), and t-distributed stochastic neighbor embedding (t-SNE), were utilized to refine the assessment process. Our findings reveal no significant disparities among the different functionals used to generate infrared spectra data. Additionally, the application of unsupervised learning demonstrated adequate segregation of NPSs within their respective groups. In conclusion, integrating theoretical data and dimension reduction techniques proves to be a powerful strategy for evaluating the spectroscopic characteristics of NPSs. This underscores the potential of this combined methodology as a diagnostic tool for distinguishing IR spectra across various NPS groups, facilitating the evaluation of newly unknown compounds. Full article

College students are a primary population for risky alcohol use behaviors, with one of every eleven students grappling with severe alcohol-related issues. The objective of this scoping review was to synthesize the existing literature to identify factors influencing the prevalence of drinking and driving (DAD) behaviors among college students. A scoping review was conducted using Medline (PubMed), ERIC, The American Journal on Addictions, and the NCHA databases. Criteria for article selection included being published in English and focused on DAD behaviors among college students. Articles excluded from the review were systematic reviews and discussion pieces without empirical findings related to college DAD. Of the included studies (n = 23), most identified a range of factors as being influential in college students’ DAD behavior including a family history of alcohol misuse, the use of other substances such as marijuana, age of initial alcohol consumption, place of residence, propensity for sensation seeking, affiliation with sorority/fraternity groups, and the perception of associated risks. Effective strategies may include education on the risks of combined alcohol and substance use, screening and brief interventions tailored to at-risk students, and the implementation of campus policies that promote responsible alcohol consumption and deter DAD. Full article

Meldonium, a promising pharmacological agent initially developed for cardiovascular indications, has sparked considerable interest in recent years due to its potential performance-enhancing effects. This review manuscript delves into the multifaceted roles of meldonium, examining its pharmacological mechanisms, therapeutic applications, and controversial implications in medicine. Beyond its cardiovascular applications, emerging research has shed light on meldonium’s neuroprotective properties and its potential for mitigating various psychiatric conditions. Moreover, recent investigations have explored meldonium’s potential in treating neurodegenerative disorders, alcohol use disorder, and even enhancing cognitive function. However, meldonium’s journey extends beyond the realm of medicine, as its use among athletes has stirred debates surrounding performance enhancement and fair competition. The substance’s inclusion in the World Anti-Doping Agency’s (WADA) prohibited list has intensified scrutiny and raised ethical considerations regarding its use in sports. This manuscript aims to provide a comprehensive resource for researchers, clinicians, and enthusiasts alike, fostering a deeper understanding of meldonium’s complex biological interactions and its potential contributions to psychiatry. Full article