Psychoactives, Volume 3, Issue 4 (December 2024) – 8 articles

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