Psychoactives, Volume 4, Issue 4 (December 2025) – 5 articles

Today’s research highlights the therapeutic potential of the hallucinogen psilocybin in the treatment of pathologies associated with mood, cognitive, and affective dysregulation. These domains of function are regulated by the serotonergic system, which can be influenced by sex hormones, like estrogen and testosterone, and psychedelic compounds including psilocybin. Current evidence supports a higher prevalence of affective disorders in females, and a growing awareness of sex-based differences in response to drug therapy. Estrogen’s influence on serotonin physiology is an aspect that must be accounted for when planning a treatment regimen that includes a psychoactive drug such as psilocybin. A review of the current literature was conducted, and an analysis of how the fluid hormonal states in females across their different reproductive phases may impact serotonin dynamics, synaptic plasticity, and therapeutic timing of psilocybin use is discussed. Future research should focus on the influence of sex hormones on psychedelic-assisted therapy in the effort to further personalize treatment plans for these pathologies. Full article

Opioid misuse and suicide among youth remain pressing public health challenges. This scoping review examined studies published between 2020 and 2024 on associations between opioid misuse and suicidal ideation, suicide attempts, or non-suicidal self-injury (NSSI) among adolescents and young adults aged 12–30, emphasizing sex and racial or ethnic differences. Guided by Arksey and O’Malley’s framework and PRISMA-ScR, we searched MEDLINE (PubMed), PsycINFO, Scopus, Embase, and CINAHL for peer-reviewed cross-sectional studies in English. Eligible studies assessed nonmedical prescription or illicit opioid use and excluded clinical or incarcerated samples and those with older participants. Seventeen studies met the inclusion criteria. Fifteen analyzed U.S. national or state data, one examined youth in the Northern Mariana Islands, and one used Canadian data. Sixteen studies identified a positive association between opioid misuse and suicide-related outcomes, while one showed a recency gradient, with current misuse carrying the highest risk. Other findings showed that frequent misuse increased risk, multiple substance use heightened danger, and females and youth from racial and ethnic minority groups were more vulnerable. Opioid misuse is strongly associated with suicide risk. Integrated, sex- and culturally responsive prevention strategies are needed, alongside further research clarifying mechanisms and protective factors. Full article

Medetomidine, a potent central acting α2 agonist, has emerged as a fentanyl adulterant in the non-medical opioid supply. Its use has been linked to a novel withdrawal syndrome that is often resistant to conventional treatment protocols. Four cases are presented exemplifying extreme, but increasingly common forms of this withdrawal syndrome. A literature review is provided demonstrating both the paucity of available literature as well as potential avenues for treatment and future research. As adulterants continue to proliferate in the illicit drug supply, clinicians should anticipate atypical withdrawal phenotypes and consider early intervention. Full article

Cannabis use (CU) motives among older adults (OA) could be an important indicator of broader mental health. OA ages 60+ (N = 78) reported on CU, alcohol consumption, and mood and anxiety. Coping, enhancement, social, conformity, expansion, and routine motives were assessed. Relationships among CU, alcohol consumption, and screenings for Cannabis Use Disorder (CUD), Alcohol Use Disorder (AUD), depression, and anxiety were examined. OA who screened positive for CUD were not different in CU frequency or alcohol consumption, but did endorse higher routine, social, coping, and conformity motives than OA endorsing non-harmful CU (d = 1.01 to 1.70). Participants who screened positive for depression or anxiety endorsed higher coping (d = 1.87, 2.18) and routine (d = 0.83, 0.85) motives in the absence of higher alcohol or CU. Higher routine motives were particularly associated with positive CUD screening, beyond other motives and CU frequency. Healthcare providers serving OA with CU should ask about motives to help determine if further mental health evaluation is warranted. Full article

Psychedelic-assisted therapy offers rapid and profound benefits for treatment-resistant psychiatric conditions but remains constrained by the need for intensive, clinic-based administration. Concurrently, advances in digital health technologies have introduced scalable tools. This systematic review evaluates the safety, efficacy, and implementation of digitally enabled psychedelic-assisted therapy delivered in non-clinical settings. A comprehensive search of five databases, registered in PROSPERO (CRD420251020968) and conducted in accordance with PRISMA guidelines, identified six eligible studies including real-world analyses, clinical trials, qualitative research, and case reports, representing a total of 12,731 participants. Most studies examined at-home ketamine or esketamine therapy supported by telehealth platforms or mobile applications. Data were synthesized narratively given the heterogeneity of designs and outcomes. Digital enablement was associated with high response rates (ranging from 56.4% to 62.8% for depression) and rapid symptom improvement, particularly in depression and anxiety. Remote monitoring and digital tools demonstrated feasibility and acceptability, but serious safety concerns—including psychiatric adverse events and one unintentional overdose—underscore the need for strict oversight. Risk of bias was moderate to serious across non-randomized studies, limiting confidence in the findings. One study on virtual ayahuasca rituals highlighted the sociocultural potential and limitations of online practices. Despite promising preliminary findings, the field is marked by low methodological rigor and absence of controlled trials. Digitally supported at-home psychedelic therapy represents a transformative but high-stakes frontier, requiring robust research and safeguards to ensure safe, equitable, and effective implementation. No funding was received for this review, and the authors declare no conflicts of interest. Full article