Psychoactives

Alcohol Use Disorder (AUD) profoundly impacts individuals and society, driven by neurobiological adaptations that sustain chronicity and relapse. Emerging research highlights neuroinflammation, particularly microglial activation, as a central mechanism in AUD pathology. Ethanol engages microglia—the brain’s immune cells—through key signaling pathways such as Toll-like receptor 4 (TLR4) and the NLRP3 inflammasome, triggering the release of proinflammatory cytokines (IL-1β, TNF-α, IL-6). These mediators alter synaptic plasticity in addiction-related brain regions, including the ventral tegmental area, nucleus accumbens, amygdala, and lateral habenula, thereby exacerbating cravings, withdrawal symptoms, and relapse risk. Rodent models reveal that microglial priming disrupts dopamine signaling, heightening impulsivity and anxiety-like behaviors. Human studies corroborate these findings, demonstrating increased microglial activation markers in postmortem AUD brains and neuroimaging analyses. Notably, sex differences influence microglial reactivity, complicating AUD’s neuroimmune landscape and necessitating sex-specific research approaches. Microglia-targeted therapies—including minocycline, ibudilast, GLP-1 receptor agonists, and P2X7 receptor antagonists—promise to mitigate neuroinflammation and reduce alcohol intake, yet clinical validation remains limited. Addressing gaps such as biomarker identification, longitudinal human studies, and developmental mechanisms is critical. Leveraging multi-omics tools and advanced neuroimaging can refine microglia-based therapeutic strategies, offering innovative avenues to break the self-sustaining cycle of AUD. Full article

States like Hawai‘i are decriminalizing psychedelics based on emerging evidence linking their use to improved psychological well-being. Yet, in many cultural contexts, stigma surrounding mental illness may lead individuals to pursue non-traditional forms of healing, including psychedelics, in place of formal care. This study examines how psychedelic use relates to mental health treatment-seeking behaviors among Asians and Native Hawaiians and Other Pacific Islanders (NHOPIs). Using the National Survey of Drug Use and Health (NSDUH) data from 2008 to 2019 (n = 458,372), the analysis compares Non-Hispanic Whites with Asian and NHOPI respondents to assess associations between MDMA and lifetime classic psychedelic use, psychological distress (K6 scale), and formal mental health service utilization. Nested logistic regression models conducted in Stata 18 indicate that psychedelic use among White individuals is associated with a lower likelihood of seeking formal treatment. In contrast, among NHOPI individuals, psychedelic use is associated with increased odds of accessing mental health care. These findings suggest that psychedelic use may serve culturally distinct roles in coping with distress, shaped by structural stigma and the perceived trustworthiness of formal treatment systems. Full article

Dementia is a progressive neurodegenerative disease which is characterised by cognitive decline, memory loss, and behavioural changes. Patients suffering from dementia often experience emotional distress, sadness and depression which also impacts the wellbeing of their caregivers. Recent research has explored the potential of psychedelics, such as psilocybin and LSD, when treating various mental health conditions. Psychedelics are known to alter perception, mood and cognition by affecting serotonin receptors in the brain. Studies suggest that psychedelics may be a promising treatment for dementia patients and promote neuroplasticity, reduce neuroinflammation and enhance cognitive flexibility. These effects could potentially lead to a reduction in the progression of neurodegenerative diseases and improve the patients’ quality of life. Additionally, psychedelics might contribute to the prevention of dementia by fostering brain health and resilience against age-related decline. The application of psychedelics in dementia care might pose significant safety and ethical concerns. The present paper provides a narrative review of the existing literature on the use of psychedelics in treatment of dementia and its different types (Alzheimer’s) with the aim to raise awareness on the topic from a critical perspective. Full article

Psychedelic substances have experienced a resurgence of clinical interest in recent years, particularly for their promising effects in the treatment of psychiatric disorders such as depression and anxiety. While evidence regarding their role in chronic pain management remains limited, emerging studies suggest potential therapeutic benefits. This case report describes a patient with persistent somatoform pain disorder and recurrent depressive disorder who underwent four sessions of psilocybin-assisted psychotherapy. The intervention was associated with a reduction in the negative impact of pain on daily life, increased pain acceptance, improved quality of life, and reduction in depressive symptoms. These findings contribute to the growing body of literature suggesting that psychedelics, when combined with psychotherapy, may offer a novel and holistic approach to the treatment of chronic pain. Further controlled studies are needed to explore the safety, efficacy, and underlying mechanisms. Full article

This review synthesizes preclinical evidence on the behavioral and neurobiological effects of cannabis exposure during prenatal and adolescent developmental periods, with a focus on anxiety, social behavior, learning and memory, and associated brain changes. Understanding the differential impact of cannabis exposure across these windows is critical, given the increasing prevalence of cannabis use and the rising potency of its primary psychoactive component, delta-9-tetrahydrocannabinol (THC). Both prenatal and adolescent periods represent vulnerable windows for disruption of the endocannabinoid system, which plays a central role in typical neurodevelopment. Exogenous activation of this system via THC can lead to atypical brain maturation and subsequent behavioral impairments. These impairments are associated with region-specific alterations in cortical and subcortical structures and are highly dependent on the timing of exposure. For instance, prenatal exposure may disrupt medial prefrontal cortex development, leading to long-term social deficits while sparing memory function. In contrast, adolescent exposure tends to impair hippocampal function, resulting in learning and memory deficits. The manuscript is organized developmentally, beginning with the effects of prenatal exposure and then discussing consequences of adolescent exposure. By delineating the distinct behavioral and neurobiological outcomes associated with the timing of cannabis exposure, this review highlights the importance of developmental stage in assessing the risks of exogenous cannabinoid use and identifies critical periods for targeted research and intervention. Full article

Numerous individuals suffer from mental health issues including depression and anxiety, resulting in substantial societal burden. Data suggests individuals are choosing to self-medicate with Novel Psychoactive Substances (NPS); however, this phenomenon is poorly understood. We aimed to investigate which NPS are being used to self-medicate, evaluate their perceived effectiveness and examine influencing factors. Data from respondents (n = 274) (Mean Age [SD] = 29.8 ± 9.1, Male = 71%, Female = 18%, non-binary 5%) were collected via an online survey, with five participants (male = 2; nonbinary = 3) undertaking further semi-structured interviews and the data examined using a Framework analysis. NPS used included bromazolam, etizolam, clonazolam, 1P-LSD and 2-FDCK. Individuals perceived self-medication to be more effective than conventional treatment (p < 0.001). A Framework analysis identified the following themes surrounding mood and anxiety disorder self-medication: (1) depression being chronic, treatment resistant and often comorbid; (2) individuals attempting to mimic existing treatments; (3) individuals having high levels of pharmacological knowledge; (4) difficulties in controlling benzodiazepine self-medication. This study brings important insight into self-medication practices with NPSs, adding to data demonstrating an increase in bromazolam use. Data suggests self-medication follows conventional treatment and, therefore, we outline the importance of affordable emerging treatment options for depression and anxiety. Full article

This study estimates the prevalence of co-use of alcohol and cannabis, assesses the sociodemographic risk factors of co-use, and examines the associations between mental health and heavy episodic drinking (HED) and alcohol–cannabis co-use in Canada during the early years of the COVID-19 pandemic. Nine successive cross-sectional surveys, held from May 2020 to January 2022, of adults (aged ≥18 years) living in Canada were pooled for 9011 participants. The prevalence of co-use was calculated across sociodemographic groups. Logistic regressions were used to assess associations. Alcohol–cannabis co-use was associated with a greater likelihood of engaging in HED and experiencing symptoms of anxiety, depression, and loneliness. The prevalence of co-use of alcohol was different across sociodemographic groups. The highest prevalence was among TGD people (35.5%), followed by individuals aged 18–39 years (14.5%). Additionally, being TGD (aOR = 3.61, 95% CI 2.09–6.25), separated/divorced/widowed (aOR = 1.60, 95% CI 1.23–2.07), living in an urban area (aOR = 1.26, 95% CI 1.07–1.56), and having a high household income (aOR = 1.41, 95% CI 1.09–1.82) increased the likelihood of reporting alcohol–cannabis co-use. These findings underscore the fact that developing public health and clinical interventions for preventing and treating excessive alcohol or cannabis use must consider both alcohol and cannabis use patterns and should be tailored to the highest-risk TGD and young adults. Full article

Despite growing evidence supporting the efficacy of LSD-assisted psychotherapy in treating major depressive disorder (MDD), identifying reliable psychopharmacological biomarkers remains necessary. Oxytocin, a neuropeptide implicated in social bonding and flexibility, is a promising candidate due to its release following serotonergic psychedelic administration in healthy individuals; however, its dynamics in psychiatric populations are currently unexplored. This observational pilot study aimed to characterize salivary oxytocin dynamics during a single LSD-assisted psychotherapy session in our patients with treatment-resistant MDD. Participants received 100 or 150 µg LSD, and salivary oxytocin was measured at baseline, 60, 90, and 180 min post-LSD. Concurrently, participants rated subjective drug intensity (0–10 scale) at 60, 90, and 180 min. A linear mixed model revealed significant variation of oxytocin levels over time. Perceived psychedelic intensity also significantly varied over time. This supports oxytocin as a potential biomarker. Larger, controlled trials are warranted to replicate these findings and clarify the mechanistic links between oxytocin dynamics and clinical outcomes, including changes in depressive symptoms and mental flexibility. Full article

Shaboo is a street name commonly used in parts of Asia, particularly the Philippines and Thailand, to refer to methamphetamine, a powerful and highly addictive stimulant. Its long-term effects are related to chronic exposure to the drug effects, primarily neurotoxicity phenomena, which could lead to cognitive impairment, or psychiatric symptoms. We aim to present one case of problematic shaboo use in a patient referring to an addiction outpatient clinic in Northern Italy. This case highlights that the treatment of these patients involves careful multidisciplinary management. An accurate knowledge of the physical and psychological effects of New Psychoactive Substances is essential, as well as the implementation of a tailored psychological and social support program. Full article

Pain is a protective mechanism that can be classified into acute and chronic types. Ayahuasca is a psychoactive brew rich in dimethyltryptamine or DMT (a 5-HT_2A receptor agonist), and harmine (a monoamine-oxidase (MAO) inhibitor) used for religious and therapeutic purposes. Previous preclinical and anecdotal evidence suggests that ayahuasca and its compounds have antinociceptive and anti-inflammatory effects due to 5-HT_2A agonism and MAO inhibition. Thus, the current study aims to provide a systematic review of the antinociceptive and anti-inflammatory effects of ayahuasca and its alkaloids in preclinical models. All studies published up to December 2024 were screened and evaluated for eligibility. A total of 1535 publications were identified, of which 29 adhered to the predefined criteria. Reviewed articles reported antinociceptive effects of ayahuasca, harmine, and harmaline. Regarding anti-inflammatory effects, the compounds of ayahuasca, especially harmine, have demonstrated a reduction and an increase in pro-inflammatory and anti-inflammatory cytokines, respectively. Although there are promising results regarding the antinociceptive and anti-inflammatory effects of ayahuasca and its alkaloids, further investigation is needed. Full article

Canada’s national surveillance shows an 11% year-over-year decline in deaths from opioid and other unregulated drug poisonings, and a 10% drop in related hospitalisations in 2024. In stark contrast, Québec, home to more than nine million residents, and Montréal, the country’s second-largest city, experienced a continued rise in suspected drug-poisoning mortality through 2024, with fentanyl or analogues detected in almost two-thirds of opioid deaths. We conducted a narrative synthesis of provincial coroner and public-health surveillance tables, Health Canada dashboards, and the 2022–2025 Québec Strategy on Psychoactive-Substance Overdose Prevention. Results indicate a 40% increase in opioid-related mortality since 2018, a parallel uptick in stimulant toxicity, and a five-fold rise in overdose reversals at Montréal supervised-consumption services during the COVID-19 pandemic recovery. We aim to summarise the key problems underlying this epidemic and offer province-specific public-health strategies while also sending a call to action for first-line clinicians and psychiatrists to integrate overdose-risk screening, take-home naloxone, and stimulant-use-disorder treatments into routine care. We further urge Québec healthcare professionals to deepen their knowledge of provincial services such as supervised-injection sites and stay up to date with the rapidly evolving substance-use-prevention literature. Québec’s divergent trajectory underscores the need for region-tailored harm-reduction investments and stronger policy-to-clinic feedback loops to reduce preventable deaths. Full article

Background: Persisting symptoms after concussion is a complex syndrome warranting exploration into further treatment options. Emerging research highlights the potential of classic psychedelics, such as psilocybin, in managing neuropsychiatric conditions and promoting neuroprotection. Case Report: A case is presented of a 22-year-old male intercollegiate athlete who sustained a concussion and developed persisting symptoms despite multidisciplinary standard care. The symptom burden remained relatively stable for the first month post-concussion. He independently administered three 250 milligram (mg) doses of the dried fruiting body of Psilocybe cubensis (2.5 mg of psilocybin) on days 42, 45, and 46 post-injury. He reported immediate symptom relief, including improvements in headache, noise sensitivity, and cognitive function. His symptom severity score decreased from 25 to 11 and his affective symptom burden resolved completely. Functional improvements allowed him to return to full activity. No adverse effects were reported. Conclusions: This case highlights the potential role of classic psychedelics as adjuvant agents in treating persisting symptoms after concussion. Clinicians should be aware that athletes may explore psychedelics as alternative treatments. Further research is needed to evaluate the efficacy and safety of psilocybin in concussion recovery. Full article

Psychedelic treatments are emerging as promising interventions for many mental health conditions. These interventions are not offered in a standardized fashion across studies and between different healthcare centers. Beyond differences in substances and doses, there is also a great heterogeneity in the interventions provided by therapists. The current review offers a summary of important elements that should be reported when describing psychedelic-assisted therapies. Clinical trials involving psilocybin for depression are systematically reviewed to synthesize available descriptions of their interventions. This review demonstrates that the exact nature of these psychotherapeutic interventions tends to be poorly defined in most scientific papers on psychedelic treatments. This problem and its implications are examined. The field stands to gain from optimized psychotherapeutic methods; however, insufficient documentation in scientific papers currently hinders the dissemination and improvement of evidence-based protocols. This article offers ideas to encourage the progress of research on psychedelic-assisted therapies. Full article

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