Journal of affective disorders • November 1, 2026 • Dian-jeng Li, Tien-Wei Hsu, Te-chang Changchien et al.
Patients with major depressive disorder who are prescribed esketamine have higher rates of comorbid substance use disorders compared to those treated with antidepressants or repetitive transcranial magnetic stimulation. Among esketamine users, those with a substance use disorder face greater risks of self-harm, suicide attempt, emergency visits, hospitalization, and mortality. The findings indicate a prescription bias toward patients with comorbid substance use disorders and highlight the need for careful monitoring and specialized care for this population.
July 12, 2026 • Fahd François Hilal, Méléna Dreinaza, Quentin Lebel et al.
S-ketamine, but not R-ketamine, dose-dependently suppresses binge-like alcohol self-administration in male rats, with the strongest effect at 40 mg/kg. This suppression is selective, occurring without sedation or motor impairment, and is most pronounced on front-loaded drinking. However, the effect rapidly diminishes with repeated doses, indicating rapid tolerance. R-ketamine does not alter alcohol intake under the same conditions, nor does prior R-ketamine exposure affect subsequent S-ketamine efficacy. The findings suggest that stereochemistry, dosing schedule, and alcohol exposure pattern are key determinants of ketamine's potential for treating alcohol use disorder.
Frontiers in Psychiatry • July 9, 2026 • Alqassem Y. Hakami
Ketamine, a drug that rapidly alters brain connections, shows promise for treating both treatment-resistant depression and substance use disorders, particularly alcohol and cocaine addiction. When combined with psychotherapy, small-to-moderate Phase 2 trials found it reduced cravings and increased days of abstinence. However, results vary widely due to differences in dosing, comparison treatments, and follow-up lengths, and effects on preventing relapse have been inconsistent. Ketamine works by blocking NMDA receptors and boosting synaptic plasticity, which may help disrupt harmful reward memories. While supervised use causes only temporary side effects, the drug carries a clear risk of misuse, especially without supervision. Larger, longer studies are needed before it becomes standard care.
Expert Opinion on Drug Discovery • July 4, 2026 • Christopher D. Verrico, Lynnette A. Averill, Cameron J Moore et al.
Ibogaine, a natural alkaloid, shows potential for treating substance use disorders, trauma, mood disorders, and suicidality, but clinical use is limited by safety concerns and regulatory barriers. Researchers are pursuing two main strategies: developing ibogaine-like compounds that keep broad effects while reducing risks, and creating selective 'bespoke' analogs targeting specific conditions like opioid use disorder, traumatic brain injury, or PTSD. The authors emphasize that the field should avoid oversimplified views that derivatives are uniformly better or interchangeable, and call for greater conceptual clarity and mechanistic humility as ibogaine-based therapies move toward regulated medical use.
BMJ Open • July 1, 2026 • Kirsten C. Morley, S Arunogiri, Katherine L. Mills et al.
Combining MDMA with an integrated exposure-based therapy may improve outcomes for people with both post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD), a comorbidity where standard treatments help only about half of patients. This double-blind trial will randomly assign 100 participants to receive either MDMA (80–160 mg) or an active control (niacin 250 mg) alongside 12 sessions of Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure (COPE). The primary PTSD outcome is the clinician-administered PTSD Scale for DSM-5; the primary drinking outcome is heavy drinking days per week, validated by phosphatidylethanol. Secondary measures include depression, sleep disturbances, adverse events, and cost-effectiveness. Results will provide first data on safety, efficacy, and cost-effectiveness of MDMA-augmented therapy for this comorbidity.
Revista CienciaUANL • July 1, 2026 • Armando Ordaz‐hernández, M. Corona-ramírez, Israel Jesús Orlando Guerrero
Psilocybin from magic mushrooms and 5-MeO-DMT from the Incilius alvarius toad, used ancestrally in Mexican spiritual rituals, are now recognized as promising therapies for depression, anxiety, PTSD, and treatment-resistant addictions. These substances act on serotonin receptors and stimulate neuroplasticity, helping the brain adapt and overcome negative mental patterns. Although further clinical studies are needed, their traditional use inspires therapies that integrate ancestral knowledge with modern science to improve emotional well-being.
American Journal of Medicine and Health Studies • June 26, 2026 • Mehrdad F. Falavarjani
A spiritually oriented intervention that emphasizes self-transcendence and identity transformation helped a person with substance use disorder move from an addiction-centered identity toward a more integrated spiritual self. Through narrative reconstruction and contemplative practices, the participant became better able to engage with everyday life, suggesting that reorganizing identity through spiritual approaches may be an important mechanism of change in treatment.
Pharmacological Reports • June 22, 2026 • Magdalena Zaniewska
Serotonin (5-HT) is a key neuromodulator involved in mood, appetite, aggression, and impulse control. Dysregulation of central 5-HT function is implicated in alcohol use disorder (AUD) and comorbid depression. Reduced 5-HT activity increases the risk of developing AUD, particularly Cloninger's type II, characterized by early onset, violent, and antisocial behaviors. Tph2-deficient mice, which lack central 5-HT, exhibit increased ethanol consumption and behavioral features resembling type II alcohol dependence. Alcohol-preferring rat lines show reduced 5-HT levels, decreased serotonergic projections to the cortex, and reduced prefrontal 5-HT2A receptor binding. The efficacy of selective 5-HT reuptake inhibitors (SSRIs) is limited, with beneficial effects only in less severe, later-onset forms. Serotonergic psychedelic-assisted therapies may activate 5-HT2A receptors in the prefrontal cortex, a region dysfunctional in AUD.
Journal of Psychoactive Drugs • June 19, 2026 • Carla J. Berg, Darcey M. Mccready, Cassidy R. Loparco et al.
Among a sample of young adults with high rates of past-month cannabis use, lifetime and past-year psychedelic use were 27.7% and 11.9%, respectively, with psilocybin/amanita, MDMA, and LSD being most common. Nearly half used psychedelics only for nonmedical purposes. Of those who had ever used, 26.5% had microdosed. Older age, male sex, Black race, metropolitan residence, more depressive symptoms, and more adverse childhood events were linked to lifetime use. Microdosing was associated with not having children, more anxiety, and more adverse childhood events. Mental health symptoms and adverse childhood events were also tied to higher use motives, including expansion, mood enhancement, and symptom management.
Leiden Repository • June 18, 2026 • W.c. Naber
Cluster headache is characterized by recurring 'waves' of attacks. Long-term remission is linked to episodic disease, later onset age, more painful attacks, and smoking cessation, suggesting smoking may play a role in disease development. People with cluster headache more often use psilocybin and LSD, with some reporting reduced attack frequency or duration. Risk-taking behavior is increased in episodic but reduced in chronic disease, indicating adaptive changes. Testosterone deficiency is more prevalent, especially in chronic cases, likely originating in the brain. A Dutch version of the Cluster Headache Quality of Life questionnaire was developed; quality of life is more strongly tied to mental health and activity limitations than attack frequency alone. Greater occipital nerve infiltration is clinically effective, but its mechanism remains unresolved.
Nature • June 14, 2023 • Romain Nardou, Young Jun Song, Noelle Wright et al. • 335 citations
Psychedelic drugs share the ability to reopen a critical period for social reward learning in adult mice, and the duration of this reopening matches the length of subjective effects in humans. The reinstatement of social reward learning is accompanied by a metaplastic restoration of oxytocin-mediated long-term depression in the nucleus accumbens. Analysis of gene expression in the open versus closed state indicates that reorganization of the extracellular matrix is a common downstream mechanism. These findings suggest a unifying mechanism for psychedelics' therapeutic properties and may guide clinical use and drug design for neuropsychiatric diseases.
JAMA Psychiatry • August 24, 2022 • Michael P. Bogenschutz, Stephen Ross, Snehal Bhatt et al. • 668 citations
Two doses of psilocybin, given alongside psychotherapy, substantially reduced heavy drinking in people with alcohol use disorder compared to an active placebo (diphenhydramine) plus psychotherapy. Over 32 weeks, heavy drinking days averaged 9.7% in the psilocybin group versus 23.6% in the placebo group—a mean difference of 13.9 percentage points. Daily alcohol consumption was also lower with psilocybin. No serious adverse events occurred in the psilocybin group. The findings support further research into psilocybin-assisted treatment for alcohol use disorder.
Proceedings of the National Academy of Sciences • April 13, 2020 • Morten L. Kringelbach, Josephine Cruzat, Joana Cabral et al. • 326 citations
By combining multimodal neuroimaging data, a framework was developed that demonstrates the fundamental principles of bidirectional coupling between neuronal and neurotransmitter dynamical systems. The work causally explains the functional effects of stimulating specific serotoninergic receptors (5-HT2AR) with psilocybin in healthy humans. This could lead to a better understanding of why psilocybin shows promise as a therapeutic intervention for neuropsychiatric disorders such as depression, anxiety, and addiction.
Pharmacology & therapeutics • May 1, 2019 • Matthew W Johnson, Peter S Hendricks, Frederick S Barrett et al. • 520 citations
Classic psychedelics like LSD, mescaline, and psilocybin are serotonin 2A receptor agonists with a long history of sacramental use and a resurgence in research. Epidemiological studies suggest naturalistic nonmedical use may be linked to positive mental health and prosocial outcomes, though some individuals are harmed in unsupervised settings. Recent therapeutic studies indicate efficacy in treating psychological distress from life-threatening diseases, depression, and nicotine and alcohol addictions. These compounds fairly reliably occasion mystical experiences, which are associated with improved psychological outcomes in healthy volunteers and patients. Neuroimaging studies reveal neurobiological mechanisms, broadening understanding of the brain, serotonin system, and consciousness. Overall, classic psychedelics show strong therapeutic potential and as tools for investigating mystical experiences and brain function.
International Review of Psychiatry • July 4, 2018 • Thomas W. Flanagan, Charles D. Nichols • 263 citations
Serotonin 5-HT2A receptor agonists, including psychedelics like psilocybin, show promise as anti-inflammatory agents beyond their known effects on anxiety, depression, OCD, and addiction. Activation of 5-HT2A receptors produces potent anti-inflammatory effects in animal models of human inflammatory disorders at sub-behavioral levels. This review discusses the role of the 5-HT2A receptor in inflammation, highlights studies using the agonist (R)-DOI in cellular and animal models, and examines potential mechanisms. Psychedelics regulate inflammatory pathways through novel mechanisms, potentially offering a new treatment strategy for inflammatory disorders.
Journal of Psychopharmacology • June 25, 2018 • Tehseen Noorani, Albert Garcia‐romeu, Thomas Cody Swift et al. • 285 citations
In a follow-up study of a psilocybin-facilitated smoking cessation pilot, 12 of 15 original participants were interviewed about 30 months after their psilocybin sessions. Participants described gaining vivid insights into their self-identity and reasons for smoking, and reported that experiences of interconnectedness, awe, and curiosity persisted long after the drug's acute effects. The content of the psilocybin experience overshadowed short-term withdrawal symptoms. Participants also emphasized the importance of preparatory counseling, strong rapport with the study team, and a sense of momentum from being engaged in the treatment. Beyond quitting smoking, many reported lasting positive changes such as increased aesthetic appreciation, altruism, and pro-social behavior.
Clinical Pharmacology & Therapeutics • November 4, 2016 • De Nichols, Mw Johnson, Cd Nichols • 366 citations
Serotonergic psychedelics like psilocybin and LSD, which activate 5-HT2A receptors, show preliminary efficacy in treating anxiety, depression, and addiction to tobacco and alcohol when combined with psychotherapy. Recent research suggests these compounds may also combat inflammatory diseases through novel mechanisms, potentially offering advantages over existing anti-inflammatory drugs. The authors propose that psychedelics work by temporarily destabilizing brain network hubs and global connectivity via amplified neuronal avalanches, allowing the brain to reset after acute effects subside. Anti-inflammatory effects could benefit both psychiatric and nonpsychiatric inflammation-related conditions, warranting rigorous further research.
Journal of Psychopharmacology • March 1, 2015 • Pål-ørjan Johansen, Teri Suzanne Krebs • 300 citations
A large study of 135,095 randomly selected US adults, including 19,299 who had used psychedelics such as LSD, psilocybin, or mescaline, found no link between lifetime psychedelic use and mental health problems. After adjusting for sociodemographics, other drug use, and childhood depression, there were no significant associations with past-year serious psychological distress, mental health treatment, suicidal thoughts, plans, or attempts, depression, or anxiety. Psychedelic use was not an independent risk factor for mental health issues. Serious adverse events are extremely rare, and psychedelics are not known to harm organs or cause addiction. The authors argue that prohibiting psychedelics as a public health measure is difficult to justify.
Journal of Psychopharmacology • January 13, 2015 • Michael P. Bogenschutz, Alyssa A. Forcehimes, Jessica A. Pommy et al. • 1,164 citations
In a small proof-of-concept study, ten volunteers with alcohol dependence received one or two supervised doses of psilocybin alongside therapy. Abstinence did not increase during the first four weeks of treatment but increased significantly after psilocybin administration, with gains largely maintained up to 36 weeks. The intensity of effects during the first psilocybin session strongly predicted reduced drinking and craving and increased abstinence self-efficacy in the following weeks. No serious adverse events occurred. These preliminary findings support larger controlled trials to test efficacy and mechanisms.
Current Drug Abuse Reviews • January 9, 2015 • Albert Garcia‐romeu, Roland R. Griffiths, Matthew W. Johnson • 480 citations
In an open-label pilot study, 15 smokers received 2 or 3 doses of psilocybin alongside cognitive behavioral therapy for smoking cessation. Twelve of 15 participants (80%) had biologically verified smoking abstinence at 6-month follow-up. Those who quit scored significantly higher on a measure of psilocybin-occasioned mystical experience than those who relapsed, while general drug intensity did not differ between groups. Nine of 15 participants (60%) met criteria for a complete mystical experience. Smoking cessation outcomes correlated with measures of mystical experience on session days and with retrospective ratings of personal meaning and spiritual significance. The results suggest mystical experience may mediate psychedelic-facilitated addiction treatment.
Journal of Psychopharmacology • September 11, 2014 • Mary P Cosimano, Matthew W. Johnson, Albert Garcia‐romeu et al. • 910 citations
In an open-label pilot study, 15 nicotine-dependent smokers received moderate (20 mg/70 kg) and high (30 mg/70 kg) doses of psilocybin as part of a structured 15-week smoking cessation program. At 6-month follow-up, 12 of 15 participants (80%) showed seven-day point prevalence abstinence, a rate substantially exceeding the typical 35% or less reported for other behavioral or pharmacological therapies. The authors note the open-label design prevents definitive conclusions about efficacy, but the findings suggest psilocybin may be a potentially useful adjunct to smoking cessation treatment.
Current Drug Abuse Reviews • June 1, 2013 • Gerald Thomas, Philippe Lucas, N. Rielle Capler et al. • 327 citations
Ayahuasca-assisted therapy was linked to meaningful improvements in factors related to problematic substance use among a rural aboriginal population. The observed changes suggest positive psychological and behavioral shifts, indicating that this therapeutic approach merits further, more rigorous investigation.
Addiction • July 21, 2011 • Celia J. A. Morgan, H. Valerie Curran • 645 citations
Repeated misuse of ketamine, both acute and chronic, causes significant physical, psychological, and social harms. A major physical harm is ketamine-induced ulcerative cystitis, particularly linked to chronic, frequent use. Frequent daily use is also associated with neurocognitive impairment, most robustly deficits in working and episodic memory. Recent studies suggest neurological abnormalities that may underlie these cognitive effects. Many frequent users report trying but failing to stop using ketamine, indicating addiction concerns. Treatment for ketamine-induced ulcerative cystitis should coordinate urologists and addiction specialists. Neurocognitive impairment can negatively impact educational and work achievement and compound addiction. Prevention and harm minimization campaigns are needed to alert young people to these potentially chronic effects.
Substance Abuse • October 1, 2009 • Aleksandra Zgierska, David Rabago, Neharika Chawla et al. • 349 citations
Relapse is common in substance use disorders even after treatment. This systematic review examined mindfulness meditation-based interventions for substance use disorders, identifying 25 eligible manuscripts from over 2000 abstracts. The studies included 8 randomized controlled trials, 7 controlled nonrandomized trials, 6 noncontrolled prospective studies, 2 qualitative studies, and 1 case report. Overall, preliminary evidence suggests mindfulness meditation may be efficacious and safe, but conclusive data for its use as a treatment are lacking. Most studies had significant methodological limitations, and it remains unclear which individuals with substance use disorders might benefit most. Future trials need larger sample sizes and should assess both effect size and mechanisms of action.