Frontiers in Psychiatry
December 17, 2021
John R. Kelly, Claire M. Gillan, Jack Prenderville et al.
66 citations
Psychedelic therapy, combining psychedelic drugs with psychological support, shows promise for treating disorders marked by rigid and unhealthy patterns of emotion, thought, and behavior, including depression, treatment-resistant depression, addiction, and potentially anxiety, OCD, PTSD, and eating disorders. This review examines preclinical and clinical evidence through the Research Domain Criteria (RDoC) framework, mapping the drugs' effects across molecular, cellular, and network levels to RDoC constructs like negative and positive valence, arousal, social processing, cognition, and sensorimotor systems. The goal is to clarify the specific clinical dimensions psychedelics affect and their underlying neurobiology, aiming toward a mechanistic understanding and personalized psychedelic therapy.
British Journal of Pharmacology
June 1, 2012
Natacha Vanattou‐saïfoudine, Ruth Mcnamara, Andrew Harkin
60 citations
Consuming caffeine with recreational psychostimulant drugs like MDMA (ecstasy) can cause severe acute adverse reactions and long-term harm. Caffeine increases toxicity by disrupting body temperature regulation, causing heart damage, and lowering the seizure threshold. In rats, co-administering caffeine with MDMA dramatically raises core body temperature, heart rate, and death rates, and worsens long-term damage to serotonin neurons. The interaction involves MDMA boosting dopamine release while caffeine blocks adenosine receptors and inhibits PDE. Similar mechanisms apply to interactions with cocaine, d-amphetamine, and ephedrine. Understanding these mechanisms helps guide interventions for managing severe reactions and drug-related toxicity from combined caffeine and psychostimulant use.
British Journal of Pharmacology
May 24, 2010
Natacha Vanattou‐saïfoudine, Ruth Mcnamara, Andrew Harkin
39 citations
Caffeine worsens the rise in body temperature caused by MDMA ('Ecstasy') in rats. The interaction depends on the combined release of the neurotransmitters serotonin and catecholamines (like dopamine). Blocking dopamine D1, serotonin 5-HT2, or alpha-1 adrenergic receptors prevented both MDMA-induced hyperthermia and its exacerbation by caffeine. Caffeine's effect was mimicked by combining a PDE-4 inhibitor with an adenosine A2A receptor antagonist, but not with an A1 receptor antagonist. The findings suggest that caffeine exacerbates MDMA hyperthermia through a mechanism involving both adenosine A2A receptor antagonism and phosphodiesterase inhibition.
International journal of clinical and health psychology : IJCHP
January 1, 2023
John R Kelly, Gerard Clarke, Andrew Harkin et al.
33 citations
A systems psychiatry approach recognizes complex interactions across biological levels and requires integrated treatment strategies. Serotonergic psychedelics primarily target cortical 5-HT2A receptors, but their therapeutic mechanisms span molecular, cellular, and network levels, influenced by biofeedback from the periphery and environment. The gut microbiome, through the gut-brain axis, regulates host neurophysiology via unconscious parallel processing systems. Although psychedelic and microbial signaling operate on different timescales, the microbiota-gut-brain axis may contribute to the preparatory, acute, and integration phases of psychedelic therapy. This review examines the gut microbiome and mycobiome, pathways of the MGB axis, and potential interactions with psychedelic therapy, discussing implications for precision medicine.
Pharmacology & Toxicology
May 1, 1997
Ivone de Souza, John Kelly, Andrew Harkin et al.
29 citations
Acute oral administration of MDMA (Ecstasy) to adult female rats produced dose-related effects including hyperthermia, reduced food and water intake, and hyperactivity. Deaths occurred from 40 mg/kg upward. Lower doses (20 and 40 mg/kg) caused prolonged hyperactivity lasting about 9 hours, while higher doses led to serotonin syndrome. The likely cause of death was a combination of serotonin syndrome and hyperthermia.
Irish Journal of Psychological Medicine
November 7, 2024
Andrew Gribben, Tara Burke, Colm Harrington et al.
5 citations
A survey of 151 psychiatrists in Ireland found that most hold positive attitudes toward psilocybin therapy: 81.5% agreed it shows promise for treating psychiatric disorders, 86.8% supported funding research, 86.8% would refer a patient if licensed, and 78.1% would consider it for themselves. However, only 40.0% felt knowledgeable and just 9.9% felt adequately prepared to participate. A minority expressed concerns: 6.6% thought it unsafe under medical supervision, 21.9% considered it potentially addictive, and 15.9% reported at least one concern about evidence, effectiveness, safety, cost, or impartiality. Consultant psychiatrists were less optimistic than trainees about its role in bipolar depression and emotionally unstable personality disorder.
Acta neuropsychiatrica
July 25, 2025
Guillaume Thuery, Christopher Sheridan, Patricia Iusan et al.
4 citations
This narrative review synthesizes clinical and preclinical research on how 5-HT2A receptor psychedelics interact with the immune system. The evidence shows these compounds have direct immunomodulatory properties, including downregulation of gene regulators like NF-κB and reduced expression of cytokines such as TNF-α, IL-6, and IL-1β in both the central and peripheral nervous systems. These effects are accompanied by modulation of corticotrophin releasing hormone, adrenocorticotrophic hormone, and cortisol. The immunomodulation occurs through pathways involving serotonin receptors, the Sigma-1 receptor, and the TrkB receptor, as well as indirectly via the HPA axis. The review identifies that modulation of brain glia and glial-neuronal interactions remains to be determined, representing a promising direction for future research on the therapeutic potential of these psychedelics for mental health and brain disorders.
Therapeutic Advances in Psychopharmacology
March 1, 2026
Guillaume Thuery, Frank Crossen, Daniel Mc Loone et al.
1 citation
About 15% of pregnant women experience postpartum depression, and many remain impaired despite available antidepressants. Serotonergic psychedelics may offer a viable therapeutic approach for postpartum depression, though the benefit-risk ratio is unclear. This review summarizes immune, endocrine, and neural pathways underlying postpartum depression and explores how psychedelics interact with these pathways in relation to maternal motivation, bonding, and caregiving. Special considerations for psychedelic therapy in the postpartum period are outlined. Further research, especially longitudinal trials with adaptations for the postpartum context, is needed to determine efficacy and safety.
The international journal of neuropsychopharmacology
June 2, 2026
John R Kelly, Christopher Sheridan, Patricia Iusan et al.
Classical serotonergic psychedelics like psilocybin show emerging evidence of therapeutic potential across depression, anxiety, and substance use disorders, with indications of transdiagnostic efficacy. Early-phase studies yielded encouraging results, but recent larger-scale phase 3 trials for treatment-resistant depression have shown more modest effects. No regulatory approvals from the U.S. FDA or EMA exist, though a few countries permit psychedelic therapies in regulated clinical settings. The long-term trajectory and real-world impact within public health systems remain uncertain. This paper examines challenges for integrating psychedelic therapies into Ireland's public healthcare system, covering regulatory approval, Health Technology Assessment, service implementation, workforce capacity, and evaluation of long-term patient outcomes.
Journal of psychopharmacology (Oxford, England)
May 1, 2026
Brian O'Mahony, Colm Harrington, Andrew Harkin et al.
Psychedelic drugs are being studied as treatments for mental health conditions and used recreationally, but they can cause intense psychological distress known as a "bad trip," which may lead to emergency care or psychiatric hospitalization. Managing these episodes should prioritize non-pharmacological strategies, but when those are insufficient, medications that can safely end the psychedelic state are needed. This review systematically evaluates candidate abortive agents, including serotonin antagonists, antipsychotics, and certain anxiety and depression drugs, considering their mechanisms, safety, and suitability for acute care. The authors propose a provisional framework for pharmacological management and identify priorities for future research.