Journal of Psychopharmacology

This perspectives piece reflects on some of the major scientific contributions in psychopharmacology, cognitive neuroscience, and public policy of Professor Barbara J. Sahakian, Commander of the Most Excellent Order of the British Empire (CBE). Her pioneering research has advanced the understanding of brain mechanisms, including neurotransmitter modulation, and psychological processes involved in cognition, emotion, and motivation, leading to novel treatments for disorders such as Alzheimer’s disease, attention deficit hyperactivity disorder, obsessive-compulsive disorder, and depression. She has also contributed to a better understanding of brain mechanisms underlying and psychological processes involved in these disorders. She has championed early detection of Alzheimer’s disease through neuropsychological tools, such as the Cambridge Neuropsychological Test Automated Battery (CANTAB) paired associates learning (PAL) test and contributed to identifying cognitive and neural changes in Huntington’s disease gene carriers. Beyond clinical research, Sahakian has influenced public health policy through initiatives such as the UK Government Foresight Project on Mental Capital and Wellbeing and the National Institute for Health and Care Excellence guidelines on gambling-related harms. She has also led efforts in neuroethics and public engagement, co-authoring accessible science books and participating in global forums. Recent research emphasises preventative psychiatry, including lifestyle interventions, such as diet, sleep, social connection, and lifelong learning as preventive strategies for cognitive decline and mental health problems. Through interdisciplinary collaborations and mentorship, Sahakian continues to inspire the next generation of scientists to pursue innovative research for societal benefit in neuropsychopharmacology and cognitive neuroscience.

The occupancy-driven pharmacology model in psychopharmacology has guided drug discovery and development for decades, whereby the goal is stable receptor occupancy over an extended period with a direct relationship of drug exposure to pharmacodynamic and therapeutic response. Event-driven pharmacology (EDP) is a concept where the acute pharmacodynamic actions of a plastogen, a transient binding event, drive changes resulting in sustained pharmacodynamic effects that greatly outlast the time frame of drug exposure. Such plastogens may be neuroplastogens producing a measurable change in neuroplasticity without inducing subjective mental states or psychoplastogens exerting neuroplastic effects in addition to causing dissociation, hallucinations, or psychotomimetic symptoms. Within neuropsychiatry, plastogens have been shown to induce long-lasting neural plasticity and persistently activate synaptic machinery that primes synapses to respond to subsequent stimuli (metaplasticity), often following either a single dose or repeated administration of intermittent doses. Developing rapid-acting plastogens to adhere to a traditional target occupancy dose optimization model that achieves consistent drug target occupancy over an extended period of time may paradoxically exert few or no durable benefits while increasing side effect burden. We review evidence supporting the concept that plastogens, including the rapid-acting antidepressant ketamine and classical psychedelics, operate within the EDP model. With the emergence of EDP, new methods for drug development, clinical dosing, and biomarker adoption will need to be developed to account for distinctive pharmacological actions. Rapid-onset plastogens, rationally administered, have profound potential in the treatment of depression and many other neurological and psychiatric diseases characterized by synaptic dysfunction.

The therapeutic potential of psychedelics is currently being explored in a range of neuropsychiatric conditions. Nevertheless, their designation as Schedule 1 substances causes substantial regulatory and economic barriers to research. Rigorous human mechanistic studies are required to address the critical knowledge gaps surrounding the mechanisms underlying the putative treatment effects of psychedelics. This article presents practical guidance for navigating challenges relating to study design, legislation, and drug sourcing, to assist researchers in navigating the complex process of setting up human psychedelic studies, drawing on our experience of setting up non-clinical studies in the United Kingdom, while acknowledging that some of the content will be relevant for investigator-initiated studies more broadly.

The current era is characterized by the pursuit of novel medications and drug repurposing through innovative mechanisms that modulate systems beyond the monoaminergic, focusing on novel synaptic signaling targets. Against this backdrop, it can be challenging to recall a time when psychopharmacology was in its infancy, and every discovery represented the cutting edge. Nathan S. Kline, a clinician and researcher, was a pivotal figure in introducing the first psychoactive substances into clinical practice. His seminal work on reserpine as a sedative and his evaluation of the antidepressant properties of iproniazid, a monoamine oxidase inhibitor (MAOI), positioned him at the scientific vanguard of pharmacological psychiatry. Kline made multiple substantial contributions to the medical-scientific literature, publishing foundational papers on the use of reserpine in neuropsychiatric hospitals, the application of Rauwolfia serpentina for neuropsychiatric conditions, and comparative studies of iproniazid and other MAOIs, among numerous other manuscripts. Kline’s enduring legacy extends beyond psychopharmacology, encompassing early efforts in health informatics to optimize psychiatric logistics and advocacy for the expansion of global mental health care networks, including in low- and middle-income countries.

In the past decade, interest in studying psychedelic compounds as potential therapeutic agents has resurged. These studies carefully exclude individuals at risk for developing psychotic symptoms in response to psychedelic use. Given the potential for psychedelics to be established as treatments in psychiatry, it is important to more robustly understand their link with psychosis and schizophrenia spectrum disorders (SSDs). In this narrative review, we examine the historical and theoretical relationship between psychedelic drugs and SSDs, including the origins of the psychotomimetic hypothesis. For key psychedelic compounds, we review their phenomenological manifestations in relation to the experiential alterations characteristic of SSDs, revealing both areas of overlap and important qualitative differences that challenge the uniform psychotomimetic classification. We also review putative neural mechanisms underlying altered experiential states associated with psychedelic use and SSDs, with attention to serotonergic, dopaminergic, and glutamatergic contributions. Clinical evidence demonstrates that psychedelics can exacerbate pre-existing psychotic illness and may trigger psychosis in vulnerable individuals, though the magnitude of these risks remains inadequately quantified. However, phenomenological and mechanistic distinctions suggest that potential therapeutic applications may exist for carefully selected symptoms (negative symptoms, depression) in stable patients using low-dose, controlled approaches. Based on published work, we provide recommendations regarding psychosis-related risk and potential avenues for the treatment of SSDs as psychedelics gain traction as therapeutics.

With growing research on the use of psychedelics to treat mental health conditions, greater attention to the psychosocial procedures accompanying substance administration is warranted. This scoping review aims to categorize psychosocial protocols used in research involving psychedelics as psychiatric treatment according to their purpose, denomination, format, therapeutic orientation, formalization, and duration. Experimental and observational studies were identified through online search platforms, covering Ayahuasca, Dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, Lysergic Acid Diethylamide, Ibogaine, Mescaline, 3,4-methylenedioxymethamphetamine, Psilocybin, and 4-hydroxy-N,N-diisopropyltryptamine, yielding 62 eligible studies that were also assessed for methodological quality. Seven categories were defined, reflecting distinct emphases on the substance, participant, research team, and sociocultural context. Although limited reporting and heterogeneity remain methodological challenges, these features reveal divergent research intentions and contextual constraints. The proposed parameters suggest a shared language to describe, compare, and examine psychosocial protocols across studies and reduce conceptual uncertainty in the field. This review may facilitate research decision-making and support the development of structured and replicable study designs, while predicting flexibility to accommodate individualized, culturally responsive, and population-specific care. Ultimately, researchers explicitly defining the intended purpose of psychosocial protocols may improve its transparent reporting, and evaluation. Future research should balance methodological rigor with attention to real-world studies, interdisciplinary perspectives, and demographic diversity for responsible advancing.

A popular model organism for studying neural and molecular mechanisms of behavior, the zebrafish (Danio rerio) displays a wide range of robust and quantifiable social phenotypes, including shoaling/schooling, social preference and learning, as well as aggression and mating behaviors. Zebrafish social behavior is influenced by various neurotransmitters and hormones (including serotonin, dopamine, isotocin, cortisol, and endocannabinoids) and can be modulated experimentally, including genetically and pharmacologically. Here, we summarize current knowledge on neurobiology and neuropharmacology of zebrafish social behavior, and discuss various effects of drugs and other manipulations that target this critical behavioral domain.