Expert Review of Clinical Pharmacology
May 26, 2021
Suresh Muthukumaraswamy, Anna Forsyth, Thomas Lumley
312 citations
Psychedelic drugs like psilocybin, LSD, and ketamine show promise for treating mental health disorders, but their effectiveness in randomized controlled trials may be overstated. Previous research indicates that participants in psychedelic trials often become unblinded—they can tell whether they received the drug or a placebo—and may have strong expectations of improvement. A systematic review of trials from 1990 to 2020 found that most did not measure pre-trial expectancy or check whether blinding was successful. The authors argue that reported treatment effect sizes are likely overestimated due to these confounds. They recommend routine measurement of de-blinding and expectancy, careful trial design, and caution when interpreting existing effect size estimates.
Expert Review of Clinical Pharmacology
August 13, 2018
Rafael G. Dos Santos, José Carlos Bouso, Miguel Ángel Alcázar‐córcoles et al.
231 citations
Serotonergic hallucinogens/psychedelics such as ayahuasca, psilocybin, and LSD show promise for reducing anxiety, depression, and substance dependence. Psilocybin and LSD reduced anxiety and depression in cancer patients and symptoms of alcohol and tobacco dependence; ayahuasca reduced depression symptoms in treatment-resistant depression. However, many studies were open-label, few were randomized controlled trials, most had small sample sizes and short duration. Single or few doses appear well tolerated, but long-term studies are lacking. New RCTs with larger samples and longer duration are needed to confirm these findings.
Expert Review of Clinical Pharmacology
June 1, 2020
Kyle T. Greenway, Nicolas Garel, Lisa Jerome et al.
87 citations
Combinations of psychotherapy with antidepressants and psychedelic-assisted psychotherapy both work through complex, interactional mechanisms. A review of therapeutic mechanisms behind conventional and psychedelic paradigms, including the evolution of this knowledge and explanatory frameworks, finds that the contextual model of common factors in psychotherapy provides a powerful perspective on psychotherapy, antidepressants, psychedelics, MDMA, and ketamine. Conventional antidepressants and especially psychedelics may improve psychotherapy's efficacy via neurochemical changes and increased environmental sensitivity. Combined treatments hold significant promise for advancing knowledge and treatment of many forms of psychopathology.
Expert Review of Clinical Pharmacology
March 17, 2016
Fabrizio Schifano, Gabriele Duccio Papanti, Laura Orsolini et al.
66 citations
Novel psychoactive substances (NPS), including stimulants and hallucinogens, disrupt multiple neurotransmitter pathways, particularly dopamine, cannabinoid CB1, and 5-HT2A receptors. Their intake is almost never detected by standard drug screening tests. Acute management of NPS misusers should prioritize reducing self-directed and outward-directed aggression and agitation. Benzodiazepines are recommended as first-line treatment, with propofol or antipsychotics as alternatives. Treatment must also address possible rhabdomyolysis and hyperthermia. Future research is needed to develop better-tailored management strategies.
Expert Review of Clinical Pharmacology
January 1, 2024
Lucas F Borkel, Jaime Rojas-Hernández, Luis Alberto Henríquez-Hernández et al.
40 citations
Growth motivations for using psychedelics, natural settings, and the presence of significant others during use predict less psychopathology, greater wellbeing, and more meaningful experiences. Problematic motivations predict greater psychopathology, lower wellbeing, and do not predict meaningfulness. These findings come from an online survey of 1022 Spanish-speaking participants, using a newly developed Psychedelic Use Scale to measure use of nine substances including LSD, psilocybin, and MDMA. The results suggest experimental hypotheses for future clinical trials and longitudinal studies.
Expert Review of Clinical Pharmacology
November 2, 2023
Fabrizio Schifano, Alessandro Vento, Norbert Scherbaum et al.
30 citations
Clinicians need regular updates on novel psychoactive substances (NPS) and their acute and long-term medical, psychobiological, and psychopathological risks. Future research should combine pro-drug website analysis with computational chemistry to organize preclinical studies of new psychoactives. Psychedelic research should develop robust study designs to assess potential therapeutic benefits, as these molecules likely have limited dependence liability.
Expert Review of Clinical Pharmacology
April 1, 2023
Jeffrey M. Witkin, Lalit K Golani, Jodi L Smith
18 citations
Standard antidepressants have limitations, driving the search for new drugs. Rapid-acting antidepressants, such as those based on ketamine, show promise for treatment-resistant depression. This review documents newly approved and emerging medicines for major depressive disorder, evaluating their efficacy, tolerability, and safety. Many new drugs rely on glutamatergic mechanisms, including mGlu2/3 receptor antagonists, AMPA receptor potentiators, and novel NMDA receptor modulators. Companies are also developing novel psychedelic drugs, though the necessity of psychedelic activity remains unclear. Gaps persist in matching patients to specific treatments and in developing medicines to prevent MDD or its progression.
Expert Review of Clinical Pharmacology
July 10, 2020
Justin P. Reinert, Kayla N. Colunga, Alexandria Etuk et al.
11 citations
Use of salvia, kratom, and psilocybin mushrooms is rising globally, and healthcare practitioners should consider these substances when triaging overdose cases. Although overdoses from these agents are not typically fatal, clinicians need to be prepared to identify them as a possible cause and provide appropriate supportive care.
Expert Review of Clinical Pharmacology
March 1, 2025
Danny Diep, Sara de la Salle, Julien Thibault Lévesque et al.
8 citations
Ketamine's subjective effects have been interpreted in three major ways since its 1962 synthesis: as dissociative, dream-like, or psychedelic, depending on the clinical context and dose. Biomedical frameworks often label its effects as dissociative or psychotomimetic, while psychedelic paradigms highlight potential therapeutic benefits. Factors such as language, dose, and environmental setting influence both the drug's effects and treatment outcomes. The authors argue that ketamine is best understood as a chameleon whose effects shift with context, rather than a tiger to be tamed. A nuanced, interdisciplinary approach is needed to maximize its clinical potential.
Expert Review of Clinical Pharmacology
January 1, 2023
Luke J. Ney, Wole Akosile, Chris Davey et al.
8 citations
Preclinical and experimental research suggests medicinal cannabis may help treat posttraumatic stress disorder, but integrating it into routine clinical therapies poses clinical, practical, and safety challenges, especially when combined with trauma-focused psychotherapy. Key issues include dose timing and titration, addiction potential, product formulation, windows of intervention, and route of administration. Exposure therapy for PTSD involves recalling intense emotions, and the interaction between cannabis use and reliving trauma memories requires exploration for patient safety and therapeutic outcomes.
Expert Review of Clinical Pharmacology
October 3, 2025
Lorena Terene Lopes Guerra, Isabella Caroline Da Silva Dias, Jaime E. C. Hallak et al.
2 citations
Whether subjective experience contributes to therapeutic mechanisms of ayahuasca is debated and may depend on the targeted condition. Few controlled studies exist, limiting conclusions on safety and efficacy. Ayahuasca's highly variable composition poses an additional challenge, prompting studies using isolated compounds.
Expert Review of Clinical Pharmacology
February 3, 2026
Kaitlin R Mcmanus, Lara A Ray
A review of current and emerging treatments for alcohol use disorder (AUD), which affects 27.1 million U.S. adults, argues that existing medications have mixed efficacy and that a shift toward precision medicine—identifying subgroups most responsive to existing or combination pharmacotherapies—is needed. The review also synthesizes novel agents on the treatment horizon, including glucagon-like peptide 1 receptor agonists, classic psychedelics, ketamine, immune modulators, and cannabinoids. Adopting precision medicine and these new compounds requires changes in healthcare systems, moving away from a one-size-fits-all model to improve cost-effectiveness and patient outcomes, though distribution challenges remain.
Expert Review of Clinical Pharmacology
June 11, 2025
Victor Pablo Acero, Taylor A Flatt, Peter M. Gooch et al.
Psychedelic compounds can produce rapid and lasting depression symptom reduction after one or two administrations paired with psychotherapy, unlike traditional antidepressants. Current evidence on their antidepressant mechanisms is fragmented across biological, psychological, social, and spiritual domains. This review identifies key mechanisms in each domain, comparing them with those of conventional antidepressants to highlight overlaps and differences. The authors caution that focusing too narrowly on discrete pathways may limit progress, as psychedelics likely work through complex, interwoven processes. Future research should examine how suprapharmacological factors—set, setting, therapy modality, and integration—shape outcomes, moving beyond frameworks used for standard antidepressants.
Expert Review of Clinical Pharmacology
July 6, 2021
E. Schenberg
A letter commends a review on unblinding in psychedelic clinical trials but critically questions whether the proposed solutions are pragmatic, ethical, and conceptually sound. The author notes that suggested multi-arm designs increase patient numbers and costs, may face ethical issues such as patient deception, and could violate clinical equipoise. The letter argues that isolating pharmacological effects from placebo, therapeutic alliance, and expectancy may be impossible in principle, as psychiatric drugs target subjective experience and patients becoming aware of changes may be inherent to therapeutic action. The author questions whether maintaining blinding would indicate a drug had no useful effect.