The New England journal of medicine
November 3, 2022
Guy M. Goodwin, Scott T Aaronson, Oscar Alvarez et al.
1,095 citations
A single 25 mg dose of psilocybin, but not 10 mg, reduced depression scores more than a 1 mg control dose over three weeks in adults with treatment-resistant depression. In this phase 2 trial, 233 participants were randomly assigned to 25 mg, 10 mg, or 1 mg of synthetic psilocybin with psychological support. The 25 mg group showed an average 12-point drop on the MADRS depression scale versus a 5.4-point drop in the 1 mg group, a significant difference. The 10 mg group did not differ significantly from control. Response and remission rates at three weeks supported the primary result, but sustained response at 12 weeks was not significantly different.
Journal of Psychopharmacology
November 6, 2020
Luke A. Jelen, Allan H. Young, James Stone
244 citations
The discovery that the dissociative anaesthetic ketamine produces rapid antidepressant effects is considered the most important breakthrough in depression research in the last 50 years. Ketamine, a racemic mixture of (S)-ketamine and (R)-ketamine, remains an off-label treatment for treatment-resistant depression, limited by dissociative effects and abuse potential. An (S)-ketamine nasal spray is approved in the United States and Europe, though concerns about efficacy and side effects persist. Preclinical evidence suggests (R)-ketamine may have more potent and longer-lasting antidepressant effects than (S)-ketamine with fewer side effects, and a pilot trial showed rapid-acting and sustained antidepressant effects in individuals with treatment-resistant depression. Research continues on the cellular and molecular mechanisms underlying these effects.
Journal of Psychopharmacology
November 18, 2016
James Rucker, Luke A. Jelen, Sarah Kalen Flynn et al.
187 citations
Unipolar mood disorders such as major depressive disorder and dysthymia cause high disability, mortality, and socioeconomic burden, with current treatments often suboptimal and little new pharmaceutical development. Psychedelic drugs like psilocybin were used extensively before prohibition in the late 1960s and are relatively safe in medically controlled environments with no dependence risk. A systematic review of 19 clinical treatment studies found that of 423 individuals, 335 (79.2%) showed clinician-judged improvement after psychedelic treatment. A recent UK pilot study supports psilocybin with psychological support for treatment-resistant depression. The evidence strongly suggests psychedelics should be re-examined in modern clinical trials for unipolar mood disorders.
Psychopharmacology
September 5, 2022
Matthew Butler, Luke A. Jelen, James Rucker
91 citations
Expectancy and unblinding in psychedelic trials likely cause overestimation of treatment effects, but this problem is not unique to psychedelics. The authors argue that premature hype directly inflates participant expectations, yet placebo-controlled RCTs are imperfect for many therapies and blinding issues should not automatically disqualify medications from approval. Practical measures like independent raters and active placebos can partially mitigate these effects, and alternative methods such as naturalistic studies can supplement RCT results. Early data should neither be dismissed nor taken as firm evidence of effectiveness.
Neuroscience & Biobehavioral Reviews
May 10, 2021
Laith Alexander, Luke A. Jelen, Mitul A. Mehta et al.
79 citations
The anterior cingulate cortex (ACC), including its subgenual, perigenual, and dorsal zones, plays a key role in major depression and its treatment. Ketamine, a rapidly acting antidepressant, induces acute (over minutes) and post-acute (over hours to days) changes in subgenual and perigenual ACC activity, and these changes can correlate with antidepressant efficacy. The subgenual and dorsal ACC zones are specifically linked to ketamine's anti-anhedonic effects. The review emphasizes combining human neuroimaging with animal brain manipulations to understand causal relationships between brain activity and therapeutic outcomes. Circuit-based perspectives highlight ACC function in a central network mediating affective pain and its role as the anterior node of the default mode network.
Journal of Psychopharmacology
December 20, 2020
Benjamin Illingworth, Declan J Lewis, Andrew T Lambarth et al.
47 citations
A meta-analysis of four randomized controlled trials found that MDMA-assisted psychotherapy can reduce symptoms of treatment-resistant post-traumatic stress disorder (PTSD), as measured by the Clinician Administered PTSD Scale (CAPS-IV). Doses of 75 mg and 125 mg of MDMA, but not 100 mg, produced significant decreases in CAPS-IV scores compared to active placebo. A significant reduction in Beck's Depression Inventory scores was only seen with the 75 mg dose. Participants reported more episodes of low mood, nausea, jaw-clenching during sessions, and lack of appetite within seven days. The authors conclude there is potential therapeutic benefit with minimal physical and neurocognitive risk, though better-powered trials are needed.
Depression and Anxiety
July 5, 2020
N. Weston, Damian Gibbs, Catherine Bird et al.
38 citations
A systematic review of literature from 1940 to 2000 examined the combined use of psychological therapies and psychedelic drugs for treating ICD-10 anxiety disorders. Twenty studies were included in the final analysis. Three studies reported improvements in anxiety on standardized measures, with two finding a dose-related effect. Among 145 cases of psychoneurotic anxiety reaction, 94 (65%) showed improvement ranging from moderate to full recovery. The majority of studies indicated that combining psychedelic drug administration with psychological therapy was most beneficial; no study suggested that the drug alone was sufficient.
Nature Medicine
July 24, 2025
Luke A. Jelen, David J Lythgoe, James Stone et al.
29 citations
Blocking the opioid system with naltrexone reduced both the brain glutamate response and the antidepressant effect of ketamine in adults with major depressive disorder. In a double-blind crossover study of 26 adults, naltrexone before ketamine infusion attenuated the rise in glutamate+glutamine relative to N-acetylaspartate in the anterior cingulate cortex and lessened the drop in depression scores the next day. The opioid system modulates ketamine's acute brain effects and subsequent mood improvement, suggesting interactions between glutamate and opioid systems may inform new depression treatments.
BJPsych Open
May 10, 2024
Luke A. Jelen, Rupert McShane, Allan H. Young
7 citations
Ketamine shows promise for treatment-resistant depression, but its use requires careful management through evidence-based guidelines. The editorial emphasizes the need for comprehensive protocols to oversee both licensed and off-licence ketamine formulations, referencing recent efforts to develop such guidelines in New Zealand. It advocates for national registries to monitor ketamine therapy, ensuring responsible and effective treatment for depression.
The American journal of psychiatry
June 1, 2026
Luke A. Jelen, Owen O'Daly, Fernando O Zelaya et al.
2 citations
Ketamine increased blood flow in specific brain regions (subgenual, pregenual, and dorsal anterior cingulate cortices) in adults with major depressive disorder, and this effect was not blocked by the opioid blocker naltrexone. However, naltrexone did disrupt the relationships between blood flow changes and both acute subjective effects and antidepressant response. The blood flow changes aligned with patterns of opioid and glutamate receptor distribution, suggesting that ketamine's effects involve interactions among multiple neurotransmitter systems.
Journal of psychopharmacology (Oxford, England)
May 29, 2026
Elliot Hampsey, Kirsty Martin, Michail Kalfas et al.
A systematic review of 32 trials in healthy adults found that LSD and psilocybin show dose-proportional peak concentrations (Cmax), while DMT's oral and intravenous formulations differ in ways that may be clinically significant. LSD was the most studied psychedelic, followed by DMT and psilocybin; mescaline appeared in only two trials. Single studies examined intravenous LSD, intravenous psilocybin, inhaled 5-MEO-DMT, and intranasal 5-MEO-DMT. Variations in absorption, distribution, and elimination among the compounds may have important implications for clinical and research settings.