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.