The American journal of psychiatry
August 1, 2023
Henry R Kranzler
92 citations
Alcohol is consumed by nearly half the U.S. population aged 12 or older, and heavy drinking contributes to over 140,000 deaths annually. Alcohol use disorder (AUD) has a current U.S. prevalence of 11%, yet less than 15% of individuals with a lifetime diagnosis receive treatment. Risk is nearly equally genetic and environmental. AUD responds to psychosocial treatments like cognitive-behavioral therapy and to pharmacotherapy. Three FDA-approved medications—disulfiram, naltrexone, and acamprosate—are underprescribed despite being first-line treatments. Off-label topiramate and gabapentin show efficacy, and novel candidates like psychedelics and phosphodiesterase-4 inhibitors are promising but need further evaluation. AUD remains highly stigmatized.
The American journal of psychiatry
March 1, 2025
Konstantinos N Fountoulakis, Athanasios Saitis, Alan F Schatzberg
78 citations
Intranasal esketamine, approved as an add-on therapy for treatment-resistant major depression with acute suicidal thoughts, shows only modest benefit for depression and no effect on suicidality itself. A systematic review and meta-analysis of 87 studies found a weak but significant positive effect on depression at weeks 2-4 (effect size 0.15-0.23), similar to adding atypical antipsychotics. However, the effect on suicidality was not significant at any time point. The authors highlight esketamine's abuse potential, unknown long-term effects, and alarming signs of deaths and emerging suicidality during testing, urging caution in light of these regulatory and safety concerns.
The American journal of psychiatry
May 1, 2023
Bryan L. Roth, Ryan H. Gumpper
55 citations
Psychedelic compounds show promise as treatments for several neuropsychiatric conditions such as depression, cluster headaches, migraines, anxiety, and obsessive-compulsive disorder. Historically, basic science has used these compounds to study neurotransmitter systems, primarily the serotonin 5-HT2A receptor. This review covers recent advances in understanding the biological mechanisms of psychedelics, new drug discovery efforts, and potential pitfalls in their widespread therapeutic use. Understanding the pharmacology behind their therapeutic mechanisms is crucial for their safe and effective application.
The American journal of psychiatry
March 1, 2025
Marjorie R Levinstein, Reece C Budinich, Jordi Bonaventura et al.
49 citations
Ketamine, a racemic compound used as an anesthetic, analgesic, and recreational drug, is being investigated for treating refractory depression and comorbid conditions like anxiety, obsessive-compulsive disorder, and opioid use disorder. Although ketamine is traditionally classified as an NMDA receptor antagonist, this review argues its pharmacology should be redefined to include opioid receptors and the endogenous opioid system. The authors propose that ketamine's antidepressant effects may arise from bifunctional, synergistic interactions involving both NMDA and opioid receptors.
The American journal of psychiatry
January 1, 2025
Aaron S Wolfgang, Gregory A Fonzo, Joshua C Gray et al.
47 citations
MDMA-assisted therapy (MDMA-AT) using pharmaceutical-grade MDMA in controlled clinical settings is a safe and efficacious treatment for PTSD. After three MDMA administrations supported by psychotherapy, 67%–71% of individuals with PTSD no longer meet diagnostic criteria, compared with 32%–48% for placebo-assisted therapy, and effects persist at long-term follow-up. Unlike recreational use, which is confounded by adulterants and lack of precautions, MDMA-AT uniquely induces prosocial effects of trust and self-compassion while maintaining cognitive clarity. The review distinguishes evidence from recreational and therapeutic settings, describes neurobiological mechanisms, clinical evidence, public health and policy considerations, and future research directions.
The American journal of psychiatry
October 1, 1975
W T Carpenter, E B Fink, N Narasimhachari et al.
31 citations
Acutely schizophrenic patients and healthy individuals are equally likely to have the compounds bufotenine and N,N-dimethyltryptamine in their urine, and show similar levels of a related enzyme in their blood. The findings suggest these substances occur naturally in both groups and do not support the transmethylation hypothesis of schizophrenia.
The American journal of psychiatry
January 1, 2025
Roger S McIntyre, Angela T H Kwan, Rodrigo B Mansur et al.
23 citations
Psychedelics show promise for treating difficult-to-treat psychiatric disorders like major depressive disorder, treatment-resistant depression, and posttraumatic stress disorder, with preliminary evidence also supporting efficacy in tobacco and alcohol use disorders. However, concerns exist about the interpretability and translatability of study results due to insufficiently characterized short- and long-term safety, abuse liability, and the essentiality of the psychedelic experience and psychological support. This overview reviews methodological aspects affecting inferences and interpretation of extant psychedelic studies and provides guidance for future research and development critical to study interpretation and clinical implementation.
The American journal of psychiatry
May 1, 2025
Barbara Olasov Rothbaum, Laura E Watkins
13 citations
Most trauma survivors recover without intervention, but a minority develop chronic PTSD that requires treatment. Only two medications—sertraline and paroxetine—are FDA-approved for PTSD, with brexpiprazole-sertraline and MDMA-assisted therapy applications pending. Medication and medication-psychotherapy combinations are not recommended as first-line treatments. Instead, trauma-focused psychotherapies—prolonged exposure, cognitive processing therapy, eye movement desensitization and reprocessing, cognitive therapy, and trauma-focused cognitive-behavioral therapy—are the only first-line interventions. Psychedelic-assisted psychotherapy trials have shown higher response rates than other combination treatments, though they have not incorporated evidence-based PTSD psychotherapies. The review covers these state-of-the-art psychotherapies and their clinical and neurobiological effects.
The American journal of psychiatry
September 1, 2024
Evan M Hess, Dede K Greenstein, Olivia L Hutchinson et al.
12 citations
Ketamine increases pleasure from social situations in people with treatment-resistant depression and promotes helping behavior in rats. In a randomized, double-blind, placebo-controlled study, participants who received a single intravenous dose of ketamine (0.5 mg/kg) reported greater pleasure from being with family or close friends, seeing smiling faces, helping others, and receiving praise for up to one week after treatment, compared to those given placebo. In a rodent experiment, ketamine-treated rats were more willing to forgo obtaining sucrose to protect a cage mate from electric shock, maintaining lower response rates for six days and delivering fewer shocks overall. These findings indicate that ketamine has prosocial, entactogen effects.
The American journal of psychiatry
December 1, 2024
11 citations
PTSD is common and can become chronic without treatment. First-line treatments are individual trauma-focused psychotherapies, with antidepressants and non-trauma-focused psychotherapies also evidence-based. Many patients do not fully recover, prompting a search for novel treatments. This review critically evaluates emerging pharmacological and somatic interventions, including medication-assisted psychotherapy (e.g., MDMA), novel monotherapies (e.g., ketamine, cannabidiol), and neuromodulation (e.g., transcranial magnetic stimulation), as well as treatments of increasing interest (hyperbaric oxygen, stellate ganglion block, neurofeedback). Evidence for most novel treatments is preliminary and highly variable, though data for transcranial magnetic stimulation are encouraging.
The American journal of psychiatry
January 1, 2025
David E. Olson
8 citations
Psychedelics promote cortical neuron growth in the prefrontal cortex in preclinical studies, but measuring this structural plasticity in humans has been difficult. New positron emission tomography imaging advances could enable measurement of synaptic proteins after psychedelic administration. A translatable biomarker of psychedelic-induced neuroplasticity would help stratify patients, determine optimal dosing, and aid discovery of novel compounds with similar effects on structural neuroplasticity.
The American journal of psychiatry
June 1, 2026
Jason M Tucciarone, Igor D Bandeira, Christine Blasey et al.
5 citations
Ketamine rapidly reduces suicidal thoughts in major depressive disorder, but the effect is short-lived. In this trial, adults with major depression and active suicidal ideation received a single ketamine infusion, then were randomly assigned to take either low-dose buprenorphine or a placebo daily for four weeks. Suicidal thoughts dropped significantly more in the buprenorphine group (average decrease of 11.6 points on the Scale for Suicide Ideation) than in the placebo group (average decrease of 6.3 points). Depression scores did not differ between groups. No serious side effects occurred. Buprenorphine appears to sustain and boost ketamine's antisuicidal effects, offering a potentially safe, scalable option for suicide prevention.
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.
The American journal of psychiatry
June 1, 2026
Mina M Rizk, J John Mann
1 citation
Lithium and clozapine are associated with reductions in suicidal behavior in bipolar disorder and schizophrenia spectrum disorders, respectively, through mechanisms beyond disease stabilization. Intravenous ketamine rapidly reduces suicidal ideation in randomized controlled trials, partially independent of antidepressant effects, though the benefit is generally transient and studies were not powered for suicidal behavior. Antidepressants reduce suicidal ideation primarily through improvement in depressive symptoms, and observational studies generally find reduced suicidal behavior risk. Electroconvulsive therapy rapidly reduces suicidal ideation and suicide mortality, while transcranial magnetic stimulation appears to reduce suicidal ideation primarily via antidepressant effects. Targeting the diathesis for suicidal behavior is a largely unexplored therapeutic strategy.