American Journal of Psychiatry
August 29, 2018
Nolan Williams, Boris D. Heifets, Christine Blasey et al.
510 citations
Blocking opioid receptors with naltrexone dramatically reduced the antidepressant effect of ketamine in adults with treatment-resistant depression, while leaving ketamine's dissociative effects unchanged. In a double-blind crossover trial, 12 participants received either placebo or 50 mg of naltrexone before a ketamine infusion. Seven of 12 met the response criterion (≥50% reduction in depression scores) after ketamine plus placebo, but depression score reductions were significantly smaller when naltrexone was given. The trial was halted at an interim analysis because naltrexone blocked the antidepressant effect. The findings indicate that ketamine's acute antidepressant effect requires opioid system activation, while its dissociative effects do not.
The American journal of psychiatry
January 1, 2025
Aaron 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.
Nature Communications
October 19, 2023
Laura M Hack, Xue Zhang, B. Heifets et al.
20 citations
Ketamine rapidly induces altered states of consciousness, but the neural mechanisms are unclear. In a randomized, placebo-controlled study with nonclinical adults, functional neuroimaging examined brain activity during emotional tasks under placebo, low-dose (0.05 mg/kg), and high-dose (0.5 mg/kg) ketamine. Different dissociative experiences had opposing effects on right anterior insula activity: depersonalization reduced task-evoked activity by 0.39 standard deviations, while dissociative amnesia increased it by 0.32 standard deviations. These findings suggest that specific dissociative states may influence how ketamine affects brain activity, potentially informing treatment responses in depression.
FOCUS The Journal of Lifelong Learning in Psychiatry
January 1, 2021
Collin Reiff, Elon E. Richman, Charles B. Nemeroff et al.
17 citations
A review of clinical trials on psychedelic drugs for psychiatric disorders found the strongest evidence for MDMA and psilocybin, both designated by the FDA as breakthrough therapies for PTSD and treatment-resistant depression, respectively. Evidence for LSD and ayahuasca is observational but suggests potential therapeutic effects for mood, anxiety, trauma, and substance use disorders, as well as end-of-life care. Of 1,603 articles screened, 14 well-designed trials were identified. The database remains insufficient for FDA approval of any psychedelic for routine clinical use, but continued research is warranted.
American Journal of Psychiatry
January 1, 2025
Adrienne Grzenda, Gregory A. Fonzo, Aaron Wolfgang et al.
14 citations
Current evidence does not support recommending psilocybin combined with psychological support (PST) as a psychiatric treatment. More rigorous clinical trials are needed to confirm its effectiveness in larger and more diverse patient groups, determine appropriate dosing, improve blinding methods, and understand how it works and for whom it works best. Comparing it directly with other proven treatments will clarify its potential future role in treating major psychiatric disorders.
The American journal of psychiatry
December 1, 2024
Lauren M. Sippel, Jessica L. Hamblen, Benjamin Kelmendi et al.
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.
JAMA Network Open
April 1, 2025
Xue Zhang, Laura M Hack, Claire Bertrand et al.
10 citations
In a double-blind, placebo-controlled trial, 16 adults with subthreshold PTSD symptoms and early life trauma but no current psychiatric disorders were given 120 mg of MDMA or placebo. Participants were split into two groups based on baseline brain activity in the amygdala in response to nonconscious threat cues: those with high amygdala reactivity (NTNA+) and those with low reactivity (NTNA-). MDMA, compared with placebo, reduced activity in the amygdala and subgenual anterior cingulate cortex (sgACC), increased connectivity between the sgACC and amygdala, and increased liking of threatening facial expressions, but only in the NTNA+ subgroup. These findings suggest that baseline neural circuit profiles can identify who may benefit most from MDMA therapy and point to possible biomarkers for personalized treatment.
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.
bioRxiv Preprint Server
September 20, 2021
Laura M Hack, Katherine G. Warthen, Xue Zhang et al.
2 citations
preprint
Ketamine, a drug used for depression and anesthesia, causes dose-dependent increases in dissociation and intoxication, reduces emotional insensitivity, and raises stress as measured by cortisol. It alters brain connectivity, particularly between reward and negative affect circuits and thalamic sub-regions. Increased coupling between the amygdala and anteroventral thalamus correlates with greater dissociation and intoxication, while decreased coupling of anteromedial and posterior parietal thalamus correlates with increased sensory reward responsiveness. Drug-altered connectivity involving the nucleus accumbens and thalamic sub-regions shows negative associations with anxiety. These findings help disentangle the brain states underlying ketamine's acute effects, informing its therapeutic use and abuse risk.
Brazilian Journal of Psychiatry
January 1, 2025
David S. Mathai, Jill O. Robinson, Kevin Wagner et al.
1 citation
Among 2,639 Hispanic and Latin American adults with obsessive-compulsive disorder (OCD) living across the Americas, 9% reported using psychedelics or related substances for treatment. Most (72%) had received traditional treatments like psychiatric medication or psychotherapy. Psilocybin, LSD, and MDMA were the most used psychedelics. Users were more likely to be male, have received non-ERP therapy, and have a comorbid psychiatric diagnosis. Outcomes for OCD symptoms varied widely by drug and were difficult to predict, but were most favorable for classic serotonergic psychedelics. Real-world evidence suggests Hispanic and Latin American adults are exploring psychedelics as a treatment for OCD, though further research is needed to establish safe and effective use.
bioRxiv Preprint Server
July 6, 2020
Gwynne L. Davis, Adelaide R. Minerva, Argentina Lario et al.
preprint
Ketamine rapidly reduces compulsive grooming in a mouse model of obsessive-compulsive disorder by increasing activity in a specific brain circuit connecting the dorsomedial prefrontal cortex to the dorsomedial striatum. Optogenetically mimicking this increased fronto-striatal activity also rescued compulsive behavior, while inhibiting this circuit in normal mice increased grooming. These findings suggest this neural pathway may underlie ketamine's fast-acting therapeutic effects in OCD.