American Journal of Psychiatry
October 1, 1991
2,916 citations
Phencyclidine (PCP, "angel dust") produces a psychotic state that closely resembles schizophrenia, including both positive symptoms (hallucinations, paranoia) and negative symptoms (emotional withdrawal, motor retardation), as well as formal thought disorder and neuropsychological deficits. At the low serum concentrations that cause these effects, PCP selectively blocks a specific binding site (the PCP receptor) associated with the NMDA-type glutamate receptor, thereby inhibiting NMDA receptor-mediated neurotransmission. Other NMDA antagonists, such as ketamine, produce similar effects in proportion to their ability to bind the PCP receptor. These findings suggest that impaired NMDA receptor function may contribute to schizophrenia.
American Journal of Psychiatry
July 1, 1992
1,950 citations
A group stress reduction program based on mindfulness meditation effectively reduced symptoms of anxiety and panic in patients with generalized anxiety disorder or panic disorder, with or without agoraphobia. Twenty participants showed significant reductions in anxiety and depression scores after treatment, and these improvements were maintained during a three-month follow-up. The number of participants experiencing panic symptoms also substantially decreased. Similar reductions in anxiety scores were observed in a comparison group of non-study participants who met the same screening criteria, suggesting the findings may apply more broadly.
American Journal of Psychiatry
August 28, 2013
1,207 citations
A single intravenous infusion of ketamine produced greater improvement in depression severity 24 hours later than the active placebo midazolam in patients with treatment-resistant major depression. In a randomized controlled trial of 73 participants, the ketamine group scored 7.95 points lower on the Montgomery-Åsberg Depression Rating Scale than the midazolam group. Response rates were 64% for ketamine and 28% for midazolam, with an odds ratio of 2.18 favoring ketamine. The findings support NMDA receptor modulation as a mechanism for rapid improvement in severe, chronic depression, though more information on durability and safety is needed before clinical use.
American Journal of Psychiatry
May 21, 2019
879 citations
Switching to esketamine nasal spray plus a new antidepressant led to a significantly greater reduction in depression severity after 28 days than switching to a new antidepressant alone in adults with treatment-resistant depression. The average improvement on the Montgomery-Åsberg Depression Rating Scale was 4 points greater with esketamine (95% CI -7.31 to -0.64). Earlier improvements were also seen. Common side effects included dissociation, nausea, vertigo, dysgeusia, and dizziness, which typically appeared shortly after dosing and resolved within 1.5 hours. Seven percent of esketamine patients discontinued due to adverse events versus 0.9% in the comparator group. The findings support esketamine as a rapidly acting option for this difficult-to-treat population.
American Journal of Psychiatry
March 17, 2021
R. Mcintyre, J. Rosenblat, C. Nemeroff et al.
694 citations
Ketamine and esketamine are the first non-monoamine-based antidepressants with rapid-onset efficacy for adults with treatment-resistant depression, offering hope to those who do not recover fully with standard antidepressants. However, concerns remain about their safety, tolerability, and appropriate placement in treatment algorithms. An international group of mood disorder experts synthesizes evidence on efficacy, safety, and tolerability, and provides guidance for clinical implementation, including practice parameters at point of care. Areas of consensus and future research directions are discussed.
American Journal of Psychiatry
October 3, 2017
S. Wilkinson, Elizabeth D. Ballard, M. Bloch et al.
680 citations
A single dose of ketamine rapidly reduces suicidal thoughts within one day and for up to one week in depressed patients with suicidal ideation. The effect is moderate to large and partially independent of changes in depressive symptoms. The analysis combined data from 167 participants across 10 studies comparing ketamine to a placebo (saline or midazolam). Ketamine significantly improved clinician-rated and self-reported suicidal ideation, though not on one self-report measure (the Beck Depression Inventory). The authors call for further research on long-term safety and suicide risk reduction before clinical use.
American Journal of Psychiatry
April 16, 2018
666 citations
Adding intranasal esketamine to standard care rapidly reduced depression symptoms in people at imminent suicide risk. In a double-blind trial, 68 participants received either esketamine (84 mg) or placebo twice weekly for four weeks. Depression scores improved significantly more with esketamine at 4 hours and 24 hours after the first dose, but not at 25 days. Suicidal thoughts improved at 4 hours but not later. Clinician-rated suicide risk did not differ between groups at any time. Common side effects of esketamine included nausea, dizziness, dissociation, unpleasant taste, and headache. The findings suggest esketamine may offer rapid but temporary relief for severe depression with suicide risk.
American Journal of Psychiatry
October 1, 2015
594 citations
A systematic review and meta-analysis of placebo-controlled, double-blind, randomized trials found that ketamine produces a rapid but short-lived antidepressant effect. In seven trials with 147 participants, ketamine greatly increased the odds of treatment response and transient remission of symptoms at 24 hours, though it also caused brief psychotomimetic and dissociative effects. When ketamine was added to electroconvulsive therapy (ECT) in five trials with 89 participants, depressive symptoms were reduced after the first treatment but not by the end of the ECT course. Other NMDA receptor antagonists generally did not show consistent efficacy, but two partial agonists, d-cycloserine and rapastinel, reduced depressive symptoms without psychotomimetic or dissociative effects. The fleeting benefit of ketamine, along with its abuse potential and neurotoxicity, warrant caution in clinical use.
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.
American Journal of Psychiatry
December 5, 2017
M. Grunebaum, H. Galfalvy, Tse-Hwei Choo et al.
428 citations
A single dose of intravenous ketamine, added to usual care, reduced suicidal thoughts more than the comparison drug midazolam in adults with major depressive disorder and clinically significant suicidal ideation. Twenty-four hours after infusion, suicidal ideation scores dropped by an average of 4.96 points more with ketamine, and 55% of ketamine-treated patients had at least a 50% reduction in suicidal thoughts compared with 30% of those given midazolam. The benefit was partly independent of improvement in depression and lasted up to six weeks with continued pharmacotherapy. Side effects were short-lived. Ketamine appears to rapidly reduce suicidal ideation in depressed patients, though its mechanism remains unclear.
American Journal of Psychiatry
March 29, 2019
J. Phillips, S. Norris, J. Talbot et al.
416 citations
A single infusion of ketamine reduces depressive symptoms more than an active placebo (midazolam) in people with treatment-resistant depression 24 hours after treatment. Repeated infusions produce cumulative antidepressant effects and double the response rate; 59% of participants responded after a median of three infusions. Weekly maintenance infusions sustain the reduction in depressive symptoms among responders but do not produce further improvement. The findings suggest that repeated ketamine infusions offer a viable strategy for prolonging antidepressant effects in this population.
American Journal of Psychiatry
November 1, 2003
Jacqueline Borg, Bengt Andrée, Henrik Söderström et al.
247 citations
In 15 normal male subjects aged 20–45, the density of serotonin 5-HT(1A) receptors, measured with PET imaging, correlated inversely with scores for self-transcendence, a personality trait that includes religious behavior and attitudes. No correlations appeared for the other six dimensions of the Temperament and Character Inventory. Further analysis showed that the subscale for spiritual acceptance, but not the other two subscales of self-transcendence, was significantly linked to receptor binding potential. The finding suggests the serotonin system may serve as a biological basis for spiritual experiences, and the several-fold variability in receptor density may help explain why people differ greatly in spiritual zeal.
American Journal of Psychiatry
January 5, 2021
A. Feder, Sara Costi, S. Rutter et al.
239 citations
Repeated intravenous infusions of ketamine, given over two weeks, significantly reduced symptom severity in chronic PTSD compared to a psychoactive placebo (midazolam). At two weeks, the ketamine group scored nearly 12 points lower on the Clinician-Administered PTSD Scale, and 67% of participants responded to treatment versus 20% in the placebo group. Among responders, the median time to loss of response was 27.5 days after the infusion course. Ketamine was well tolerated with no serious adverse events. This is the first randomized controlled trial to show efficacy of repeated ketamine infusions for chronic PTSD.
American Journal of Psychiatry
July 12, 2023
Guy M. Goodwin, Ekaterina Malievskaia, Gregory A. Fonzo et al.
187 citations
Psilocybin, a hallucinogen derived from mushrooms, significantly improved psychological well-being in 70% of participants in a recent drug study. Involving 100 adults undergoing therapy, those receiving psilocybin experienced enhanced emotional processing and reduced anxiety. This effect is attributed to psilocybin's influence on neurotransmitter receptors, which alters behavior and mood. Psychotherapists reported that patients showed increased openness and decreased fear of death after treatment, highlighting the potential of psychedelics like psilocybin for therapeutic use in mental health care.
American Journal of Psychiatry
July 1, 2004
Ralph Buchert, Rainer Thomasius, Florian Wilke et al.
183 citations
Repeated use of MDMA (ecstasy) may cause long-lasting changes to the brain's serotonin system, but these changes could be reversible over time. Brain scans using PET show reduced availability of serotonin transporters in people who have used MDMA, suggesting damage to serotonin-producing neurons. The study also finds that women are more vulnerable than men to these MDMA-induced alterations. The findings support the idea that MDMA use leads to protracted changes in the serotonergic system, but the reduced serotonin transporter availability might recover with abstinence.
American Journal of Psychiatry
December 2, 2019
E. Dakwar, F. Levin, C. Hart et al.
179 citations
A single low-dose ketamine infusion, combined with motivational enhancement therapy, increased the likelihood of abstinence and reduced heavy drinking days in adults with alcohol dependence. In a pilot study, 40 participants received either ketamine or the active control midazolam. Ketamine delayed relapse and was well tolerated, with no dropouts due to adverse events. The results suggest a potential new approach integrating pharmacotherapy with behavioral treatment, though larger studies are needed to confirm these findings.
American Journal of Psychiatry
June 24, 2019
E. Dakwar, E. Nunes, C. Hart et al.
179 citations
A single infusion of ketamine, combined with mindfulness-based relapse prevention, helped adults dependent on cocaine stay abstinent longer and reduce cravings. In a trial with 55 participants, 48.2% of those receiving ketamine maintained abstinence over the final two weeks, compared to 10.7% in the control group receiving midazolam. The ketamine group was 53% less likely to relapse or drop out, and their craving scores were 58.1% lower throughout the study. The infusions were well tolerated with no serious adverse events. The authors suggest these results are promising but need replication in a larger sample.
American Journal of Psychiatry
October 1, 1980
174 citations
People who report near-death experiences often have had prior experiences suggesting transcendence of death, more so than control populations, but prior experiences suggesting extrasensory phenomena are less common. After such an experience, changes in attitudes are more common than in people who have had other psychic experiences. Cultural and psychological factors, sensory deprivation, and reflex adaptive responses to stress explain some but not all features of near-death experiences. Their potential value to understanding dying, suicide prevention, and care of the terminally ill justifies further investigation.
American Journal of Psychiatry
January 11, 2022
Meryem Grabski, Amy Mcandrew, Will Lawn et al.
169 citations
Three weekly infusions of ketamine (0.8 mg/kg) helped people with severe alcohol use disorder stay abstinent more days over six months than placebo infusions did. The ketamine group averaged 10.1% more days abstinent than the placebo group. Combining ketamine with mindfulness-based relapse prevention therapy produced the largest improvement, with 15.9% more abstinent days compared with placebo plus alcohol education. No serious adverse events occurred. Relapse rates did not differ significantly between ketamine and placebo groups. The findings suggest ketamine is safe and may support abstinence, especially when paired with psychological therapy.
American Journal of Psychiatry
January 1, 1985
165 citations
Meditation and psychotherapy can be integrated synergistically. Meditation's psychobiological nature, particularly the relaxation response, and mindfulness meditation as a cognitive technique for developing self-awareness, are examined. The emotional and cognitive changes produced by meditation have therapeutic value, and combining psychotherapy with meditation offers synergistic advantages.
American Journal of Psychiatry
March 3, 2021
J. Dwyer, A. Landeros-Weisenberger, Jessica A. Johnson et al.
163 citations
A single intravenous dose of ketamine (0.5 mg/kg) significantly reduced depressive symptoms in adolescents with major depressive disorder compared with an active placebo (midazolam) 24 hours after infusion, with a large effect size. The improvement appeared to persist for up to 14 days on one depression scale but not another. More participants responded to ketamine during the first three days (76%) than to midazolam (35%). Ketamine caused temporary dissociative symptoms but no serious adverse events. This first controlled trial in adolescents suggests ketamine is well tolerated and has short-term efficacy for treatment-resistant depression.
American Journal of Psychiatry
June 1, 1952
Charles Savage
137 citations
A single oral dose of LSD as low as 20 micrograms produces depersonalization, derealization, and increased imagery in healthy individuals, while larger doses are needed to produce the same effects in psychotic patients. In a treatment study of 15 patients with depressive reactions given daily oral doses of 20–100 micrograms of LSD for one month, 3 recovered and 4 improved, 4 showed no improvement, and treatment was discontinued in 4 cases before proper evaluation. Anxiety was a prominent reaction; euphoria occurred less frequently. In 3 patients who developed euphoria, it aided psychotherapy by encouraging expression of feeling, whereas heightened anxiety in others encouraged reticence.
American Journal of Psychiatry
July 1, 2000
Robert Klitzman, Harrison G. Pope, James I. Hudson
132 citations
Among 169 gay and bisexual men at New York City dance clubs, about one-third reported using MDMA at least monthly. MDMA use was strongly and significantly linked to recent unprotected anal intercourse, and this link held even after accounting for age, ethnicity, and other drug use including alcohol. The authors suggest MDMA abuse and its association with high-risk sexual behaviors represent important but unexplored public health problems for some gay and bisexual men.
American Journal of Psychiatry
November 1, 1974
Bernard Albaugh, Philip O. Anderson
128 citations
A treatment program for alcoholism among American Indians combines occupational and cultural therapy, including participation in Native American Church peyote meetings. During these meetings, participants ingest peyote (mescaline), which facilitates cathartic expression and enhances suggestibility. The authors do not propose that the peyote meeting is a cure for alcoholism but suggest it offers specific advantages for treating the unique problems of Indian alcoholics.
American Journal of Psychiatry
October 1, 1969
Mardi J. Horowitz
125 citations
Flashbacks are the return of imagery long after the immediate effects of hallucinogens have subsided. The most symptomatic form involves recurrent, involuntary intrusions of the same frightening image into awareness. The author compares flashbacks with other clinical phenomena and believes psychotherapy is helpful, particularly when it focuses on the traumatic and screening aspects of the imagery.