Archives of General Psychiatry
August 1, 2006
3,762 citations
A single intravenous dose of ketamine, an N-methyl-D-aspartate receptor antagonist, produced rapid and robust antidepressant effects in treatment-resistant major depression. Improvement was significant within 110 minutes and remained so for one week. The effect size was very large after 24 hours and moderate to large after one week. Among 17 subjects, 71% met response and 29% met remission criteria the day after infusion; 35% maintained response for at least one week. These findings suggest a role for glutamatergic modulation in achieving rapid relief from depression.
Archives of General Psychiatry
March 1, 1994
3,339 citations
Ketamine, a drug that blocks a specific brain receptor called NMDA, produces a broad set of effects in healthy people that resemble schizophrenia and dissociative states. In a randomized, double-blind, placebo-controlled study with 19 healthy adults, ketamine caused behaviors similar to both positive and negative symptoms of schizophrenia, altered perceptions, and impaired performance on tests of attention, verbal fluency, and cognitive flexibility. It disrupted delayed recall of words while sparing immediate and postdistraction recall. Ketamine also increased blood pressure and dose-dependently raised cortisol and prolactin levels, but did not affect a measure of general mental status. These findings suggest that NMDA receptor dysfunction may contribute to psychotic disorders.
Archives of General Psychiatry
September 7, 2010
Gurpreet S Chopra, Marycie Hagerty, Charles S. Grob et al.
1,220 citations
In a double-blind, placebo-controlled study, twelve adults with advanced-stage cancer and anxiety received a moderate dose (0.2 mg/kg) of psilocybin. Safe physiological and psychological responses were documented, with no clinically significant adverse events. The State-Trait Anxiety Inventory trait anxiety subscale showed a significant reduction in anxiety at 1 and 3 months after treatment. The Beck Depression Inventory indicated improved mood that reached significance at 6 months; the Profile of Mood States showed mood improvement that approached but did not reach significance. The results support the need for more research into psilocybin for cancer-related anxiety.
Archives of General Psychiatry
August 1, 2010
969 citations
A single intravenous dose of ketamine, an N-methyl-D-aspartate-receptor antagonist, produced rapid antidepressant effects in patients with treatment-resistant bipolar depression. Depressive symptoms improved within 40 minutes and remained significantly better than placebo through day 3. The largest drug effect occurred at day 2. Seventy-one percent of subjects responded to ketamine versus 6% to placebo. One subject in each group developed manic symptoms. Ketamine was generally well tolerated, with dissociative symptoms only at the 40-minute point.
Archives of General Psychiatry
September 1, 1966
Arnold M. Ludwig
640 citations
A large and scattered body of clinical and research reports on daydreaming, sleep and dreams, hypnosis, sensory deprivation, dissociative and depersonalization states, and drug-induced mental changes has not been organized into a consistent theoretical framework. This work aims to integrate current knowledge about various altered states of consciousness to determine the conditions necessary for their emergence, the factors influencing their outward manifestations, their common denominators, and the adaptive or maladaptive functions they may serve.
Archives of General Psychiatry
December 1, 2000
590 citations
In healthy volunteers, the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine significantly reduced the amplitude of mismatch negativity (MMN) brain responses to pitch and duration changes by 27% and 21%, respectively. Ketamine also impaired performance on a continuous performance test, decreasing hit rates and increasing specific context-dependent errors (BX errors), indicating a failure to form and use transient memory traces. These findings suggest that NMDARs are critically involved in generating MMN and that NMDAR dysfunction may underlie deficits in transient memory at different levels of information processing in schizophrenia.
Archives of General Psychiatry
February 1, 1994
Ruck J. Strassman
454 citations
Intravenous DMT produces rapid, intense hallucinogenic effects that peak within two minutes and resolve within half an hour, closely tracking blood levels. At higher doses (0.2 and 0.4 mg/kg), volunteers experienced brightly colored, rapidly moving visual images, a dissociative state with alternating euphoria and anxiety, and a complete replacement of ongoing mental experience. Lower doses (0.05–0.1 mg/kg) primarily caused emotional and bodily sensations, with 0.1 mg/kg producing the least desirable effects. A new Hallucinogen Rating Scale captured dose-related differences better than biological measures, offering a tool for comparing DMT with other agents affecting brain receptors.
Archives of General Psychiatry
March 1, 2000
425 citations
A drug that inhibits glutamate release, lamotrigine, reduced several effects of ketamine in healthy adults. Lamotrigine given before ketamine decreased perceptual abnormalities, positive and negative schizophrenia-like symptoms, and learning and memory impairment. However, it increased the immediate mood-elevating effects of ketamine. These findings suggest that glutamate release plays a role in some effects of NMDA receptor blockade and that drugs reducing glutamate release might help treat conditions like schizophrenia, though more research is needed.
Archives of General Psychiatry
September 1, 2005
John H. Krystal, Edward Perry, Ralitza Gueorguieva et al.
323 citations
Ketamine and amphetamine produce different patterns of psychotic and cognitive effects in healthy people. Ketamine causes perceptual changes, negative symptoms, and memory disruption, while amphetamine triggers hostility, grandiosity, and somatic concern. Both drugs produce positive symptoms and euphoria, but their interaction reveals three patterns: amphetamine reduces ketamine-induced working memory impairment; the drugs additively increase thought disorder, arousal, and euphoria; and their combined effect on psychosis is less than additive. These results suggest that glutamate and dopamine systems contribute differently to psychosis, thought disorder, and euphoria, and that boosting prefrontal dopamine may help cognitive problems linked to glutamate dysfunction.
Archives of General Psychiatry
February 1, 2008
J.f.w. Deakin, Jane Lees, Shane Mckie et al.
315 citations
Ketamine, which blocks NMDA glutamate receptors and secondarily increases glutamate release, produces psychosis-like symptoms. Using fMRI, a double-blind crossover study with 33 healthy men found that ketamine caused a rapid decrease in ventromedial frontal cortex activity that predicted dissociative effects, and increased activity in posterior cingulate, thalamus, and temporal regions that correlated with psychosis scores. Pretreatment with lamotrigine, a glutamate release inhibitor, prevented many brain changes and symptoms. The findings suggest ketamine's effects involve increased glutamate release and may model two core psychosis processes: abnormal perceptions and impaired cognitive-emotional evaluation.
Archives of General Psychiatry
October 1, 2001
Liesbeth Reneman, Jules Lavalaye, Ben Schmand et al.
192 citations
MDMA may cause lasting memory problems even after its toxic effects on serotonin neurons in the brain's cortex reverse. The study suggests that damage to memory function from MDMA use can persist over the long term, while the neurotoxic effects on serotonin-producing neurons might be reversible.
Archives of General Psychiatry
August 1, 1983
Henry David Abraham
172 citations
Among 123 people who had used LSD, a syndrome of ten specific distance visual disturbances was identified, persisting for five years in half of the group. The condition responded to benzodiazepines, worsened with phenothiazines, and could be triggered by 19 different stimuli, most often entering a dark environment. Compared with 40 control participants, the data suggest that sensitivity to LSD, as indicated by flashbacks, divides the sample into three distinct subgroups, and a genetic basis for this sensitivity may exist.
Archives of General Psychiatry
June 1, 1973
Charles Savage
150 citations
A controlled trial assigned 78 volunteer inmates with chronic heroin abuse to either a six-week residential program that included a single high-dose LSD session or to an outpatient clinic with daily urine checks and weekly group therapy. Among the 37 completers in each group, verified abstinence during the first year after discharge was significantly higher in the residential psychedelic therapy group.
Archives of General Psychiatry
August 1, 1983
Michael M. Vardy
145 citations
Patients hospitalized for LSD-induced psychosis are clinically similar to patients with first-episode schizophrenia in family history of psychosis, premorbid adjustment, most cognitive measures, and rates of rehospitalization over three to five years. The two groups differed on some clinical features, but the rate of parental alcoholism among LSD psychotics far exceeded that among schizophrenics and the general population. The findings suggest LSD psychosis represents a drug-induced schizophreniform reaction in individuals vulnerable to both substance abuse and psychosis.
Archives of General Psychiatry
March 1, 1968
Daniel X. Freedman
143 citations
Throughout history, humans have sought to escape dreary reality or dread through magic, drugs, drama, festival rites, and dreams. This urge to transcend limits also appears in utopian ideologies, which promise omnipotent mastery—whether for the proletariat, youth, or other groups. Drugs thus play a role not only in individual behavior but also in social and ideological processes, driven by these enduring motives.
Archives of General Psychiatry
May 1, 1962
B. Cohen, G. Rosenbaum, E. Luby et al.
131 citations
Phencyclidine hydrochloride, a compound with anesthetic and sedative properties, produced profound disturbances in reaction time, motor learning, and weight discrimination in normal subjects given subanesthetic doses. The degree and pattern of these deficits closely matched those found in chronic schizophrenic patients who took the same tests without drugs. These psychotomimetic effects were not due solely to the drug's hallucinogenic or sedative properties, as lysergic acid diethylamide and amobarbital sodium did not produce the same degree or pattern of deficits. The deficits seen in normal subjects under phencyclidine and in chronic schizophrenia may share a common underlying cause.
Archives of General Psychiatry
March 1, 1981
Patricia M. Whitaker
126 citations
Earlier reports suggested that LSD binding to serotonin receptors in the frontal cortex is reduced in schizophrenia, indicating fewer receptors. However, this analysis of 13 schizophrenic brains compared to 8 control brains found no overall decrease in binding. Residual neuroleptic drugs in brain tissue, which are difficult to wash out, may have caused the earlier findings; chlorpromazine-treated rats showed reduced binding affinity consistent with this. In five patients likely neuroleptic-free for the year before death, LSD binding was significantly increased, though this requires replication in larger samples.
Archives of General Psychiatry
November 1, 1967
William McGlothlin
118 citations
A single 200μg dose of LSD produced measurable changes in anxiety and attitudes one week later, but no changes in creativity. The study assessed personality, attitude, value, interest, and performance changes in normal subjects after a single LSD session. Some significant changes appeared in anxiety and attitude tests, while creativity measures showed no significant effects. The authors note that evaluating lasting effects of hallucinogens involves more extradrug variables than most drug studies.
Archives of General Psychiatry
January 1, 1971
William H. Mcglothlin
116 citations
A follow-up survey of 247 people who had taken LSD in experimental or psychotherapeutic settings found little evidence of lasting changes in personality, beliefs, values, attitudes, or behavior across the whole sample. Twenty-three percent reported later nonmedical use of LSD and attributed more personality changes to the drug, but compulsive patterns of use rarely developed. The drug's effects appear to become less attractive with continued use, making long-term use almost always self-limiting.
Archives of General Psychiatry
May 1, 1963
105 citations
Adverse reactions to hallucinogenic drugs like LSD are increasing, yet their therapeutic value remains unsettled due to a lack of definitive studies. The authors argue these compounds are unique tools for studying altered states of awareness, perception, and ideation, and emphasize the need for continued research to understand their advantages and limitations. The term 'hallucinogen' is considered a poor name since true hallucinations occur infrequently.
Archives of General Psychiatry
January 1, 1989
Lawrence H. Price
92 citations
MDMA, also known as ecstasy, damages serotonin neurons in lab animals. In humans, this study compared nine recreational MDMA users with nine matched controls by measuring prolactin and mood responses to an intravenous dose of L-tryptophan, a serotonin precursor. L-Tryptophan normally raises prolactin levels, but this response was blunted in MDMA users, although the difference did not reach statistical significance. The findings suggest altered serotonin function in MDMA users, but more definitive studies are needed.
Archives of General Psychiatry
January 1, 1980
91 citations
A controlled study compared muscle biofeedback, transcendental meditation, and relaxation therapy for chronic anxiety over a six-week treatment period with follow-up of three to 18 months. Forty percent of subjects experienced a clinically significant decrease in anxiety. No differences emerged between treatments in efficacy, timing of symptom improvement, or durability of gains. The degree of muscle relaxation achieved did not relate to therapeutic outcome. Relaxation therapies alone appear to have limited value for chronic anxiety.
Archives of General Psychiatry
June 6, 2011
David Erritzøe, Vibe G. Frøkjær, Klaus K. Holst et al.
86 citations
MDMA use, but not hallucinogen use, is linked to changes in the brain's presynaptic serotonin system. Because hallucinogens primarily act on serotonin 2A receptors, the negative association between MDMA use and serotonin transporter (SERT) binding is likely due to MDMA's direct presynaptic effect rather than its serotonin 2A agonistic actions. Cross-sectional data suggest that subcortical, but not cortical, SERT binding may recover after several months of MDMA abstinence.
Archives of General Psychiatry
March 1, 1960
Arthur L. Chandler
77 citations
Drug-facilitated psychotherapy can help repressed material become conscious and increase insight. Certain drugs including mescaline, psilocybin, and LSD-25 broaden a patient's spectrum of awareness, enabling them to see and experience affects, childhood memories, conflicts, and impulse strivings previously blocked by repression. The present study aimed to further evaluate LSD-25 as an aid to psychotherapy and develop procedures for its most effective use.
Archives of General Psychiatry
September 1, 1959
Antonio Balestrieri
76 citations
Tolerance to LSD-25 develops rapidly in both humans and animals, while tolerance to mescaline develops more slowly, as observed in rats. Crossed tolerance between LSD-25 and mescaline was previously demonstrated in three human subjects. The present study aims to confirm these findings and investigate whether rapid tolerance to mescaline occurs in humans, whether such tolerance confers resistance to LSD-25, and whether prolonged administration of BOL-148 produces tolerance to itself and to LSD-25.