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At least 19 recordsLinked to original sources
PubMed2026

Blinding integrity in psychedelic research: Evidence from a comparative randomized controlled trial of psilocybin, MDMA, and methylphenidate in healthy volunteers.

Maintaining effective blinding is a major methodological challenge in psychedelic research. This study provides a comprehensive evaluation of blinding integrity in 120 healthy volunteers who received either psilocybin, MDMA, or methylphenidate (active placebo) in a double-blind, randomized controlled trial. Using a multi-level assessment incorporating forced-choice substance guesses, certainty ratings, decision factors, and subjective substance effects, the analyses characterize blinding integrity and its relation to the substance experience. Results indicate that overall blinding was insufficient, with psilocybin showing the highest rates of functional unblinding, MDMA moderate levels, and methylphenidate the lowest. As an active placebo, methylphenidate provided more effective blinding for MDMA than for psilocybin. Incorporating certainty levels of substance guesses revealed a more differentiated pattern, with lower functional unblinding rates. Decision factors and subjective substance experiences were associated with phenomenological substance effects. Prior substance experiences did not influence accuracy of forced-choice substance guesses. These findings provide empirical guidance for the design and reporting of blinding procedures in psychedelic trials and underscore the value of systematic, multi-level assessment of blinding integrity.

Humans↗
PubMed1997

LSD before Leary. Sidney Cohen's critique of 1950s psychedelic drug research.

In 1962 Sidney Cohen presented the medical community with its first warning about the dangers of the drug LSD. LSD had arrived in the United States in 1949 and was originally perceived as a psychotomimetic capable of producing a model psychosis. But in the mid 1950s intellectuals in Southern California redefined LSD as a psychedelic capable of producing mystical enlightenment. Though LSD was an investigational drug, authorized only for experimental use, by the late 1950s psychiatrists and psychologists were administering it to cure neuroses and alcoholism and to enhance creativity. Cohen's 1960 study of LSD effects concluded that the drug was safe if given in a supervised medical setting, but by 1962 his concern about popularization, nonmedical use, black market LSD, and patients harmed by the drug led him to warn that the spread of LSD was dangerous. The subsequent government crackdown and regulation of LSD preceded the 1960s drug movement and was prompted by medical, not social, concerns.

History, 20th Century↗
PubMed2026

Redefining the real problem in psychedelic trials: Why fighting the Lessebo matters more than blinding integrity.

Imperfect blinding is not specific to psychedelic trials. In randomized trials, treatment allocation is frequently correctly guessed, yet blinding integrity is rarely assessed outside of psychedelic research and is generally not considered a barrier in regulatory evaluation. The intense debate in psychedelics may reflect a broader double standard affecting mental health research, when uncertainties arising from imperfect blinding are confounded by those linked to patient-reported outcome measures. Indeed, people living with mental disorders are often viewed as unreliable reporters, despite well-documented limitations of clinician-rated scales and the absence of robust biological markers of symptomatic change. Importantly, it is the maintenance of reasonable doubt of treatment allocation that sustains internal validity and ethical feasibility of placebo-controlled designs, rather than perfect blinding. Concerns about expectancy bias in psychedelic trials are closely tied to blinding debates. When allocation is inferred, expectations may cluster in the arm perceived as active or in stereotyped experiences and influence outcomes differently in active and control arms, leading to a risk of lessebo, a negative placebo effect due to the negative expectation related to receiving a placebo. However, we argue that an underrecognized mechanism of lessebo is disappointment. This risk may reflect insufficient clinical management of disappointment rather than pre-treatment expectation alone. We therefore propose shifting the emphasis from preserving inevitably imperfect blinding towards mitigating disappointment in both arms. Establishing non-stereotyped expectations prior to treatment through structured psychoeducation, strengthened therapeutic alliance, and realistic preparation would help avoid lessebo effects. Such strategies would enhance ethical rigor, interpretability, and the clinical usefulness of psychedelic trials.

Humans↗
PubMed1998

Second thoughts on psychedelic drugs.

Psychedelic drugs are making a comeback. Proponents of psychedelics point to the widespread medical experimentation with mescaline and lysergic acid diethylamide-125 (LSD) in the 1950s as proof of their safety and efficacy. However, a review of the private and published writings of Sidney Cohen, MD, who conducted the first study of the safety of psychedelics, reveals that serious medical concerns about psychedelics arose before the public backlash against the drugs in the 1960s. The story of psychedelic research is a reminder of the inevitable complications involved in testing drugs on human subjects.

Drug Approval↗
PubMedDate not supplied

Treatment of alcoholism using psychedelic drugs: a review of the program of research.

Following Albert Hofmann's discovery of LSD's psychoactive properties in 1943, and previous to their scheduling as controlled substances, the psychedelic drugs were widely studied--six international conferences and hundreds of papers discussed their potential therapeutic usefulness. The observation that the frightening experience of delirium tremens sometimes led alcoholics to moderate their alcohol intake suggested to early psychedelic researchers that the "psychotomimetic" experience thought to be produced by LSD could be used to treat alcoholism. A number of hypothesis-generating studies employing a variety of research designs to examine this premise were completed, but relatively few controlled trials attempted hypothesis testing. After twenty-five years of study, a combination of flawed methodology, uneven results and social reprehension led to the abandonment of research on the therapeutic use of psychedelic drugs, leaving many avenues of inquiry unexplored and many questions unanswered. Today, after a thirty-year hiatus, this research is gradually being resumed, and there is renewed interest in the findings of previous studies. This article explores the history of one branch of psychedelic research, the therapeutic use of LSD in the treatment of alcoholism, and of the events that led to the relabeling of the "hallucinogens" as drugs of abuse.

Alcoholism↗
PubMed1998

History, rationale and potential of human experimental hallucinogenic drug research in psychiatry.

Systematic scientific interest in psychedelic substances has a tradition of about 100 years. Numerous human experimental studies have confirmed the existence of a common nucleus of experiences in hallucinogen-induced states and the acute stages of schizophrenic psychoses. However, the degree of resemblance between endogenous and drug-induced psychotic states has been an issue of controversial debate. After the scheduling of psychedelics in the 1960s, human research became highly restricted worldwide and scientific interest in this field faded. The debate about the appropriateness of the psychedelic state as a model for endogenous psychosis therefore seemed to have little practical relevance. Currently there is a revival of scientific interest in human experimental psychedelic research. Consequently, the appropriateness of hallucinogen-induced states as models for psychosis needs to be reappraised. The arguments for and against are summarized in this paper. In conclusion, the drug-induced model psychosis is shown to be a useful model for acute psychotic stages, but not for the nosological entity schizophrenia.

Hallucinogens↗
PubMed1986

Taking birth trauma seriously.

Virtually all mainstream schools of psychology, including biological psychology, reject the idea that people sustain psychological trauma at birth. Their objections are basically those raised by Freud more than 50 years ago: (1) lack of solid evidence that difficult births are related to mental disturbances and (2) a general conviction that the neonatal brain is not sufficiently developed to experience birth psychologically. But recent empirical evidence gathered by Stanislav Grof in over 3500 psychotherapy sessions using psychedelic drugs as a facilitator seems to show that a link does exist between birth trauma memory "matrices" in the unconscious and various mental conditions. And separate research on psychedelic drug effects, subcortical learning mechanisms and the nature of emotional response suggest that birth trauma memories might be explained in a way that circumvents without refuting Freud's basic objections. The following briefly reviews these developments, concluding that birth trauma theories--especially Grof's--deserve more serious consideration by mainstream psychologists and medical researchers.

Anxiety↗
PubMed2002

Effects of ayahuasca on sensory and sensorimotor gating in humans as measured by P50 suppression and prepulse inhibition of the startle reflex, respectively.

RATIONALE: Ayahuasca, a South American psychotropic plant tea, combines the psychedelic agent and 5-HT(2A/2C) agonist N, N-dimethyltryptamine (DMT) with beta-carboline alkaloids showing monoamine oxidase-inhibiting properties. Current human research with psychedelics and entactogens has explored the possibility that drugs displaying agonist activity at the 5-HT(2A/2C) sites temporally disrupt inhibitory neural mechanisms thought to intervene in the normal filtering of information. Suppression of the P50 auditory evoked potential (AEP) and prepulse inhibition of startle (PPI) are considered operational measures of sensory (P50 suppression) and sensorimotor (PPI) gating. Contrary to findings in lower animals, unexpected increases in sensorimotor gating have been found in humans following the administration of the serotonergic psychedelic psilocybin and the serotonin releaser 3,4-methylenedioxymethamphetamine (MDMA). In addition, to our knowledge P50 suppression has not been assessed previously in humans following the administration of a 5-HT(2A/2C) agonist. OBJECTIVES: To assess the effects of the acute administration of ayahuasca on P50 suppression and PPI in humans, in order to evaluate the drug's modulatory actions on these measures of sensory and sensorimotor gating. METHODS: Eighteen healthy volunteers with prior experience of psychedelic drug use participated in a clinical trial in which placebo or ayahuasca doses (0.6 mg and 0.85 mg DMT/kg body weight) were administered according to a double-blind, cross-over balanced design. P50 and startle reflex (pulse-alone and 60 ms, 120 ms, 240 ms and 2000 ms prepulse-to-pulse intervals) recordings were undertaken at 1.5 h and 2 h after drug intake, respectively. RESULTS: Ayahuasca produced diverging effects on each of the two gating measures evaluated. Whereas significant dose-dependent reductions of P50 suppression were observed after ayahuasca, no significant effects were found on the startle response, its habituation rate, or on PPI at any of the prepulse-to-pulse intervals studied. CONCLUSION: The present findings indicate, at the doses tested, a decremental effect of ayahuasca on sensory gating, as measured by P50 suppression, and no distinct effects on sensorimotor gating, as measured by PPI.

Acoustic Stimulation↗
PubMedDate not supplied

Ketamine psychedelic therapy (KPT): a review of the results of ten years of research.

Ketamine is a prescription drug used for general anesthesia. In subanesthetic doses, it induces profound psychedelic experiences and hallucinations. The subanesthetic effect of ketamine was the hypothesized therapeutic mechanism in the authors' use of ketamine-assisted psychotherapy for alcoholism. The results of a controlled clinical trial demonstrated a considerable increase in efficacy of the authors' standard alcoholism treatment when supplemented by ketamine psychedelic therapy (KPT). Total abstinence for more than one year was observed in 73 out of 111 (65.8%) alcoholic patients in the KPT group, compared to 24% (24 out of 100 patients) of the conventional treatment control group (p < 0.01). The authors' studies of the underlying psychological mechanisms of KPT have indicated that ketamine-assisted psychedelic therapy of alcoholic patients induces a harmonization of the Minnesota Multiphasic Personality Inventory (MMPI) personality profile, positive transformation of nonverbalized (mostly unconscious) self-concept and emotional attitudes to various aspects of self and other people, positive changes in life values and purposes, important insights into the meaning of life and an increase in the level of spiritual development. Most importantly, these psychological changes were shown to favor a sober lifestyle. The data from biochemical investigations showed that pharmacological action of KPT affects both monoaminergic and opioidergic neurotransmitter metabolism, i.e., those neurochemical systems which are involved in the pathogenesis of alcohol dependence. The data from EEG computer-assisted analysis demonstrated that ketamine increases theta activity in cerebrocortical regions of alcoholic patients. This is evidence of the reinforcement of limbic cortex interaction during KPT session.

Adult↗
PubMedDate not supplied

Shamans, sacraments, and psychiatrists.

This article reviews the role of psychedelic drugs as potential tools for psychiatric research and practice. The decline in the utilization of these substances is linked to social reactions, which led to psychedelics being scheduled as controlled substances and consequently unavailable for human research. Three different paradigms for the use of psychedelics in psychiatry are reviewed: the psychotomimetic, the psycholytic, and the psychedelic approaches. The psychotomimetic paradigm, which viewed hallucinogens as agents for temporarily inducing psychoses, proved to be of limited value to the understanding and treatment of mental illness. The psycholytic approach, which was derived from the psychoanalytic paradigm, is a technique employing low doses of psychedelic drugs to reduce psychological defenses and to release unconscious information. The high-dose psychedelic paradigm frequently produced reports of mystical or spiritual experiences, thus recasting the psychiatrist as the modern-day shaman. This paradigm has alienated many in the psychiatric profession and has led to a reaction against the use of psychedelics in psychotherapy. If the opportunity should arise to pursue sanctioned clinical research with these unique psychoactive substances, however, it will be imperative to learn from the traditional models of shamanic healers in order to optimally assess true clinical efficacy and safety.

Hallucinogens↗
PubMed2004

Effects of the South American psychoactive beverage ayahuasca on regional brain electrical activity in humans: a functional neuroimaging study using low-resolution electromagnetic tomography.

Ayahuasca, a South American psychotropic plant tea obtained from Banisteriopsis caapi and Psychotria viridis, combines monoamine oxidase-inhibiting beta-carboline alkaloids with N,N-dimethyltryptamine (DMT), a psychedelic agent showing 5-HT(2A) agonist activity. In a clinical research setting, ayahuasca has demonstrated a combined stimulatory and psychedelic effect profile, as measured by subjective effect self-assessment instruments and dose-dependent changes in spontaneous brain electrical activity, which parallel the time course of subjective effects. In the present study, the spatial distribution of ayahuasca-induced changes in brain electrical activity was investigated by means of low-resolution electromagnetic tomography (LORETA). Electroencephalography recordings were obtained from 18 volunteers after the administration of a dose of encapsulated freeze-dried ayahuasca containing 0.85 mg DMT/kg body weight and placebo. The intracerebral power density distribution was computed with LORETA from spectrally analyzed data, and subjective effects were measured by means of the Hallucinogen Rating Scale (HRS). Statistically significant differences compared to placebo were observed for LORETA power 60 and 90 min after dosing, together with increases in all six scales of the HRS. Ayahuasca decreased power density in the alpha-2, delta, theta and beta-1 frequency bands. Power decreases in the delta, alpha-2 and beta-1 bands were found predominantly over the temporo-parieto-occipital junction, whereas theta power was reduced in the temporomedial cortex and in frontomedial regions. The present results suggest the involvement of unimodal and heteromodal association cortex and limbic structures in the psychological effects elicited by ayahuasca.

Administration, Oral↗
PubMed1976

The psychedelic model of schizophrenia: the case of N,N-dimethyltryptamine.

The authors review the research on N,N-dimethyltryptamine (DMT) as a possible "schizotoxin." DMT produces psychedelic effects when administered to normal subjects, the means are present to synthesize it in man, it has occasionally been found in man, and tolerance to its behavioral effects is incomplete. However, DMT concentrations have not been proven to differ significantly in schizophrenics and normal controls. Also, in vivo synthesis of DMT has not been convincingly demonstrated, and the psychological changes it produces do not closely mimic the symptoms of schizophrenia. The authors conclude that more data are necessary before the validity of this theory can be determined.

Chlorpromazine↗