Effects of ayahuasca on psychometric measures of anxiety, panic-like and hopelessness in Santo Daime members.

The use of the hallucinogenic brew ayahuasca, obtained from infusing the shredded stalk of the malpighiaceous plant Banisteriopsis caapi with the leaves of other plants such as Psychotria viridis, is growing in urban centers of Europe, South and North America in the last several decades. Despite this diffusion, little is known about its effects on emotional states. The present study investigated the effects of ayahuasca on psychometric measures of anxiety, panic-like and hopelessness in members of the Santo Daime, an ayahuasca-using religion. Standard questionnaires were used to evaluate state-anxiety (STAI-state), trait-anxiety (STAI-trait), panic-like (ASI-R) and hopelessness (BHS) in participants that ingested ayahuasca for at least 10 consecutive years. The study was done in the Santo Daime church, where the questionnaires were administered 1h after the ingestion of the brew, in a double-blind, placebo-controlled procedure. While under the acute effects of ayahuasca, participants scored lower on the scales for panic and hopelessness related states. Ayahuasca ingestion did not modify state- or trait-anxiety. The results are discussed in terms of the possible use of ayahuasca in alleviating signs of hopelessness and panic-like related symptoms.

Psychometric assessment of the Hallucinogen Rating Scale.

Reliability and convergent-discriminant validity of a Spanish version of the Hallucinogen Rating Scale (HRS) were assessed in two differentiated populations of hallucinogen users involving the retrospective assessment of drug effects. In Study 1 (immediate assessment), 75 European users of the South American hallucinogenic drink ayahuasca answered the HRS 4 h after drug intake in their habitual setting. In Study 2 (delayed assessment), 56 adult polydrug users answered the HRS and a short form of the Addiction Research Center Inventory (ARCI) recalling the effects they experienced when they last took a hallucinogen, in order to test the convergent-discriminant validity of HRS with the scales of the standard questionnaire used in most studies involving psychoactive drugs. The HRS scales showed increases after both the immediate and delayed retrospective assessment of drug effects. Reliability data indicated that four of the six scales show an acceptable level of internal consistency. Significant but limited correlations were found between the Perception and Somaesthesia scales and the ARCI LSD scale, pointing out the questionnaire's construct validity. Thus, the HRS was sensitive to hallucinogenic drug effects other than those elicited by intravenous N,N-dimethyltryptamine (DMT), for which it was originally designed, and showed reasonable reliability and convergent validity. Results suggest its usefulness in the evaluation of subjective effects elicited by psychoactive drugs with hallucinogenic properties, and constitute a preliminary approach to the effects of ayahuasca in European subjects.

Psychedelic effects of ketamine in healthy volunteers: relationship to steady-state plasma concentrations.

BACKGROUND: Ketamine has been associated with a unique spectrum of subjective "psychedelic" effects in patients emerging from anesthesia. This study quantified these effects of ketamine and related them to steady-state plasma concentrations. METHODS: Ketamine or saline was administered in a single-blinded crossover protocol to 10 psychiatrically healthy volunteers using computer-assisted continuous infusion. A stepwise series of target plasma concentrations, 0, 50, 100, 150, and 200 ng/ml were maintained for 30 min each. After 20 min at each step, the volunteers completed a visual analog (VAS) rating of 13 symptom scales. Peripheral venous plasma ketamine concentrations were determined after 28 min at each step. One hour after discontinuation of the infusion, a psychological inventory, the hallucinogen rating scale, was completed. RESULTS: The relation of mean ketamine plasma concentrations to the target concentrations was highly linear, with a correlation coefficient of R = 0.997 (P = 0.0027). Ketamine produced dose-related psychedelic effects. The relation between steady-state ketamine plasma concentration and VAS scores was highly linear for all VAS items, with linear regression coefficients ranging from R = 0.93 to 0.99 (P < 0.024 to P < 0.0005). Hallucinogen rating scale scores were similar to those found in a previous study with psychedelic doses of N,N-dimethyltryptamine, an illicit LSD-25-like drug. CONCLUSIONS: Subanesthetic doses of ketamine produce psychedelic effects in healthy volunteers. The relation between steady-state venous plasma ketamine concentrations and effects is highly linear between 50 and 200 ng/ml.

Differential tolerance to biological and subjective effects of four closely spaced doses of N,N-dimethyltryptamine in humans.

Tolerance of the behavioral effects of the short-acting, endogenous hallucinogen, N,N-dimethyltryptamine (DMT) is seen inconsistently in animals, and has not been produced in humans. The nature and time course of responses to repetitive, closely spaced administrations of an hallucinogenic dose of DMT were characterized. Thirteen experienced hallucinogen users received intravenous 0.3 mg/kg DMT fumarate, or saline placebo, four times, at 30 min intervals, on 2 separate days, in a randomized, double-blind, design. Tolerance to "psychedelic" subjective effects did not occur according to either clinical interview or Hallucinogen Rating Scale scores. Adrenocorticotropic hormone (ACTH), prolactin, cortisol, and heart rate responses decreased with repeated DMT administration, although blood pressure did not. These data demonstrate the unique properties of DMT relative to other hallucinogens and underscore the differential regulation of the multiple processes mediating the effects of DMT.

Human psychopharmacology of hoasca, a plant hallucinogen used in ritual context in Brazil.

A multinational, collaborative, biomedical investigation of the effects of hoasca (ayahuasca), a potent concoction of plant hallucinogens, was conducted in the Brazilian Amazon during the summer of 1993. This report describes the psychological assessment of 15 long-term members of a syncretic church that utilizes hoasca as a legal, psychoactive sacrament as well as 15 matched controls with no prior history of hoasca ingestion. Measures administered to both groups included structured psychiatric diagnostic interviews, personality testing, and neuropsychological evaluation. Phenomenological assessment of the altered state experience as well as semistructured and open-ended life story interviews were conducted with the long-term use hoasca group, but not the hoasca-naive control group. Salient findings included the remission of psychopathology following the initiation of hoasca use along with no evidence of personality or cognitive deterioration. Overall assessment revealed high functional status. Implications of this unusual phenomenon and need for further investigation are discussed.

Human psychopharmacology of N,N-dimethyltryptamine.

We generated dose-response data for the endogenous and ultra-short-acting hallucinogen, N,N-dimethyltryptamine (DMT), in a cohort of experienced hallucinogen users, measuring multiple biological and psychological outcome measures. Subjective responses were quantified with a new rating scale, the HRS, which provided better resolution of dose effects than did the biological variables. A tolerance study then was performed, in which volunteers received four closely spaced hallucinogenic doses of DMT. Subjective responses demonstrated no tolerance, while biological measures were inconsistently reduced over the course of the sessions. Thus, DMT remains unique among classic hallucinogens in its inability to induce tolerance to its psychological effects. To assess the role of the 5-HT1A site in mediating DMT's effects, a pindolol pre-treatment study was performed. Pindolol significantly increased psychological responses to DMT, suggesting a buffering effect of 5-HT1A agonism on 5-HT2-mediated psychedelic effects. These data are opposite to those described in lower animal models of hallucinogens' mechanisms of action.

Farmacologia humana da hoasca, planta alucinogena usada em contexto ritual no Brasil: I. Efeito psicologico

Uma investigacao biomedica em cooperacao multinacional dos efeitos da hoasca (ayahuasca), uma potente decoccao de plantas alucinogenas, foi conduzida na Amazonia brasileira durante o verao de 1993. Esta comunicacao descreve os achados psicologicos de membros filiados ha 15 anos de uma religiao sincretica que utiliza a hoasca legalmente como sacramento, assim como de 15 individuos-controle sem historia anterior de ingestao da hoasca. Avaliacoes administradas a ambos os grupos incluiram entrevistas para diagnostico psiquiatrico estruturado, teste de personalidade e avaliacao neuropsicologica. Achados fenomenologicos dos estados alterados de consciencia, bem como entrevistas semi-estruturadas e abertas de historias de vida foram conduzidas com o primeiro grupo, mas nao com o grupo controle. Os achados incluiram a presenca de psicopatologias em grau significativo no passado do grupo usuario, anterior a primeira experiencia com a hoasca, que pareceu haver remitido na sequencia. Diferencas significativas foram tambem encontradas nos testes neuropsicologicos e de personalidade entre os dois grupos, entretanto, nao houve evidencia de deterioracao cognitiva ou de personalidade nos usuarios da hoasca. De fato a avaliacao global revelou status funcional elevado, atribuido pelos individuos ao uso ritual do seu sacramento psicoativo, hoasca. Embora as interpretacoes destes resultados sejam na por ora preliminares devido a limitacoes metodologicas, investigacao futura quanto ao risco de sequelas adversas, assim como ao potencial para efeito solutar deste fenomeno nao usual, e indicada.

Hallucinogenic drugs in psychiatric research and treatment. Perspectives and prospects.

Clinical research with hallucinogens has resumed after a generation's hiatus. To place these new studies in context, this article reviews the history of hallucinogens' use and abuse, discusses their pharmacological properties, and highlights previous human studies. Research with lysergic acid diethylamide and related hallucinogens with thousands of patients and control subjects was associated with acceptable safety when subjects were carefully screened, supervised, and followed up. Data were generated regarding hallucinogens' psychopharmacology, overlap with endogenous psychoses, and psychotherapeutic efficacy. Current American and European studies emphasize systematic psychopharmacology, in addition to psychotherapy protocols. Human hallucinogen research will help define unique mind-brain interfaces, and provide mechanistic hypotheses and treatment options for psychiatric disorders. It is critical that human hallucinogen research in the 1990s make use of state of the art methodologies, or consensually define when modifications are required. Training and supervisory issues also must be explicitly addressed.

Dose-response study of N,N-dimethyltryptamine in humans. I. Neuroendocrine, autonomic, and cardiovascular effects.

BACKGROUND: To begin applying basic neuropharmacological hypotheses of hallucinogenic drug actions to humans, we generated dose-response data for intravenously administered dimethyltryptamine fumarate's (DMT) neuroendocrine, cardiovascular, autonomic, and subjective effects in a group of experienced hallucinogen users. METHODS: Dimethyltryptamine, an endogenous mammalian hallucinogen and drug of abuse, was administered intravenously at 0.05, 0.1, 0.2, and 0.4 mg/kg to 11 experienced hallucinogen users, in a double-blind, saline placebo-controlled, randomized design. Treatments were separated by at least 1 week. RESULTS: Peak DMT blood levels and subjective effects were seen within 2 minutes after drug administration, and were negligible at 30 minutes. Dimethyltryptamine dose dependently elevated blood pressure, heart rate, pupil diameter, and rectal temperature, in addition to elevating blood concentrations of beta-endorphin, corticotropin, cortisol, and prolactin. Growth hormone blood levels rose equally in response to all doses of DMT, and melatonin levels were unaffected. Threshold doses for significant effects relative to placebo were also hallucinogenic (0.2 mg/kg and higher). Subjects with five or more exposures to 3,4-methylenedioxymethamphetamine demonstrated less robust pupil diameter effects than those with two or fewer exposures. CONCLUSIONS: Dimethyltryptamine can be administered safely to experienced hallucinogen users and dose-response data generated for several measures hypothesized under serotonergic modulatory control. Additional studies characterizing the specific mechanisms mediating DMT's biological effects may prove useful in psychopharmacological investigations of drug-induced and endogenous alterations in brain function.

Dose-response study of N,N-dimethyltryptamine in humans. II. Subjective effects and preliminary results of a new rating scale.

BACKGROUND: Validation of animal models of hallucinogenic drugs' subjective effects requires human data. Previous human studies used varied groups of subjects and assessment methods. Rating scales for hallucinogen effects emphasized psychodynamic principles or the drugs' dysphoric properties. We describe the subjective effects of graded doses of N,N-dimethyltryptamine (DMT), an endogenous hallucinogen and drug of abuse, in a group of experienced hallucinogen users. We also present preliminary data from a new rating scale for these effects. METHODS: Twelve highly motivated volunteers received two doses (0.04 and 0.4 mg/kg) of intravenous (IV) dimethyltryptamine fumarate "nonblind," before entering a double-blind, saline placebo-controlled, randomized study using four doses of IV DMT. Subjects were carefully interviewed after resolution of drug effects, providing thorough and systematic descriptions of DMT's effects. They also were administered a new instrument, the Hallucinogen Rating Scale (HRS). The HRS was drafted from interviews obtained from an independent sample of 19 experienced DMT users, and modified during early stages of the study. RESULTS: Psychological effects of IV DMT began almost immediately after administration, peaked at 90 to 120 seconds, and were almost completely resolved by 30 minutes. This time course paralleled DMT blood levels previously described. Hallucinogenic effects were seen after 0.2 and 0.4 mg/kg of dimethyltryptamine fumarate, and included a rapidly moving, brightly colored visual display of images. Auditory effects were less common. "Loss of control," associated with a brief, but overwhelming "rush," led to a dissociated state, where euphoria alternated or coexisted with anxiety. These effects completely replaced subjects' previously ongoing mental experience and were more vivid and compelling than dreams or waking awareness. Lower doses, 0.1 and 0.05 mg/kg, were primarily affective and somaesthetic, while 0.1 mg/kg elicited the least desirable effects. Clustering of HRS items, using either a clinical, mental status method or principal components factor analysis provided better resolution of dose effects than did the biological variables described previously. CONCLUSIONS: These clinical and preliminary quantitative data provide bases for further psychopharmacologic characterization of DMT's properties in humans. They also may be used to compare the effects of other agents affecting relevant brain receptors in volunteer and psychiatric populations.

Human hallucinogen interactions with drugs affecting serotonergic neurotransmission.

The absence of relevant human research studies of hallucinogenic drugs has not curtailed their unsupervised use. Two cases are presented that suggest decreased sensitivity to the serotonergic hallucinogens psilocybin and LSD induced by drugs with effects on serotonergic neurotransmission, allopurinol and fluoxetine. These reports suggest that hallucinogens' effects in humans are mediated by serotonergic receptors.

Elevated rectal temperature produced by all-night bright light is reversed by melatonin infusion in men.

Early morning rectal body temperature is lowest when melatonin levels are highest in humans. Although pharmacological doses of melatonin are hypothermic in humans, the relationship between endogenous melatonin and temperature level has not been investigated. We measured rectal body temperature in nine normal men whose melatonin levels were suppressed by all-night sleep deprivation in bright light and compared values with those seen in sleep in the dark, sleep deprivation in dim light (to control for the stimulatory effect of wakefulness on temperature), and sleep deprivation in bright light with an infusion of exogenous melatonin that replicated endogenous levels. Minimum rectal temperature, calculated from smoothed temperature data from 2300 to 0515 h, was greater in bright-light sleep deprivation, resulting in suppression of melatonin, than in conditions of sleep deprivation in dim light or sleep in the dark. An exogenous melatonin infusion in bright light returned the minimum temperature to that seen in dim-light sleep deprivation. A nonsignificant elevation in mean and minimum temperature was noted in all conditions of sleep deprivation relative to sleep. We conclude that melatonin secretion contributes to the lowering of core body temperature seen in the early morning in humans.

Sleep deprivation reduces LH secretion in men independently of melatonin.

Melatonin affects gonadal function in non-primate mammals. Confirmatory data in man are not available. We assessed melatonin's acute effects on luteinizing hormone secretion in 17 normal men. We studied these men in conditions of sleep in the dark, and sleep deprivation in bright light, dim light, and bright light combined with a physiologically relevant infusion of melatonin, while measuring blood levels of immunoreactive LH every 20 min for 7 h. We compared overnight LH secretion, and LH pulse frequency, amplitude, length, interval and area under the curve using a modification of the PULSAR peak identification program, among the four treatments. Areas under the curve for peaks in all three conditions of sleep deprivation were lower than in normal sleep. The presence or absence of melatonin had no additional effect. We conclude that acute suppression of melatonin does not affect LH pulse parameters in normal man, but that sleep deprivation may reduce the amount of LH secreted per pulse.

Human hallucinogenic drug research in the United States: a present-day case history and review of the process.

Legitimate human research with hallucinogenic drugs, although of great theoretical and practical interest, involves daunting regulatory hurdles that have discouraged investigators from attempting such work. Using the example of the author's own application for and receipt of federal permission to administer N,N-dimethyltryptamine (DMT) to humans, this article reviews the application process, obstacles and their solutions, and the local and federal issues involved. Further human research with hallucinogens is possible if a persistent and collaborative effort is made with the relevant institutions that oversee the performance of this type of research.

Increase in plasma melatonin, beta-endorphin, and cortisol after a 28.5-mile mountain race: relationship to performance and lack of effect of naltrexone.

Strenuous exercise increases plasma melatonin, cortisol, and beta-endorphin concentrations. Furthermore, a relationship between endogenous opioids and melatonin has been proposed. We measured plasma melatonin, cortisol, and beta-endorphin in 46 subjects before and after a 28.5-mile high altitude race. Thirteen of the subjects received the orally active opioid antagonist naltrexone immediately before the race. The mean plasma melatonin, cortisol, and beta-endorphin levels were higher after the race than before it; the melatonin results were confirmed by gas chromatography-mass spectrometry assay of 12 subjects. Naltrexone had no effect on the increase in any of the three hormones. The run-induced increases in plasma melatonin, beta-endorphin, and cortisol were negatively correlated with finishing time, but only the plasma beta-endorphin and cortisol rises correlated with each other. We conclude that prolonged exercise in trained athletes can increase plasma melatonin and that this rise is not due to the concomitant opioid release.

Augmented pituitary corticotropin response to a threshold dosage of human corticotropin-releasing hormone in depressives pretreated with metyrapone.

We studied pituitary corticotropin response to exogenous corticotropin-releasing hormone infusion and attempted to control for the confounding effect of variable serum cortisol levels between depressed and control subjects. If metyrapone was given during the time of day when hypothalamic pituitary adrenal activity was otherwise low, the relative increase in the corticotropin concentration was small. Pituitary response to exogenous corticotropin-releasing hormone can be defined under conditions in which the amount of glucocorticoid-mediated negative feedback present at the level of the pituitary gland is equal in all subjects. When the ambient cortisol level was equalized (and suppressed) in all subjects at the time of study with a threshold dosage of corticotropin-releasing hormone, we found an augmented response to corticotropin-releasing hormone in depressives. This raises the possibility that either increased pituitary sensitivity to corticotropin-releasing hormone or an increased intracellular pool of corticotropin is available for release in subjects with major depressive illness.

Lack of an acute modulatory effect of melatonin on human nocturnal thyrotropin and cortisol secretion.

Using a recently developed model for investigating the neuroendocrine role of melatonin in man, we studied melatonin's effect on the nocturnal secretion of thyrotropin and cortisol in 17 normal male volunteers. The model consists of sleep in the dark and all-night sleep deprivation in conditions of: bright light with and without a melatonin infusion, and dim light. We have improved our infusion paradigm so that levels of melatonin during infusion are now indistinguishable from those occurring during sleep in the dark or dim light sleep deprivation. Sleep deprivation per se raised TSH levels compared to normal sleep. However, the three conditions of sleep deprivation could not be distinguished from each other, which suggests that the suppression of TSH by sleep (or the stimulation of TSH by sleep deprivation) is not mediated by melatonin. Cortisol secretion was unaffected by sleep deprivation regardless of melatonin's presence or absence. However, a difference in the pattern of secretion of cortisol in the sleep condition in the early morning (compared to the sleep deprivation conditions) was noted. These data do not implicate melatonin in the acute regulation of TSH or cortisol in normal man. These data also provide a method of melatonin infusion that replicates the pattern and levels seen in sleep.

A model for the study of the acute effects of melatonin in man.

The role of the pineal hormone melatonin in human physiology is uncertain. Previous studies correlated plasma melatonin levels with several physiological parameters or determined the responses to pharmacological doses of melatonin during daylight hours. We established an acute model that is more rigorously physiological. Constant nocturnal bright light in sleep-deprived normal men resulted in low plasma melatonin levels throughout the night, in contrast to sleep in the dark and dim light sleep deprivation nights. Subsequently, melatonin was infused during bright light exposure to approximate physiological levels. Plasma GH and PRL measurements in these four conditions revealed an effect of sleep deprivation independent of the presence or absence of melatonin. A subsample of these men had an intermediate level of melatonin suppression with 500 lux light intensity, relative to those during sleep and bright light. The results suggest that melatonin has no acute modulatory effect on the secretion of these two sleep-related hormones.

Cardiovascular, catecholamine and psychological responses to TRH in four types of affective disorder patients.

When 500 micrograms of TRH is given intravenously, an increase in TSH, blood pressure, plasma catecholamines and positive emotions follows. Four groups of patients with major, minor or bipolar depression or schizoaffective disorder increased their TSH levels by similar amounts after TRH. The neurohormone also significantly increased diastolic blood pressure by 5.5 +/- 1.6 mm Hg, and decreased heart rate by 7.6 +/- 1.3 beats/min. There was a weak trend for bipolar depressives to have less cardiovascular response to TRH than the other groups. Plasma norepinephrine (NE) was higher after TRH than after placebo. The NE response differed between patient groups (P = .0023) because of a smaller response by major depressives. TRH decreased anger, tension and depression, and increased friendliness. Positive emotional responses were significantly greater in the bipolar depressives than in other groups. Forty-one other studies have found a subnormal TSH response does not distinguish between subtypes of the affective disorders, but cardiovascular, catecholamine and mood responses may do so.