Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance.

RATIONALE: Although psilocybin has been used for centuries for religious purposes, little is known scientifically about its acute and persisting effects. OBJECTIVES: This double-blind study evaluated the acute and longer-term psychological effects of a high dose of psilocybin relative to a comparison compound administered under comfortable, supportive conditions. MATERIALS AND METHODS: The participants were hallucinogen-naïve adults reporting regular participation in religious or spiritual activities. Two or three sessions were conducted at 2-month intervals. Thirty volunteers received orally administered psilocybin (30 mg/70 kg) and methylphenidate hydrochloride (40 mg/70 kg) in counterbalanced order. To obscure the study design, six additional volunteers received methylphenidate in the first two sessions and unblinded psilocybin in a third session. The 8-h sessions were conducted individually. Volunteers were encouraged to close their eyes and direct their attention inward. Study monitors rated volunteers' behavior during sessions. Volunteers completed questionnaires assessing drug effects and mystical experience immediately after and 2 months after sessions. Community observers rated changes in the volunteer's attitudes and behavior. RESULTS: Psilocybin produced a range of acute perceptual changes, subjective experiences, and labile moods including anxiety. Psilocybin also increased measures of mystical experience. At 2 months, the volunteers rated the psilocybin experience as having substantial personal meaning and spiritual significance and attributed to the experience sustained positive changes in attitudes and behavior consistent with changes rated by community observers. CONCLUSIONS: When administered under supportive conditions, psilocybin occasioned experiences similar to spontaneously occurring mystical experiences. The ability to occasion such experiences prospectively will allow rigorous scientific investigations of their causes and consequences.

Enhancing caffeine reinforcement by behavioral requirements following drug ingestion.

Each morning eight adults with caffeine versus placebo discrimination histories ingested letter-coded capsules containing 100 mg caffeine or placebo and then engaged in a relaxation or vigilance activity. Subjects were first exposed to caffeine and placebo once each with each activity. Then each day for 10 days subjects made two choices; they chose which compound they would prefer if vigilance were scheduled and which they would prefer if relaxation were scheduled, with the restriction that they could not choose the same compound with both activities; only one choice (randomly selected) was reinforced. Eight of eight subjects always chose caffeine with vigilance. The next choice condition was identical, except that subjects were free to take either compound with both activities. Six of six subjects reliably chose caffeine with vigilance. Four reliably chose placebo with relaxation. In the final condition, each day for 10 days subjects chose between each drug and each of 52 monetary values; those choices were made separately for vigilance and relaxation; only one choice (randomly selected) was reinforced. For six of seven subjects, the maximum dollar value at which subjects chose drug over money was higher for caffeine in vigilance than for placebo in either activity. For five subjects, the maximum value at which subjects chose caffeine over money was higher in vigilance than in relaxation. Overall, this study demonstrates enhanced caffeine reinforcement when a vigilance activity followed drug ingestion.

Modulation of drug reinforcement by behavioral requirements following drug ingestion.

Eight volunteers with histories of drug abuse participated in two experiments examining the modulation of drug choice by behavioral requirements following drug ingestion. Each morning subjects ingested color-coded capsules containing triazolam (0.25 mg), d-amphetamine (15 mg), or placebo and then engaged in a relaxation or a computer vigilance activity. Experiment 1 involved two phases (i.e. a triazolam and a d-amphetamine phase), presented in counterbalanced order. Within each phase, subjects were first exposed to each of two compounds (placebo and either triazolam or d-amphetamine) once with each activity. Then every other day for 20 days subjects chose which compound they ingested with the vigilance and relaxation activities, with the restriction that they could not choose the same compound with both activities. Seven of eight subjects reliably chose d-amphetamine with the vigilance activity; all subjects always chose triazolam with the relaxation activity. In experiment 2 (5 days' duration), after re-exposure to the color-coded compounds used in experiment 1, subjects chose which compound (placebo, d-amphetamine or triazolam) they ingested with the vigilance activity, and on another occasion (in counterbalanced order), which they ingested with relaxation activity. Seven of eight subjects chose d-amphetamine with the vigilance activity; all subjects chose triazolam with the relaxation activity. The relaxation and vigilance activities modulated triazolam and d-amphetamine reinforcement, thereby demonstrating a new class of environmental variable that can influence drug self-administration.

Reinforcing effects of caffeine in coffee and capsules.

In a residential research ward the reinforcing and subjective effects of caffeine were studied under double-blind conditions in volunteer subjects with histories of heavy coffee drinking. In Experiment 1, 6 subjects had 13 opportunities each day to self-administer either a caffeine (100 mg) or a placebo capsule for periods of 14 to 61 days. All subjects developed a clear preference for caffeine, with intake of caffeine becoming relatively stable after preference had been attained. Preference for caffeine was demonstrated whether or not preference testing was preceded by a period of 10 to 37 days of caffeine abstinence, suggesting that a recent history of heavy caffeine intake (tolerance/dependence) was not a necessary condition for caffeine to function as a reinforcer. In Experiment 2, 6 subjects had 10 opportunities each day to self-administer a cup of coffee or (on different days) a capsule, dependent upon completing a work requirement that progressively increased and then decreased over days. Each day, one of four conditions was studied: caffeinated coffee (100 mg/cup), decaffeinated coffee, caffeine capsules (100 mg/capsule), or placebo capsules. Caffeinated coffee maintained the most self-administration, significantly higher than decaffeinated coffee and placebo capsules but not different from caffeine capsules. Both decaffeinated coffee and caffeine capsules were significantly higher than placebo capsules but not different from each other. In both experiments, subject ratings of "linking" of coffee or capsules covaried with the self-administration measures. These experiments provide the clearest demonstrations to date of the reinforcing effects of caffeine in capsules and in coffee.

Reinforcing properties of caffeine: studies in humans and laboratory animals.

Three types of experimental studies are reviewed: (1) intravenous and oral caffeine self-administration by laboratory animals, (2) oral caffeine self-administration by humans, and (3) human subjective effects of caffeine relevant to reinforcing effects. These studies show that, under appropriate conditions, caffeine can serve as a reinforcer and can produce elevations in subjective drug liking and/or euphoria. In this regard, caffeine can be distinguished from a wide range of behaviorally active compounds, such as the amphetamine analog fenfluramine and the major tranquilizer chlorpromazine, which do not produce such effects. Caffeine can also be distinguished from classic drugs of abuse such as cocaine, d-amphetamine or pentobarbital which generally maintain high levels of self-administration (or liking) in contrast to caffeine which tends to maintain lower levels of self-administration (or liking) or maintain self-administration under a more narrow range of parametric conditions. Several human studies and one animal experiment suggest that physical dependence substantially potentiates the reinforcing effects of caffeine. Other human and animal studies indicate that there may be substantial differences between individual subjects in the reinforcing effects of caffeine. An important challenge for future human and animal drug self-administration research will be to delineate more precisely the conditions under which caffeine does and does not serve reliably as a reinforcer.

Human coffee drinking: reinforcing and physical dependence producing effects of caffeine.

In a residential research ward coffee drinking was studied in nine volunteer human subjects with histories of heavy coffee drinking. The presence or absence of caffeine in the coffee was manipulated under double-blind conditions by using caffeinated (C) or decaffeinated (D) coffee. When subjects were switched alternately for 10 or more consecutive days between C and D, the daily number of cups consumed tended to be relatively stable. In a different experiment, preference for C vs. D was assessed. After experimenter-scheduled exposures, subjects were given choices between C and D. When subjects were presumably caffeine tolerant/dependent, C was rated as being better liked than D and was reliably preferred to D in choice tests. When subjects were not caffeine tolerant/dependent, C was not reliably preferred to D, nor were there pronounced differences in ratings of liking. Under these conditions, some subjects preferred D to C, citing adverse symptoms (suggesting caffeine toxicity) as reasons for avoiding C. The effects of caffeine withdrawal were studied by abruptly substituting D for C for 10 or more days. This resulted in an orderly withdrawal syndrome, having an onset latency of 19 hr, peaking on days 1 and 2, and decreasing progressively over the next 5 or 6 days. The withdrawal syndrome, which was detected on subject-rated, staff-rated and objective behavioral measures, was characterized by increased headache, sleepiness and laziness and decreased alertness and activeness. The present study demonstrates the reinforcing effects of caffeine in humans and also documents the severity of the caffeine withdrawal syndrome. It is concluded that caffeine has the cardinal features of a prototypic drug of abuse.

Human coffee drinking: manipulation of concentration and caffeine dose.

In a residential research ward coffee drinking was studied in 9 volunteer human subjects with histories of heavy coffee drinking. A series of five experiments was undertaken to characterize adlibitum coffee consumption and to investigate the effects of manipulating coffee concentration, caffeine dose per cup, and caffeine preloads prior to coffee drinking. Manipulations were double-blind and scheduled in randomized sequences across days. When cups of coffee were freely available, coffee drinking tended to be rather regularly spaced during the day with intercup intervals becoming progressively longer throughout the day; experimental manipulations showed that this lengthening of intercup intervals was not due to accumulating caffeine levels. Number of cups of coffee consumed was an inverted U-shaped function of both coffee concentration and caffeine dose per cup; however, coffee-concentration and dose-per-cup manipulations did not produce similar effects on other measures of coffee drinking (intercup interval, time to drink a cup, within-day distribution of cups). Caffeine preload produced dose-related decreases in number of cups consumed. As a whole, these experiments provide some limited evidence for both the suppressive and the reinforcing effects of caffeine on coffee consumption. Examination of total daily coffee and caffeine intake across experiments, however, provides no evidence for precise regulation (i.e., titration) of coffee or caffeine intake.

Naloxone does not affect cigarette smoking.

In order to provide information about the hypothesis that endogenous opioids mediate the reinforcing properties of cigarette smoking, the present study examined the effects of naloxone, an opioid antagonist, on cigarette smoking in seven normal volunteers. The study used experimental procedures that had previously been shown sensitive for detecting the effects of other drugs, (including a nicotine antagonist) on smoking. Isolated subjects smoked their regular brand of cigarettes freely in a naturalistic laboratory environment while watching television or reading. Sixty minutes before each 2 h smoking session subjects received an IM injection of naloxone HCl (0.0625, 0.25, 1.0, or 4.0 mg/kg) or placebo. Each subject received each treatment three times in a mixed order across days. Naloxone did not significantly affect any measure of cigarette smoking including number of cigarettes, number of puffs, or expired air carbon monoxide level. Naloxone did, however, produce significant dose-related increases in subject ratings of yawning, stretching, and relaxation. The results of the present study provide no support for the endogenous opioid theory of smoking reinforcement.

Opioids: similarity between evaluations of subjective effects and animal self-administration results.

Abuse potential studies of 33 morphine-like analgesics were compared in humans and monkeys. The results of intravenous self-administration studies in rhesus monkeys were correlated with measures of morphine-like signs, symptoms, and subjective effects in ex-addicts. Each set of data was assigned to a position in a 3 x 3 contingency table dependent upon whether the results were yes, no, or equivocal. Of the 33 drugs, 29 were given identical classifications in both the human and animal test procedures. This good concordance between the human and animal results further validates each procedure and suggests the possibility that both the human and animal procedures are measuring a common underlying pharmacological property which relates to abuse potential of drugs.