Psychedelic-assisted psychotherapy to treat psychiatric and existential distress in life-threatening medical illnesses and palliative care.

Psychiatric and existential distress commonly occur in advanced cancer and other serious, life-threatening or end-of-life medical illnesses and are associated with poor medical and psychiatric outcomes. Currently available treatment modalities in this patient population, including medication and psychotherapy, are limited in effectiveness, especially regarding existential distress. The lack of effective psycho-spiritual interventions is a critical shortcoming in palliative care and represents a high unmet need in medicine. In this commentary, we review the rationale of researching and developing psychedelic-assisted psychotherapy as a novel pharmacologic-psychotherapeutic intervention to treat psychiatric and existential distress in life-threatening medical conditions and palliative care. This paper reviews efficacy data from first and second waves of psychedelic research, and future directions for research and implementation science. More rigorous research, especially funded by governments, is needed to assess effectiveness and mechanisms of action of psychedelic therapies to treat psychiatric and existential distress in life-threatening medical illnesses and palliative care. If psychedelic-assisted treatments were made available as approved and prescribable medications in people with serious medical illnesses, it could be a significant development that opens up a pathway for clinical dissemination and public health impact internationally.

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.

An abuse liability comparison of flunitrazepam and triazolam in sedative drug abusers.

The present double-blind, placebo-controlled study compared the acute effects of oral administration of the benzodiazepine hypnotics flunitrazepam (6 mg/70 kg) and triazolam (1 and 2 mg/70 kg) on measures relevant to abuse liability as well as on psychomotor performance and observer- and participant-rated measures of drug effects in nine sedative drug abusers. Analysis of participant-rated measures collected 24 h after drug administration (next-day; assessing the overall effects of the drug received 24 h earlier) indicated that flunitrazepam, but neither triazolam dose, produced significant increases relative to placebo in next-day ratings of drug liking, the amount of money the drug would be worth on the street, and the amount of money the participant would be willing to pay for the drug on the street. Importantly, these abuse liability differences between flunitrazepam and triazolam were present at a dose of flunitrazepam (6 mg/70 kg) that produced overall drug effects that were comparable to, or significantly less than, those of a high triazolam dose (2 mg/70 kg). Consistent with results of a previous study in our laboratory, these results suggest that flunitrazepam may have a greater abuse liability than triazolam, and that this abuse liability difference emerges on measures taken 24 h after drug administration but not on same-day measures.

Physical dependence in baboons chronically treated with low and high doses of diazepam.

Physical dependence on diazepam was evaluated in male baboons chronically treated with either low or high doses of diazepam. Baboons received either a single oral daily administration of a low dose (0.5 mg/kg per day) of diazepam (n=4) or continuous intragastric infusion of a high dose (20 mg/kg per day) of diazepam (n=7). Development of physical dependence during chronic dosing with 0.5 mg/kg per day diazepam was assessed at 2 and 4 weeks and then monthly, during 1-h behavioral observations, following injections of the benzodiazepine competitive antagonist flumazenil. After 3-24 months of diazepam treatment, dosing was discontinued and physical dependence assessed via observation and responding for food pellets. In baboons that received 0.5 mg/kg per day diazepam, flumazenil precipitated a mild- to intermediate-intensity benzodiazepine withdrawal syndrome, which included decreases in the number of food pellets earned per day and increases in withdrawal postures, self-directed behaviors, aggressive behaviors and retching/vomiting. Three of four baboons showed signs of precipitated withdrawal after only 2 weeks of chronic low-dose treatment. Flumazenil continued to precipitate withdrawal signs, but with no systematic increase in severity, throughout the 6-10 months of 0.5 mg/kg diazepam administration. When 0.5 mg/kg per day diazepam dosing was discontinued, the number of food pellets earned per day decreased in two of the four baboons, but no systematic changes in behavioral signs were observed. In contrast, within 7-10 days of termination of 20 mg/kg per day diazepam dosing, withdrawal signs of intermediate intensity and a decrease in the number of food pellets earned per day occurred in all baboons. In the present study, physical dependence developed after 2 weeks of a chronic low dose of diazepam administration but did not increase further over long-term exposure to diazepam.

Cocaine-like subjective effects of nicotine are not blocked by the D1 selective antagonist ecopipam (SCH 39166).

The effects of ecopipam (a D(1) selective antagonist) or triazolam pretreatment on the subjective and physiological effects of intravenously administered nicotine were examined in 10 cigarette-smoking cocaine abusers. Under double-blind, randomized conditions, subjects received oral capsule pretreatment (0, 30 or 100 mg ecopipam, or 0.25 mg/70 kg triazolam), followed 120 min later by an intravenous injection of 2 mg/70 kg nicotine or saline. Subjective ratings, heart rate and blood pressure were assessed before and repeatedly after each intravenous injection. Compared to oral placebo pretreatment, both ecopipam and triazolam pretreatment produced significant elevations in subject-reported capsule effect and observer ratings of sleepiness/sedation. Nicotine increased ratings of 'drug effect', 'rush', 'high', 'stimulated', 'liking', 'good effects' and 'bad effects', and produced modest increases in heart rate and blood pressure. Following both intra-venous saline and nicotine injection, ecopipam tended to reduce heart rate and blood pressure. Although both ecopipam and triazolam lowered several subjective ratings following intravenous saline injection, neither ecopipam nor triazolam affected nicotine subjective effects. In contrast to Romach et al. (Arch Gen Psychiatry 56: 1101-1106, 1999), who showed that pretreatment with ecopipam blocked cocaine subjective effects, the current study found no attenuation of the subjective effects of nicotine, and thus, provides no support for the hypothesis that D(1) receptors mediate the cocaine-like subjective effects of nicotine.

Alcohol and triazolam: differential effects on memory, psychomotor performance and subjective ratings of effects.

The effects of alcohol (0.80 g/kg) and the benzodiazepine hypnotic triazolam (0.25 mg/70 kg) were compared directly in a double-dummy, double-blind, placebo-controlled, repeated-measures design in 18 healthy volunteers. While alcohol (0.80 g/kg) and triazolam (0.25 mg/70 kg) produced comparable levels of psychomotor performance impairment, a dissociation was observed, such that the magnitude of memory impairment (measured by d', participants' sensitivity in discriminating between old and new words in the recognition memory paradigm) was greater with triazolam than with alcohol, whereas subjective ratings of the overall strength of drug effect were higher with alcohol than with triazolam. Participants also adopted a more conservative response bias in the recognition memory paradigm in the alcohol (0.80 g/kg) condition relative to both placebo and triazolam (0.25 mg/70 kg). In addition to characterizing the adverse effects of two widely used psychoactive substances, the present results may also contribute to the understanding of underlying neurochemical mechanisms.

Effects of triazolam on brain activity during episodic memory encoding: a PET study.

It is well documented that acute administration of the benzodiazepine hypnotic drug triazolam (Halcion) impairs episodic memory encoding. We examined the neuroanatomical substrates of this effect in healthy adult volunteers using a double-blind, within-subject design. Following oral capsule administration (0.25 mg/70 kg triazolam or placebo), regional cerebral blood flow (rCBF) was measured using positron emission tomography (PET) with 15O-H(2)O during the performance of semantic categorization, orthographic categorization, and visual fixation (resting) tasks. rCBF associated with episodic memory encoding was measured by the difference in rCBF during the orthographic categorization task relative to that during the semantic categorization task. Results in the placebo condition (n = 9) replicated those of previous nonpharmacological encoding studies (activation in the left prefrontal cortex, cerebellum, anterior cingulate cortex, temporal cortex, and occipital cortex). Relative to placebo, results in the triazolam condition (n = 6) revealed significantly impaired memory performance, and deactivation during encoding in a subset of areas shown previously to be associated with encoding (anterior cingulate cortex, cerebellum, and precuneus). Results are discussed in relation to triazolam's effects on mnemonic versus attentional processes.

Physiological, subjective and reinforcing effects of oral and intravenous cocaine in humans.

RATIONALE: There is little comparative information on the qualitative similarity, relative potency and reinforcing effects of oral cocaine versus cocaine administered via other routes. METHODS: The present study used a within-subject, double-blind, double-dummy design to compare the physiological, subjective and reinforcing effects of placebo and oral (62.5, 125, 250 mg/70 kg) and intravenous (IV) (12.5, 25, 50 mg/70 kg) cocaine in volunteers with histories of cocaine abuse. RESULTS: Cocaine produced dose-dependent increases on heart rate and blood pressure, with effects lasting longer after oral than IV cocaine. Subjective ratings (e.g., "rush," "drug effect," "liking") were qualitatively similar and dose-dependently increased after oral and IV administration, and the duration of effects was similar under both routes. On a money versus drug choice measure of reinforcement, the monetary amounts at which participants chose drug over money increased as a function of cocaine dose under both routes of administration. At doses that produced comparable subjective, physiological, and reinforcing effects, oral cocaine was not identified as cocaine as frequently as IV cocaine. Across measures, the data suggested that IV cocaine was approximately 10 times more potent than oral cocaine. CONCLUSIONS: Overall, the results of this study support qualitatively similar effects of oral and IV cocaine and suggest that oral cocaine may be an effective tool for studying cocaine's effects in human laboratory studies.

Reinforcing effects of oral cocaine: contextual determinants.

RATIONALE: Although the behavioral, subjective, and physiological effects of oral cocaine have been investigated, its reinforcing effects have not been demonstrated. OBJECTIVE: The primary aims of this study were to examine the reinforcing effects of oral cocaine and determine whether such effects can be influenced by manipulating behavioral requirements following drug ingestion. METHODS: Nine adult volunteers with histories of cocaine abuse were trained to discriminate between orally administered cocaine (100 mg/70 kg) and placebo capsules under double-blind conditions. Following acquisition of cocaine vs placebo discrimination (80% correct), the reinforcing effects of cocaine were determined using two different choice conditions (dependent and independent). Volunteers were first exposed to cocaine and placebo once each with a relaxation activity (sitting in a cushioned chair) and a vigilance activity (performing a computer task). Following exposure to each drug with each activity, volunteers began the dependent choice condition. Every 2 days volunteers chose which drug (cocaine or placebo) they ingested with the vigilance and relaxation activities. Volunteers could not choose the same drug with both activities. This procedure occurred 5 times over a 10-day period. The independent choice condition took place over 2 days. On one day, volunteers chose which drug (cocaine or placebo) they ingested with the relaxation activity and, on the other day (in counterbalanced order), which drug they ingested with the vigilance activity. Volunteers were allowed to select the same drug with both activities. RESULTS: All volunteers successfully acquired the cocaine vs placebo discrimination. In the dependent choice condition, all volunteers significantly chose cocaine over placebo with the vigilance activity and chose placebo over cocaine with the relaxation activity. In the independent choice condition, volunteers significantly chose cocaine over placebo with the vigilance activity (i.e., cocaine functioned as a positive reinforcer in the vigilance context). Interestingly, the independent choice condition also showed that volunteers chose placebo over cocaine with the relaxation activity (i.e., cocaine functioned as a negative reinforcer because it was avoided relative to placebo). CONCLUSION: The study shows that the behavioral requirements following drug ingestion can be a determinant of whether or not oral cocaine functions as a reinforcer in volunteers with histories of cocaine abuse.

Investigation of preference for nightly triazolam versus placebo in moderate social alcohol drinkers.

This study was designed to examine whether the widely prescribed benzodiazepine hypnotic triazolam has reinforcing effects in moderate social alcohol drinkers, without histories of drug abuse or insomnia, in the context of its use as a hypnotic. Eleven healthy adult volunteers who met criteria for 'good sleepers' participated in a 60-session double-blind choice study which was conducted on an outpatient basis with participants sleeping at home. Twenty three-session sampling/choice tests were conducted sequentially to provide 20 evaluations of the reinforcing effects of 0.25 mg/70 kg triazolam versus placebo, ingested orally 30 min before bedtime. Each three-session test consisted of two sampling sessions, in which participants received exposure to each of the two drug conditions in different colored capsules, followed by one choice session, in which participants were asked to choose one of the two colour-coded capsules for self-administration. Four participants exhibited a significant choice of triazolam, three, a significant choice of placebo (i.e. triazolam avoidance), and four, a random (i.e. non-significant) choice between triazolam and placebo. The reasons provided by participants were consistent with their choices and with the expected effects of triazolam versus placebo. Analyses of post-sleep questionnaires indicated that triazolam did not produce a clinically meaningful improvement in sleep. The finding that triazolam functioned as a reinforcer in participants without insomnia suggests that triazolam has reinforcing effects in some individuals for which hypnotic treatment is not clinically indicated, and that health care professionals must continue to assess the risk/benefit ratio of benzodiazepine hypnotic prescription.

Acute dose-effects of scopolamine on false recognition.

RATIONALE: Recently, there has been increased research interest in the phenomenon of false recognition, in which participants claim to recognize words that had not been presented during an initial study phase but that are associatively related to presented words. Acute administration of the benzodiazepine hypnotic triazolam has been shown to decrease false recognition rates. However, no false recognition studies have examined the effects of scopolamine, an anticholinergic drug that might produce a different profile of memory-impairing effects than the benzodiazepines due to its distinct neurochemical profile. OBJECTIVE: This study was designed to examine the acute dose-effects of scopolamine on false recognition. METHODS: The effects of subcutaneously administered scopolamine (0.3 and 0.6 mg/70 kg) on performance in the Deese/Roediger-McDermott false recognition paradigm were examined in a repeated-measures placebo-controlled double-blind design in 18 healthy volunteers. RESULTS: Scopolamine produced dose-related reductions in both true and false recognition rates, and induced a more conservative response bias relative to placebo for recollection-based ("remember") responses to studied words. CONCLUSIONS: While scopolamine's effects on false recognition are similar to those observed previously with triazolam, its effects on response bias may differ from those of triazolam.

Intravenous nicotine and caffeine: subjective and physiological effects in cocaine abusers.

The subjective and physiological effects of intravenously administered caffeine and nicotine were compared in nine subjects with histories of using caffeine, tobacco, and cocaine. Subjects abstained from tobacco cigarette smoking for at least 8 h before each session. Dietary caffeine was eliminated throughout the study; however, to maintain consistency with the nicotine intake, subjects were administered caffeine (150 mg/70 kg b.i.d.) in capsules, with the last dose administered 15 to 18 h before each session. Under double-blind conditions, subjects received placebo, caffeine (100, 200, and 400 mg/70 kg), and nicotine (0.75, 1.5, and 3.0 mg/70 kg) in mixed order. Physiological and subjective data were collected before and repeatedly after drug or placebo administration. Compared with the highest dose of caffeine, the highest dose of nicotine produced greater subjective ratings on a number of scales. At doses that produced comparable ratings of drug effect (1.5 mg/70 kg of nicotine and 400 mg/70 kg of caffeine), both drugs produced similar increases in ratings of good effect, liking, high, stimulated, and bad effect. Nicotine showed a somewhat faster time to peak subjective effects than caffeine (2 versus 4 min). Subjective ratings that differentiated caffeine and nicotine were ratings of rush, blurry vision, and stimulant identification (elevated by nicotine) and ratings of unusual smell and/or taste (elevated by caffeine). Both caffeine and nicotine decreased skin temperature and increased diastolic blood pressure; however, caffeine decreased whereas nicotine increased heart rate. The study documents both striking similarities and some notable differences between caffeine and nicotine, which are among the most widely used mood-altering drugs.

Alcohol and false recognition: a dose-effect study.

RATIONALE: The pattern of acute memory impairment produced by alcohol is similar to that produced by the benzodiazepines. However, in contrast to demonstrations that benzodiazepines decrease false recognition rates, results of a recent study suggest that a low dose of alcohol increases false recognition rates; false recognition refers to the phenomenon of mistakenly claiming that one has been exposed previously to a novel item. OBJECTIVE: This study was designed to examine the acute dose-effects of alcohol on false recognition. METHODS: Effects of alcohol (0.27 and 0.60 g/kg) on performance in the Deese/Roediger-McDermott false recognition paradigm were examined in a repeated measures placebo-controlled double-blind design in 18 healthy volunteers. RESULTS: The 0.60 g/kg dose of alcohol significantly reduced true recognition rates (measured by hit rate) and induced a more conservative response bias (measured by C) relative to placebo; however, neither alcohol dose significantly impaired participants' sensitivity in discriminating between old and new words (d'). Neither alcohol dose affected false recognition rates. CONCLUSIONS: Effects of alcohol on false recognition and on response bias may differ from those observed previously with benzodiazepines. A direct comparison at equivalent doses will be necessary to draw conclusions about qualitative differences between alcohol and benzodiazepines.

Zaleplon and triazolam physical dependence assessed across increasing doses under a once-daily dosing regimen in baboons.

The ability of the GABA(A)-receptor-subtype-selective hypnotic zaleplon to produce physical dependence was compared to the nonselective benzodiazepine triazolam. Progressively increasing doses of zaleplon and triazolam were given to baboons by intragastric infusion once each day, with doses increasing every 17 days. Next, the highest dose was given for 10-34 additional days by continuous infusion. Both drugs produced increases in food-maintained lever pressing, ataxia, and time to complete a fine motor task. Plasma levels increased dose-dependently; drug was detectable 24 h after higher doses. Flumazenil produced a mild or intermediate precipitated-withdrawal syndrome on day 14 of all dosing conditions. When drug delivery ended after 85-100 days, a benzodiazepine-type withdrawal syndrome occurred. Physical dependence potential of zaleplon and triazolam appear similar.

Is caffeine a flavoring agent in cola soft drinks?

BACKGROUND: Concern has been expressed about the nutrition and health impact of high rates of soft drink consumption. Caffeine is an added ingredient in approximately 70% of soft drinks consumed in the United States. The soft drink manufacturers' justification to regulatory agencies and the public for adding caffeine to soft drinks is that caffeine is a flavoring agent. OBJECTIVE: To examine the claim that caffeine plays an integral role in the flavor profile of soft drinks, by examining the effect of caffeine on the threshold for detection of flavor differences in cola beverages. DESIGN: Double-blind crossover study starting November 1998 and ending July 1999. SETTING: An academic research center. PARTICIPANTS: Twenty-five adult regular consumers of cola soft drinks. Based on a screening session, all were able to detect a flavor difference between cola containing sugar and diet cola. INTERVENTION: A sensitive version of a forced-choice flavor-detection procedure was used to evaluate the effects of a wide range of caffeine concentrations (range, 0.05-1.6 mg/mL) on the ability to detect flavor differences between caffeinated and caffeine-free cola beverages. Repeated tests permitted determination of significant detection at each concentration in individual subjects. MAIN OUTCOME MEASURES: Percentage of subjects significantly detecting a flavor difference and mean percentage of trials correct at each caffeine concentration. RESULTS: Detection of flavor differences increased as a function of caffeine concentration. At the 0.1-mg/mL concentration, which is the approximate concentration in the majority of cola soft drink products, 2 subjects (8%) significantly detected a flavor difference and the mean percentage correct (53%) was at chance levels. CONCLUSIONS: The finding that only 8% of a group of regular cola soft drink consumers could detect the effect of the caffeine concentration found in most cola soft drinks is at variance with the claim made by soft drink manufacturers that caffeine is added to soft drinks because it plays an integral role in the flavor profile. It is valuable for the general public, the medical community, and regulatory agencies to recognize that the high rates of consumption of caffeinated soft drinks more likely reflect the mood-altering and physical dependence-producing effects of caffeine as a central nervous system-active drug than its subtle effects as a flavoring agent. Arch Fam Med. 2000;9:727-734

Caffeine withdrawal increases cerebral blood flow velocity and alters quantitative electroencephalography (EEG) activity.

RATIONALE: Cessation of daily caffeine consumption produces a withdrawal syndrome comprised of subjective symptoms and functional impairment. Few controlled studies have examined the physiological effects of caffeine withdrawal. OBJECTIVE: The present study examined the effect of caffeine withdrawal on cerebral blood flow velocity and quantitative EEG. METHODS: Ten volunteers reporting moderate caffeine intake (mean 333 mg/day) participated in this double-blind study. Subjects completed several tests when maintaining their normal diet (baseline period) and during two 1-day periods during which they consumed caffeine-free diets and received capsules containing placebo (placebo test session) or caffeine (caffeine test session) in amounts equal to their baseline daily caffeine consumption. Blood flow velocity was determined for four arteries: right and left middle (MCA), and right and left anterior (ACA) cerebral arteries using pulsed transcranial Doppler sonography. EEG was recorded for 3 min from eight scalp sites while subjects sat, with eyes closed, in a sound-attenuated electronically shielded chamber. Subjective effects were assessed with questionnaires. RESULTS: Results showed an effect of the placebo (21-h withdrawal) condition compared to the caffeine condition. Placebo significantly increased the mean velocity, systolic velocity and diastolic velocity (cm/s) in all four cerebral arteries. In the MCA, the pulsatility index was significantly decreased following placebo. Placebo significantly increased EEG theta power. Placebo also produces subjective effect changes, including increases in heavy feelings in arms and legs and decreases in ability to concentrate. The caffeine and baseline conditions produced similar results on both the physiological and subjective measures. CONCLUSION: Cessation of daily caffeine consumption produced changes in cerebral blood flow velocity and quantitative EEG. These changes may be related to classic caffeine withdrawal symptoms of headache, drowsiness and decreased alertness.

Acute effects of triazolam on false recognition.

Neuropsychological, neuroimaging, and electrophysiological techniques have been applied to the study of false recognition; however, psychopharmacological techniques have not been applied. Benzodiazepine sedative/anxiolytic drugs produce memory deficits similar to those observed in organic amnesia and may be useful tools for studying normal and abnormal memory mechanisms. The present double-blind, placebo-controlled repeated measures study examined the acute effects of orally administered triazolam (Halcion; 0.125 and 0.25 mg/70 kg), a benzodiazepine hypnotic, on performance in the Deese (1959)/Roediger-McDermott (1995) false recognition paradigm in 24 healthy volunteers. Paralleling previous demonstrations in amnesic patients, triazolam produced significant dose-related reductions in false recognition rates to nonstudied words associatively related to studied words, suggesting that false recognition relies on normal memory mechanisms impaired in benzodiazepine-induced amnesia. The results also suggested that relative to placebo, triazolam reduced participants' reliance on memory for item-specific versus list-common semantic information and reduced participants' use of remember versus know responses.

Caffeine as a model drug of dependence: recent developments in understanding caffeine withdrawal, the caffeine dependence syndrome, and caffeine negative reinforcement.

Caffeine is an excellent model compound for understanding drugs of abuse/dependence. The results of self-administration and choice studies in humans clearly demonstrate the reinforcing effects of low and moderate doses of caffeine. Caffeine reinforcement has been demonstrated in about 45% of normal subjects with histories of moderate and heavy caffeine use. Recent studies provide compelling evidence that caffeine physical dependence potentiates the reinforcing effects of caffeine through the mechanism of withdrawal symptom avoidance. Tolerance to the subjective and sleep-disrupting effects of caffeine in humans has been demonstrated. Physical dependence as reflected in a withdrawal syndrome in humans has been repeatedly demonstrated in adults and recently demonstrated in children. Withdrawal severity is an increasing function of caffeine maintenance dose, with withdrawal occurring at doses as low as 100 mg per day. Increased cerebral blood flow may be the physiological mechanism for caffeine withdrawal headache. Case studies in adults and adolescents clearly demonstrate that some individuals meet DSM-IV diagnostic criteria for a substance dependence syndrome on caffeine, including feeling compelled to continue caffeine use despite desires and recommendations to the contrary. Survey data suggest that 9% to 30% percent of caffeine consumers may be caffeine dependent according to DSM-IV criteria.

A controlled study of flumazenil-precipitated withdrawal in chronic low-dose benzodiazepine users.

RATIONALE: Preclinical studies of the benzodiazepine antagonist flumazenil (Romazicon) have contributed to the understanding of the physical dependence associated with chronic benzodiazepine use; when administered to animals chronically pretreated with benzodiazepines, flumazenil precipitates a withdrawal syndrome. However, few controlled clinical studies have been conducted. OBJECTIVES: The objective was to characterize the effects of flumazenil in long-term users of therapeutic doses of benzodiazepines. METHODS: The acute physiological, participant-rated, and observer-rated effects of intravenously administered flumazenil (1 mg/70 kg) and caffeine (300 mg/70 kg; active drug control) were evaluated in an experimental group of 13 long-term users (mean 4.6 years) of low therapeutic doses (mean 11.2 mg/day diazepam equivalent) relative to a matched group of 13 volunteers without prior exposure to benzodiazepines in a double-blind, placebo-controlled, mixed design. RESULTS: Whereas the experimental group did not differ from the control group with respect to the effects of placebo, and both groups showed some changes in response to caffeine (e.g., increased blood pressure and anxiety scores), only the experimental group showed considerable changes in physiological measures, participant ratings (e.g., increased ratings of dizziness, blurred vision, heart pounding, feelings of unreality, pins and needles, nausea, sweatiness, noises louder than usual, jitteriness, things moving, sensitivity to touch), and observer ratings in response to flumazenil; in addition, four participants developed panic attacks. CONCLUSIONS: This study clearly demonstrates that flumazenil can precipitate symptoms commonly associated with benzodiazepine withdrawal in chronic low-dose benzodiazepine users.

Zaleplon and triazolam in humans: acute behavioral effects and abuse potential.

Zaleplon, a pyrazolopyrimidine that is under development as a hypnotic, produces its pharmacological effects at the benzodiazepine-recognition site on the GABA(A) benzodiazepine-receptor complex. Unlike most benzodiazepines, zaleplon binds selectively to the BZ1 (omega1) subtype of the benzodiazepine receptor. The present study compared the acute subject-rated effects, performance-impairing effects, and abuse potential of zaleplon and triazolam, a triazolobenzodiazepine hypnotic, in 14 healthy volunteers with histories of drug abuse. Zaleplon (25, 50, and 75 mg), triazolam (0.25, 0.5, and 0.75 mg) and placebo were administered orally in this double-blind, crossover study. Zaleplon and triazolam produced comparable dose-related effects on several subject-rated drug-effect questionnaires. Zaleplon and triazolam also produced comparable dose-dependent decrements on several performance tasks including balance, circular lights, digit-enter and recall, DSST, picture recall/recognition and repeated acquisition. Same-day and next-day subject-rated measures reflecting abuse potential (e.g., drug liking, good effects, and monetary street value) also suggest that zaleplon and triazolam were comparable. The only notable between-drug difference observed in the present study was that the time-action function of zaleplon differed from that of triazolam. The onset time, time to maximum drug effect, and duration of action were shorter with zaleplon than triazolam. Thus, despite its non-benzodiazepine structure and unique benzodiazepine-receptor binding profile, the behavioral pharmacological profile of zaleplon is similar to that of triazolam.