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.

Precipitated withdrawal by a benzodiazepine receptor antagonist (Ro 15-1788) after 7 days of diazepam.

Baboons implanted with intragastric catheters were given diazepam (10 milligrams per kilogram of body weight) twice daily for 45 consecutive days. On days 7 and 35, they were given intramuscular injections of the benzodiazepine receptor antagonist Ro 15-1788. Mild and intermediate withdrawal signs, including retching and vomiting, were observed after 7 days of diazepam, and more frequent and intense withdrawal signs, including tremor and convulsion, occurred after 35 days of diazepam. With the termination of the diazepam injections after 45 days, a mild to intermediate withdrawal syndrome was observed over the next 15-day period.

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.

Differential effects of diazepam and pentobarbital on mood and behavior.

The effects of administering moderately high doses of diazepam and pentobarbital sodium for five consecutive days to subjects with histories of sedative drug abuse were examined. The two drugs produced similar dose-related effects on psychomotor performance, daytime sleeping, and ratings of magnitude of drug effects. Diazepam, but not pentobarbital, produced dose-related decreases in staff ratings of subjects' mood and social interactions and increases in staff ratings of subjects' hostility, complaining, and unusual behavior. During the placebo washout periods that followed drug administration. diazepam, but not pentobarbital, was associated with carry-over effects. The diazepam-produced deterioration in mood and social behavior was a subtle effect observed in a population for which usual therapeutic indications were lacking and at higher than usual therapeutic doses. The syndrome may, however, occur with long-term diazepam use or misuse in therapeutic settings and, hence, warrants clinical awareness in monitoring the course of treatment.

Double-blind evaluation of reinforcing and anorectic actions of weight control medications. Interaction of pharmacological and behavioral treatments.

Within a behavioral self-management treatment program for overweight, 59 patients were randomly assigned to receive as an adjunct either dextroamphetamine sulfate, fenfluramine hydrochloride, or placebo in a double-blind procedure. Patients self-regulated their drug intake during a four-week medication period. Two types of behavioral-pharmacological interaction were observed: (1) drug assignment influenced participation in the behavioral treatment; and (2) drug assignment influenced the extent of medication self-administration. The dextroamphetamine group was superior in terms of behavioral treatment participation, extent of eating and exercise habit change, and weight loss. Self-administration of dextroamphetamine was most well-maintained--showing it to be a reinforcer--and self-administration of fenfluramine was suppressed below placebo levels. No patient taking either drug showed excessive drug intake, and all were, in fact, conservative in drug use. These data concerning relative reinforcing efficacy within a therapeutic medication setting are discussed in relation to data from animal models used to assess relative abuse liability of these drugs.

Relative abuse liability of triazolam: experimental assessment in animals and humans.

The abuse liability of a drug is a positive, interactive function of the reinforcing and adverse effects of the drug. The relative abuse liability of the hypnotic benzodiazepine, triazolam, has been controversial. This paper reviews animal and human studies bearing on its relative abuse liability, including data on pharmacological profile, reinforcing effects, liking, speed of onset, discriminative stimulus effects, subjective effects, physiological dependence, rebound and early morning insomnia, drug produced anxiety, lethality in overdose, psychomotor impairment, interactions with ethanol, anterograde amnesia, impaired awareness of drug effect, and other psychiatric and behavioral disturbances. It is concluded that the abuse liability of triazolam is less than that of the intermediate duration barbiturates such as pentobarbital. Although there are considerable data indicating similarities of triazolam to other benzodiazepines, there is also substantial speculation among clinical investigators and some limited data suggesting that the abuse liability of triazolam is greater than that of a variety of other benzodiazepines, and virtually no credible data or speculation that it is less. Further research will be necessary to clarify definitively the abuse liability of triazolam relative to other benzodiazepines.

Relationship between anorectic and reinforcing properties of appetite suppressant drugs: implications for assessment of abuse liability.

A quantitative ratio measure was developed which permitted comparisons between the reinforcing and anorectic potency of eight phenylethylamine anorectics and cocaine in laboratory baboons. The ordering of these compounds based upon this ratio bears a reasonable correspondence to clinical drug evaluations. The measure may provide information for preclinical evaluation of relative abuse potential of anorectic drugs.

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.

Cigarette smoking and subjective response: effects of d-amphetamine.

The effects of oral d-amphetamine on cigarette smoking and subjective responses were determined in eight adults who smoked cigarettes. Subjects were tested each day in rooms that provided a comfortable, natural environment while cigarette-smoking behavior was automatically monitored. Each subject served as his own control and was tested at four d-amphetamine dose levels (0, 5, 15, 25 mg) that were scheduled according to five randomized block sequences. d-Amphetamine induced dose-related increases in the number of cigarettes smoked. total puffs, weight of tobacco consumed, expired air carbon monoxide levels, subject-related satisfaction derived from smoking, and scores on scales of the Addiction Research Center Inventory (ARCI). As measures of drug effects, both the behavioral measures of smoking and the ARCI scales were sensitive when the data from the subjects were grouped and tested for statistical significance. Behavioral measures, however, were more sensitive than the ARCI scales when a within-subject analysis was performed.

Smoking behavior and tobacco smoke intake: response of smokers to shortened cigarettes.

The response of four cigarette smokers to full-length and three different types of half-length cigarettes was examined in a naturalistic laboratory environment. During daily 100-min sessions, subjects smoked ad libitum: (1)full-length (100 mm) cigarettes, (2)the distal half of cigarettes, (3)the proximal half of cigarettes, or (4)the proximal half of previously smoked cigarettes. As a group, subjects smoked 75% more half-length cigarettes than full-length cigarettes. Subjects also puffed at a higher rate (i.e., had shorter interpuff intervals) on half-length than on full-length cigarettes. Mean puff duration (sec/puff) was higher when subjects smoked the distal-half cigarettes than when they smoked the proximal-half cigarettes and subjects spent proportionately more time puffing on the distal-half cigarettes than on the other three types. Through a combination of smoking more half-length cigarettes and modifying the way they smoked half-length cigarettes, subjects maintained the same intake of smoke (as measured by expired air carbon monoxide) during sessions as when they smoked full-length cigarettes. These results demonstrate that smokers make complex adjustments in their smoking behavior in response to changes in cigarette length.

Effects of caffeine on cigarette smoking and subjective response.

We examined the effects of oral caffeine on cigarette smoking and subjective response in a group of six smokers who smoked cigarettes ad libitum in a naturalistic laboratory environment. A within-subject, repeated-measures design was used, and each subject received placebo, caffeine base (50 to 800 mg), or d-amphetamine sulfate (25 mg) on several occasions before 90-min daily smoking sessions. There was no evidence of an increase in the number of cigarettes smoked or the amount of smoke inhaled per session after caffeine. Caffeine increased salivary caffeine concentrations, arm tremor, and self-reported measures of mood and subjective response. The major subjective effects of caffeine were increases in tension-anxiety and dysphoric-somatic effects. In contrast, d-amphetamine induced increases in the number of cigarettes smoked and in the amount of smoke inhaled per session. The major subjective effects of 25 mg of d-amphetamine were increases in measures of well-being, euphoria, and mental efficiency. Results demonstrate that caffeine and d-amphetamine have different effects on cigarette-smoking behavior as well as on subjective response and suggest that the positive correlation between cigarette smoking and coffee drinking is not the result of a simple pharmacologic effect of caffeine.

Cigarette smoking and subjective response in alcoholics: effects of pentobarbital.

The effects of oral pentobarbital on cigarette smoking and subjective response were determined in five adult men with histories of alcoholism and cigarette-smoking habits. Subjects resided in a residential research unit for the 6-wk study and were individually tested 5 days a wk in rooms that were equipped for automatic monitoring of cigarette-smoking behavior. Each subject was tested with placebo, one dose level of ethanol (either 89 or 134 gm absolute ethanol), and each of three pentobarbital doses (200 to 900 mg), in at least four randomized block sequences. Ethanol induced increases in puffs and other smoking measures in all subjects. Pentobarbital increased smoking in two subjects, whereas it did not induce change or suppress smoking in the other subjects. Both pentobarbital and ethanol increased scores on scales of the Addiction Research Center Inventory and other self-report measures. The results indicate that the effects of pentobarbital on smoking differ from those of ethanol, and that the effects of both drugs on smoking may depend on previous experience of the subject in the use of those drugs.

Alprazolam absorption kinetics affects abuse liability.

OBJECTIVE: To evaluate the behavioral, subjective, and reinforcing effects of immediate-release (IR) alprazolam and extended-release (XR) alprazolam to assess the effect of release rate on laboratory measures of abuse liability. METHODS: Fourteen healthy men with histories of sedative abuse participated as subjects in a double-blind crossover study. All subjects received placebo, 1 and 2 mg immediate-release alprazolam, and 2 and 3 mg extended-release alprazolam in random order. Behavioral performance, subjective effects, and alprazolam plasma concentrations were assessed repeatedly 1/2 hour before and 1/2, 1, 3, 5, 7, 9, 12, and 24 hours after drug administration. RESULTS: Mean peak alprazolam plasma concentrations occurred 1.7 and 9.2 hours after immediate-release alprazolam and extended-release alprazolam, respectively. Compared to placebo, 2 mg immediate-release alprazolam impaired all measures of psychomotor and cognitive performance (Digit Symbol Substitution Test), motor coordination (circular lights and balance), and memory (digit entry and recall); 2 mg extended-release alprazolam did not affect any of these measures and 3 mg extended-release alprazolam impaired circular lights only. Immediate-release alprazolam, 2 mg, increased all six measures of positive drug effects (e.g., ratings of liking or good effects); none of these measures were increased by 2 mg extended-release alprazolam and only three of the six measures were increased by 3 mg extended-release alprazolam. A drug versus money multiple-choice procedure designed to assess the relative reinforcing effects of each condition was administered 24 hour after the drug. The amount of money subjects were willing to "pay" to take the drug was significantly greater than placebo for both doses of immediate-release alprazolam but for neither dose of extended-release alprazolam. CONCLUSIONS: These data indicate that extended-release alprazolam has less potential for abuse than immediate-release alprazolam.

Diazepam and methadone interactions in methadone maintenance.

Survey study data and high rates of diazepam use/abuse in methadone maintenance suggest that acute administration of diazepam with daily methadone doses may enhance methadone effects. Acute subjective and physiologic effects of single oral doses of placebo, diazepam (20 and 40 mg), methadone (100%, 150%, and 200% of the maintenance dose), and four diazepam-methadone dose combinations (20 and 40 mg diazepam in combination with 100% and 150% of the maintenance dose) were assessed under double-blind conditions. The subjects were five adult male patients on methadone maintenance with histories of diazepam abuse who were receiving 50 to 60 mg methadone a day. Physiologic measures were continuously monitored for 30 min before and for 2 hr after dosing. Pupil diameter and subjective responses were measured 15 min before dosing and 15, 30, 45, 60, 90, and 120 min after dosing. Methadone induced dose-dependent increases in pupil constriction and scores on a subjective opioid effects rating scale, but diazepam had no significant effect on either. The combination of methadone at 150% of the maintenance dose with 40 mg diazepam induced increases in these measures greater than those induced by either drug dose alone. Drug combinations, however, were more frequently identified as being benzodiazepine/barbiturate-like than as methadone-like. Thus although the subjective effects of the drug combination are distinguishable from those of methadone alone, diazepam with methadone in methadone maintenance appears to increase some physiologic and subjective opioid effects that may be related to the relatively great use/abuse of diazepam in this population.

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.

Human drug discrimination and multiple chemical sensitivity: caffeine exposure as an experimental model.

Multiple chemical sensitivity is a controversial diagnosis. Rigorous, controlled, laboratory-based research can reduce this controversy and lead to potential clinical confirmatory tests. The literature on human caffeine discrimination provides a rigorous methodology that can address reports that patients who suffer multiple chemical sensitivity (MCS) are sensitive to usually well-tolerated chemical doses; the studies require patients to discriminate caffeine from placebo under double-blind conditions. Several issues relevant to the conduct of caffeine discrimination studies using MCS patients as subjects are addressed; these issues include study design, determination of safe and tolerable training doses, and discrimination training. Such research will benefit patients and clinicians dealing with a diagnosis of MCS.

Alprazolam and benzodiazepine dependence.

The incidence of nonmedical use of alprazolam is very low relative to its widespread legitimate medical use; in fact, given the millions of patients who have received this medication, the incidence is remarkably small. In particular, among patients with anxiety disorders, dependence does not appear to be a clinically important problem. Alprazolam abuse and dependence represent only a small fraction of the large and serious nonmedical use problem in the United States, and when they occur, are among individuals who abuse other drugs. For example, a serious problem of alprazolam abuse may exist among patients in methadone maintenance treatment. A similar problem exists with diazepam. Alcohol abusers and alcohol-dependent individuals are another group among whom concern about benzodiazepine and alprazolam abuse exists. However, more and better information about the extent and nature of this use is needed. Many patients with alcohol or drug abuse also have anxiety disorders for whom effective pharmacotherapy may be needed. In the interim, caution but not prohibition to use should prevail in prescribing alprazolam to such patients. To the extent that nonmedical alprazolam use exists, evidence suggests that the vast majority of such use is the consequence of the inappropriate prescribing of the medication by a small number of physicians. One way to reduce the inappropriate use of benzodiazepines in methadone programs is to drug test the methadone-maintenance patients and to link positive urine tests to contingency-management strategies. The available data provide some support to the idea that alprazolam and diazepam have more abuse liability than other benzodiazepines.

Effects of ventilated cigarette holders on cigarette smoking by humans.

Heavy cigarette smokers individually attended daily 3-h test sessions which were run in specially designed cigarette smoking evaluation rooms. Subjects were required to use the cigarette holder provided, and were required to extinguish each cigarette 4 min after the first puff on the cigarette. Other than these restrictions, subjects were allowed to smoke ad libitum. The concentration of delivered tobacco product was varied from 100 to 10% across sessions by using graded commercially available ventilated cigarette holders. As concentration of tobacco product was decreased, rate of puffing and total number of puffs showed robust compensatory increases. Number of cigarettes increased only moderately in response to decreases in tobacco product concentration. There was little change in subjective ratings of strength on smoking satisfaction. Finally, expired air carbon monoxide (CO) values and cigarette butt weights were relatively stable across the four ventilation conditions. These later findings suggest that a significant degree of compensation had occurred in response to the concentration manipulations.

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.

Self-injection of d,1-3,4-methylenedioxymethamphetamine (MDMA) in the baboon.

MDMA (d,1-3,4-Methylenedioxymethamphetamine HCl; "ecstasy") self-injection (0.1-3.2 mg/kg/injection) was examined in baboons under conditions in which baseline responding was maintained by intravenous injections of cocaine HCl (0.32 mg/kg/injection). Drug was available under a FR 160-response schedule of intravenous injection. Each drug injection was followed by a 3-h time out allowing a maximum of eight injections per day. MDMA or MDMA vehicle (saline) was substituted for cocaine for a period of 14 or more days followed by a return to the cocaine baseline. MDMA (0.32-3.2 mg/kg/inj) maintained more injections and higher responses rates than were maintained by saline. The maximal number of injections maintained by MDMA and the maximal response rate maintained by MDMA were less than those maintained under baseline conditions with cocaine. The highest dose of MDMA tested maintained a cyclic pattern of self-injection, i.e., days of high numbers of injections intermixed with days of low numbers of injections. At the highest dose of MDMA tested, concurrent food maintained behavior was suppressed to an extent that food intake was also decreased.