Psychedelics: Threshold of a Therapeutic Revolution.

This Special Issue of Neuropharmacology on psychedelics provides a timely and comprehensive update on progress following the previous Neuropharmacology Special Issue "Psychedelics: New Doors, Altered Perceptions". Remarkable advances have been made in basic and clinical research on psychedelics in the five years since 2018. It is partly based on the seminar series focused on psilocybin organized by the National Institutes of Health (NIH), USA from April to June 2021, the "NIH Psilocybin Research Speaker Series". Participants were world leading experts, including scientists, medical practitioners, clinical psychologists and oncologists, and attendees from additional disciplines of patient advocacy, law, government science policy and regulatory policy. To provide a global perspective, their contributions are complemented with reviews by some of the world's most eminent scientists in the field. The US Food and Drug Administration (FDA) has granted two breakthrough therapy designations for psilocybin in treatment resistant depression (TRD) in 2018 and major depressive disorder (MDD) in 2019, as well as for MDMA for the treatment of post-traumatic stress disorder (PTSD) in 2017. Clinical trials are in progress to assess the therapeutic value of psilocybin in MDD and TRD, and in other indications such as cancer-related anxiety and depression, anorexia, PTSD, substance use disorders and various types of chronic pain. The contributors' insights should assist basic and applied science for transition of psychedelics from bench to potential mainstream therapies. The implications are global, because FDA approval of these new medicines will increase international interest and efforts.

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.

The scientific basis of tobacco product regulation.

This report presents the conclusions and recommendations of TobReg from its fourth meeting, where the Study Group deliberated on a number of topics in the field of tobacco product regulation and produced the following advisory notes and recommendations: an advisory note on smokeless tobacco products: health effects, implications for harm reduction and research needs; an advisory note on 'fire safer' cigarettes: approaches to reduced ignition propensity; a recommendation on mandated lowering of toxicants in cigarette smoke: tobacco-specific nitrosamines and selected other constituents; and a recommendation on cigarette machine smoking regimens. The four sections of this report address these four issues, and the Study Group's recommendations are set out at the end of each section. Its overall recommendations are summarized in section 5.

Brand differences of free-base nicotine delivery in cigarette smoke: the view of the tobacco industry documents.

The recent availability of internal tobacco industry documents provides significant insight into industry knowledge and manipulation of tobacco smoke delivery. One critical area of research is the role of smoke chemistry in determining the absorption and effects of smoke constituents, especially harm producing or pharmacologically active compounds. Independent scientific research has suggested that the nicotine dosing characteristics, hence the addiction potential of cigarettes, may be determined in part by the amount of free-base nicotine in cigarette smoke and its effects on the location, route, and speed of absorption in the body and on the sensory perception effects of the inhaled smoke. Tobacco industry documents describe the use of a number of methods internally for measuring free-base nicotine delivery. These include the common use of cigarette "smoke pH" as a means to estimate the fraction of free-base nicotine in the particulate matter (PM) in cigarette smoke, as well as efforts to measure free-base nicotine directly. Although these methods do not provide accurate absolute measures of free-base nicotine in smoke, consistencies observed in the findings across the various manufacturers indicate: (1) real relative differences in the acid/base chemistry of the smoke from different brands of cigarettes; (2) a connection between differences in free-base levels and brand-dependent differences in sensory perception and smoke "impact"; and (3) levels of free-base nicotine that are greater than have typically been publicly discussed by the industry. Furthermore, the results of these methods are generally consistent with those of a recent study from the Centers for Disease Control and Prevention which directly measured the free-base fraction of nicotine across a range of cigarette types. Consideration of the likely fundamental importance of free-base nicotine levels in cigarette smoke, together with the efforts discussed in the tobacco industry documents to measure such levels, indicates that the public health community would benefit from additional research to assess directly the delivery of free-base nicotine in cigarette smoke across brands. This may be especially useful for those products ("light", "ultralight", "reduced carcinogen", etc) that have been promoted, either explicitly or implicitly, as "harm reducing".

Tobacco addiction: implications for treatment and cancer prevention.

The American Society of Clinical Oncology and the National Cancer Institute convened a symposium in June 1996 on tobacco addiction. Additional support for the symposium was provided by the American Medical Women's Association and the American Society of Preventive Oncology. The goals of this conference were to describe the burden and public health consequences of tobacco addiction, to describe the state of science for the treatment of nicotine dependence, and to explore new strategies to increase quit rates and to prevent the uptake of tobacco use. This article summarizes and integrates the meeting presentations on tobacco addiction and includes the topics of smoking prevalence; psychobiologic aspects of nicotine dependence; and implications for disease, treatment, and prevention. Comments on regulatory approaches and national strategies for reducing dependence are also summarized in presentations by Dr. David Kessler, former Food and Drug Administration Commissioner, and Dr. C. Everett Koop, former U.S. Surgeon General.

Toward a comprehensive long term nicotine policy.

Global tobacco deaths are high and rising. Tobacco use is primarily driven by nicotine addiction. Overall tobacco control policy is relatively well agreed upon but a long term nicotine policy has been less well considered and requires further debate. Reaching consensus is important because a nicotine policy is integral to the target of reducing tobacco caused disease, and the contentious issues need to be resolved before the necessary political changes can be sought. A long term and comprehensive nicotine policy is proposed here. It envisages both reducing the attractiveness and addictiveness of existing tobacco based nicotine delivery systems as well as providing alternative sources of acceptable clean nicotine as competition for tobacco. Clean nicotine is defined as nicotine free enough of tobacco toxicants to pass regulatory approval. A three phase policy is proposed. The initial phase requires regulatory capture of cigarette and smoke constituents liberalising the market for clean nicotine; regulating all nicotine sources from the same agency; and research into nicotine absorption and the role of tobacco additives in this process. The second phase anticipates clean nicotine overtaking tobacco as the primary source of the drug (facilitated by use of regulatory and taxation measures); simplification of tobacco products by limitation of additives which make tobacco attractive and easier to smoke (but tobacco would still be able to provide a satisfying dose of nicotine). The third phase includes a progressive reduction in the nicotine content of cigarettes, with clean nicotine freely available to take the place of tobacco as society's main nicotine source.

Stimulus functions of caffeine in humans: relation to dependence potential.

The interoceptive stimulus functions common to drugs of dependence include positive subjective effects, discriminative functions, and reinforcing functions. Data from studies measuring these stimulus functions constitute the objective assessment of a drug's dependence potential. This paper reviews the subjective effects, discriminative stimulus, and reinforcing stimulus functions of caffeine in humans to assess the dependence potential of caffeine. The stimulus effects of caffeine are compared with those of d-amphetamine, a prototypic CNS stimulant that has been studied under similar conditions, to evaluate the relative dependence potential of caffeine. Finally, caffeine's effects are evaluated in terms of generally accepted criteria for defining drug dependence. It is concluded that caffeine partially meets the primary criteria of drug dependence: 1) the majority of caffeine use is highly controlled, but not compulsive; 2) caffeine is psychoactive; and 3) caffeine functions as a reinforcer under certain conditions in humans, but not in animals. Caffeine thus has limited dependence potential. Additionally, although caffeine shares stimulus functions with d-amphetamine, it does so under limited conditions and should be considered to have a relatively lower dependence potential.

Evaluation of cranial electrostimulation therapy on short-term smoking cessation.

The effects of cranial electrical stimulation (CES) on short-term smoking cessation were evaluated in a double-blind study of cigarette smokers who wished to stop smoking. Subjects were randomly assigned to a CES- (n = 51) or a sham-treated group (n = 50). On 5 consecutive days subjects received CES treatments (30-microA, 2-msec, 10-Hz pulsed signal) or no electrical current (sham). There were no significant differences between groups on daily cigarettes smoked, exhaled carbon monoxide, urinary cotinine levels, treatment retention, smoking urges, or total tobacco withdrawal scores, although subjects in the CES group had less cigarette craving and anxiety during the first 2 experimental days. The ineffectiveness of CES to reduce withdrawal symptoms and facilitate smoking cessation are similar to results of other clinical studies of CES in drug dependence, although positive effects of CES in animal studies have been reported.

Effects of intravenous cocaine on plasma cortisol and prolactin in human cocaine abusers.

The aim of the present work was to examine the cortisol and prolactin responses to acute cocaine administration in human cocaine users. Each subject served as his own control during intravenous saline placebo and cocaine (40 mg) infusion sessions. Cocaine significantly elevated plasma cortisol but did not affect prolactin. The rise in cortisol coincided with an increase in heart rate and blood pressure after cocaine. In agreement with studies in animals, our data suggest that cocaine activates the hypothalamic-pituitary-adrenal axis in humans. However, based on the well-known importance of dopamine as a prolactin-inhibiting factor, the failure of cocaine to suppress prolactin in the present study raises questions concerning the role of dopamine in the mechanism of acute cocaine action in humans.

Effects of nicotine chewing gum on cigarette smoking and subjective and physiologic effects.

Our study was conducted to assess the effects of multiple doses of nicotine chewing gum on a variety of measures of cigarette smoking, affect, and physiologic response. Cigarette smokers resided on a research unit for the duration of the study, during which time their smoking behavior was measured during nine 12-hour test sessions. At the start of each session and every 2 hours thereafter, subjects received oral doses of nicotine (2 or 4 mg) or placebo in the form of a chewing gum (nicotine polacrilex). Each dose of active drug and placebo was given for three sessions in a randomized block sequence. Total number of puffs per day was significantly decreased at both the 2 and 4 mg doses when compared with placebo, and the total number of cigarettes smoked per day was significantly decreased at the 4 mg dose. There were dose-related changes in certain subjective effects: Self-reported ratings of dose strength were directly related to dose, desire to smoke tended to be inversely related to dose, and prominent measures of abuse liability did not change. The only cardiovascular measure that was significantly changed by nicotine dose was systolic blood pressure, which showed an attenuation of the diurnal pattern as the dose increased.

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.

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.

Human pharmacology and abuse potential of nalmefene.

Nalmefene hydrochloride was administered to six male volunteers with histories of opiate abuse using a double-blind, randomized, Latin square design to determine if it produced typical morphine-like effects. A comparison of physiologic and subject- and observer-reported effects was made between morphine, 15 and 30 mg given intramuscularly; nalmefene, 25, 50, and 100 mg given orally; and placebo. Drowsiness or sleepiness was the most common drug effect reported after the administration of each treatment. Only morphine produced miosis and increased subject-reported euphoria and "drug liking." Neither drug increased Addiction Research Inventory subscale scores measuring dysphoria or sedation or produced changes on the Profile of Mood States questionnaire. Adverse effects reported only after the administration of nalmefene included agitation/irritability and muscle tension; these did not appear to be dose related. The data indicated that nalmefene did not produce typical morphine-like effects and has no apparent abuse potential.

Characterization of the absorption phase of marijuana smoking.

Rapid blood collection, a paced smoking protocol and timely collection of physiologic and behavioral measures were used to characterize the absorption phase of marijuana smoking. Six healthy males smoked a single marijuana cigarette (placebo, 1.75%, or 3.55% delta-9-tetrahydrocannabinol) in a double-blind, randomized, Latin square study design. Rapid blood sampling with a continuous withdrawal pump allowed simultaneous collection with concurrent physiologic and behavioral measures. Mean plasma levels of 7.0 and 18.1 ng/ml delta-9-tetrahydrocannabinol were observed after the first inhalation of a 1.75% and 3.55% delta-9-tetrahydrocannabinol cigarette, respectively. Blood levels increased rapidly and peaked at 9 minutes, before initiation of the last puff sequence at 9.8 minutes. Three of six subjects reported increases in drug "liking" scores after the first puff, and all subjects responded by the second puff of a high dose cigarette. Significant increases in heart rate and diastolic blood pressure occurred shortly after peak blood levels. Previous studies have indicated that there is a substantial time delay between peak plasma levels of delta-9-tetrahydrocannabinol and drug-induced effects. This study showed that behavioral and physiologic effects appear concurrently or within minutes after the rapid appearance of delta-9-tetrahydrocannabinol in blood during marijuana smoking.

Use of buprenorphine in the treatment of opiate addiction. I. Physiologic and behavioral effects during a rapid dose induction.

A new, rapid dose-induction procedure was used in the evaluation of buprenorphine hydrochloride (buprenorphine) as a treatment for opiate dependence. Nineteen heroin-dependent men were given buprenorphine sublingually in ascending daily doses of 2, 4, and 8 mg and then maintained on 8 mg daily. The observations of the transition from heroin to buprenorphine for the first 4 days are described. During this period, subjects reported significantly elevated ratings of "good effects" and feelings of "overall well-being" and decreased ratings of "overall sickness." Data from subscales of the Addiction Research Center Inventory indicated increasing euphoria and decreasing dysphoria and sedation after buprenorphine administration. Subjects and observers consistently identified buprenorphine as an opiate and not as an opiate antagonist. These findings indicate that a rapid dose induction with buprenorphine is acceptable to heroin-dependent persons and that it causes minimal withdrawal symptoms.

Pharmacologic basis and treatment of cigarette smoking.

Data are reviewed which support the contention of the American Psychiatric Association and the U.S. Public Health Service that cigarette smokers may become addicted to nicotine. Available data indicate that 1) tobacco use shares many factors in common with previously studied forms of drug abuse--most notably, narcotic addiction, 2) the rate and pattern of cigarette smoking are partially determined by nicotine dose level, and 3) nicotine meets established criteria for a prototypic drug of abuse. These findings have implications for the understanding and treatment not only of cigarette smoking but of other forms of drug abuse and psychiatric disorders in which tobacco use is a cofactor.

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.

Discriminative stimulus effects of d-amphetamine, methylphenidate, and diazepam in humans.

Eight male community volunteers, who reported current psychomotor stimulant use, were trained to discriminate between the presence and absence of orally administered d-amphetamine 30 mg. During daily experimental sessions, in which a single drug dose or placebo was tested, physiological and subjective measures were assessed and subjects indicated their discrimination by responding on an operant color-tracking procedure. During four test of acquisition sessions, discriminative responding indicated that all subjects learned the discrimination, and d-amphetamine produced physiological and subjective effects typical of psychomotor stimulants. Generalization testing then followed in which dose-response curves were determined for the following drugs: d-amphetamine (3.75, 7.5, 15 and 30 mg), diazepam (5, 10, 20 and 40 mg), and methylphenidate (7.5, 15, 30 and 60 mg). d-Amphetamine and methylphenidate produced dose-related increases in d-amphetamine-appropriate responding, whereas no dose of diazepam substituted for d-amphetamine in any subject. d-Amphetamine and methylphenidate produced a similar pattern of subjective changes, including increased ratings of euphoria and drug liking and decreased sedation. In contrast, diazepam increased subjective scales of sedation and dysphoria. These results are consistent with similar studies testing animals and humans and demonstrate the utility of human drug discrimination research as an integral component of drug abuse liability testing.

Ethanol drinking by rhesus monkeys as a function of concentration.

Ethanol deliveries maintained fixed-ratio (FR) responding of three rhesus monkeys during daily 3-h sessions. At FR values of 8 or 16, ethanol concentration was varied in the sequence 0 (water), 8, 11.3, 16, 22.6 32, 8, and 0% (w/v). As the ethanol concentration increased, number of liquid deliveries decreased somewhat. Blood ethanol levels were usually greater than 200 mg% and occasionally greater than 300 mg%.