04 - 20.4 Cannabis Related Disorders

20.4 Cannabis-Related Disorders

caffeine: A near infrared spectroscopy study. Biol Psychol. 2011;86:298. Lieberman JA III, Sylvester L, Paik S. Excessive sleepiness and self-reported shift work disorder: an Internet survey of shift workers. Postgrad Med. 2013;125:162. Ludden AB, Wolfson AR. Understanding adolescent caffeine use: Connecting use patterns with expectancies, reasons, and sleep. Health Educ Behav. 2010;37:330. Mahoney CR, Brunyé TT, Giles GE. Caffeine effects on aggression and risky decision making. In: Kanarek RB, Lieberman HR, eds. Diet, Brain, Behavior: Practical Implications. Boca Raton: Taylor & Frances Group, LLC; 2012:293. Reissig CJ, Strain EC, Griffiths RR. Caffeinated energy drinks—A growing problem. Drug Alcohol Depend. 2009;99:1. Sepkowitz KA. Energy drinks and caffeine-related adverse effects. JAMA. 2013;309:243. Stafford LD, Wright C, Yeomans MR. The drink remains the same: Implicit positive associations in high but not moderate or non-caffeine users. Psychology Addict Behav. 2010;24:274. Yang A, Palmer AA, de Wit H. Genetics of caffeine consumption and responses to caffeine. Psychopharmacology. 2010;211:245. 20.4 Cannabis-Related Disorders Cannabis is the most widely used illegal drug in the world, with an estimate 19 million users in 2012. Over the last 30 years cannabis has become a common part of youth culture in most developed societies, with first use now occurring in the mid- to late teenage years. Cannabis is the fourth most commonly used psychoactive drug among adults in the United States, after caffeine, alcohol, and nicotine. CANNABIS PREPARATIONS Cannabis preparations are obtained from the plant Cannabis sativa (Fig. 20.4-1), which has been used in China, India, and the Middle East for approximately 8,000 years, primarily for its fibers and secondarily for its medicinal properties. The plant occurs in male and female forms. The female plant contains the highest concentrations of more than 60 cannabinoids that are unique to the plant. Delta-9-tetrahydrocannabinol (Δ9THC) is the cannabinoid that is primarily responsible for the psychoactive effects of cannabis. The most potent forms of cannabis come from the flowering tops of the plants or from the dried, black–brown, resinous exudate from the leaves, which are referred to as hashish or hash. The cannabis plant is usually cut, dried, chopped, and rolled into cigarettes (commonly called “joints”), which are then smoked. The common names for cannabis are marijuana, grass, pot, weed, tea, and Mary Jane. Other names, which describe cannabis types of various strengths, are hemp, chasra, bhang, ganja, dagga, and sinsemilla. The potency of marijuana preparations has increased in recent years because of improved agricultural techniques used in cultivation so that plants may contain up to 15 or 20 percent THC.

FIGURE 20.4-1 Marijuana (Cannabis sativa). EPIDEMIOLOGY Prevalence and Recent Trends Based on the 2012 National Surveys on Drug Use and Health (NSDUH), an estimated 19 million persons age 12 years and older (7 percent) had used marijuana in the past month. Of this age group, 2.4 million initiated use within the last year, 57 percent of which initiated use before age 18 years. The Monitoring the Future survey of adolescents in school indicates recent increases in lifetime, annual, current (within the past 30 days), and daily use of marijuana by eighth and tenth graders, continuing a trend that began in the early 1990s. In 1996, about 23 percent of eighth graders and about 40 percent of tenth graders reported having used marijuana and, in 1998 and 1999, more than a quarter of marijuana initiates were aged 14 years or younger. The average age was 17. In 2012, approximately 1 percent of eighth graders, 4 percent of tenth graders, and 7 percent of twelfth graders reported daily use of marijuana. Demographic Correlates

The rate of past year and current marijuana use by males was almost twice the rate for females overall among those aged 26 and older. This gap between the sexes narrows with younger users; at ages 12 to 17, there are no significant differences. Race and ethnicity were also related to marijuana use, but the relationships varied by age group. Among those aged 12 to 17, whites had higher rates of lifetime and past-year marijuana use than blacks. Among those 17 to 34 years of age, whites reported higher levels of lifetime use than blacks and Hispanics. But among those 35 and older, whites and blacks reported the same levels of use. The lifetime rates for black adults were significantly higher than those for Hispanics. NEUROPHARMACOLOGY As stated above, the principal component of cannabis is Δ9-THC; however, the cannabis plant contains more than 400 chemicals, of which about 60 are chemically related to Δ9THC. In humans, Δ9-THC is rapidly converted into 11-hydroxy-Δ9-THC, the metabolite that is active in the central nervous system (CNS). A specific receptor for the cannabinols has been identified, cloned, and characterized. The cannabinoid receptor, a member of the G-protein-linked family of receptors, is linked to the inhibitory G protein (Gi), which is linked to adenylyl cyclase in an inhibitory fashion. The cannabinoid receptor is found in highest concentrations in the basal ganglia, the hippocampus, and the cerebellum, with lower concentrations in the cerebral cortex (Figure 20.4-2). This receptor is not found in the brainstem, a fact consistent with cannabis’s minimal effects on respiratory and cardiac functions. Studies in animals have shown that the cannabinoids affect the monoamine and γ-aminobutyric acid (GABA) neurons. FIGURE 20.4-2 Autoradiography of cannabinoid receptor distribution in a sagittal section of rat brain.

Binding of tritiated ligand is dense in the hippocampus (Hipp), the globus pallidus (GP), the entopeduncular nucleus (EP), the substantia nigra pars reticulata (SNr), and the cerebellum (Cer). Binding is moderate in the cerebral cortex (Cx) and the caudate putamen (CP) and sparse in the brainstem (Br St) and spinal cord. (From Howlett AC, Bidaut-Russell M, Devane WA, Melvin LS, Johnson MR, Herkenham M. The cannabinoid receptor: Biochemical anatomical, and behavioral characterization. Trends Neurosci. 1990;13:422, with permission.) According to most studies, animals do not self-administer cannabinoids as they do most other substances of abuse. Moreover, some debate questions whether the cannabinoids stimulate the so-called reward centers of the brain, such as the dopaminergic neurons of the ventral tegmental area. Tolerance to cannabis does develop, however, and psychological dependence has been found, although the evidence for physiological dependence is not strong. Withdrawal symptoms in humans are limited to modest increases in irritability, restlessness, insomnia, and anorexia and mild nausea; all these symptoms appear only when a person abruptly stops taking high doses of cannabis. When cannabis is smoked, the euphoric effects appear within minutes, peak in about 30 minutes, and last 2 to 4 hours. Some motor and cognitive effects last 5 to 12 hours. Cannabis can also be taken orally when it is prepared in food, such as brownies and cakes. About two to three times as much cannabis must be taken orally to be as potent as cannabis taken by inhaling its smoke. Many variables affect the psychoactive properties of cannabis, including the potency of the cannabis used, the route of administration, the smoking technique, the effects of pyrolysis on the cannabinoid content, the dose, the setting, and the user’s past experience, expectations, and unique biological vulnerability to the effects of cannabinoids. DIAGNOSIS AND CLINICAL FEATURES The most common physical effects of cannabis are dilation of the conjunctival blood vessels (red eye) and mild tachycardia. At high doses, orthostatic hypotension may appear. Increased appetite—often referred to as “the munchies”—and dry mouth are common effects of cannabis intoxication. That no clearly documented case of death caused by cannabis intoxication alone reflects the substance’s lack of effect on the respiratory rate. The most serious potential adverse effects of cannabis use are those caused by inhaling the same carcinogenic hydrocarbons present in conventional tobacco, and some data indicate that heavy cannabis users are at risk for chronic respiratory disease and lung cancer. The practice of smoking cannabis-containing cigarettes to their very ends, so-called “roaches,” further increases the intake of tar (particulate matter). Many reports indicate that long-term cannabis use is associated with cerebral atrophy, seizure susceptibility, chromosomal damage, birth defects, impaired immune reactivity, alterations in testosterone concentrations, and dysregulation of menstrual cycles; these reports, however, have not been conclusively

replicated, and the association between these findings and cannabis use is uncertain. Cannabis Use Disorder The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) includes the diagnosis of cannabis use disorder. People who use cannabis daily over weeks to months are most likely to become dependent. The risk of developing dependence is around one in ten for anyone who uses cannabis. The earlier the age of first use, the more often cannabis has been used, and the longer it has been used, the higher the risk of dependence. Cannabis Intoxication Cannabis intoxication commonly heightens users’ sensitivities to external stimuli, reveals new details, makes colors seem brighter and richer, and subjectively slows the appreciation of time. In high doses, users may experience depersonalization and derealization. Motor skills are impaired by cannabis use, and the impairment in motor skills remains after the subjective, euphoriant effects have resolved. For 8 to 12 hours after using cannabis, users’ impaired motor skills interfere with the operation of motor vehicles and other heavy machinery. Moreover, these effects are additive to those of alcohol, which is commonly used in combination with cannabis. Mr. M was an unemployed 20-year-old man who lived with his parents. He was brought to a hospital by some friends in a state of anxiety and agitation. He had been out for the evening with some friends at a restaurant, and after a couple of beers, he decided to have some cannabis. He had smoked cannabis on previous occasions; however, this time he ate a lump of cannabis despite warnings from his friends. After about half an hour, Mr. M appeared tense and anxious and complained that everything was changing. He could see the faces of his friends increasing to about three times their natural size. The room became distorted, and its proportions and colors kept altering. He felt that the other guests in the restaurant were talking about him and his friends in a menacing way, so he suddenly rushed outside because he felt that he was in danger. He became increasingly agitated and started running down the middle of the street, dodging in and out among the traffic. Eventually, his friends were able to catch him. They were unable to quiet his anxiety, however, and had a hard time persuading him to go with them to the hospital. On examination Mr. M appeared tense and apprehensive, looking around the room as if he felt uneasy with the surroundings, but he denied perceptual symptoms and did not really believe that he was the subject of persecution. He was fully aware of his surroundings, but his attention was fleeting, and he did not always answer questions. There was no marked impairment of memory, and he was fully oriented. Physical examination revealed conjunctival injection and an increased pulse rate of 120 beats per minute, but otherwise no abnormalities were found. Neurological

examination also revealed no abnormalities. In the course of a few hours, he quieted down. When he felt recovered, he left the hospital with his friends. Cannabis Intoxication Delirium The delirium associated with cannabis intoxication is characterized by marked impairment on cognition and performance tasks. Even modest doses of cannabis impair memory, reaction time, perception, motor coordination, and attention. High doses that also impair users’ levels of consciousness have marked effects on cognitive measures. Cannabis Withdrawal Studies have shown that cessation of use in daily cannabis users results in withdrawal symptoms within 1 to 2 weeks of cessation. Withdrawal symptoms include irritability, cannabis cravings, nervousness, anxiety, insomnia, disturbed or vivid dreaming, decreased appetite, weight loss, depressed mood, restlessness, headache, chills, stomach pain, sweating, and tremors. Cannabis-Induced Psychotic Disorder Cannabis-induced psychotic disorder is diagnosed in the presence of a cannabis-induced psychosis. Cannabis-induced psychotic disorder is rare; transient paranoid ideation is more common. Florid psychosis is somewhat common in countries in which some persons have longterm access to cannabis of particularly high potency. The psychotic episodes are sometimes referred to as “hemp insanity.” Cannabis use rarely causes a “bad-trip” experience, which is often associated with hallucinogen intoxication. When cannabisinduced psychotic disorder does occur, it may be correlated with a preexisting personality disorder in the affected person. Cannabis-Induced Anxiety Disorder Cannabis-induced anxiety disorder is a common diagnosis for acute cannabis intoxication, which in many persons induces short-lived anxiety states often provoked by paranoid thoughts. In such circumstances, panic attacks may be induced, based on illdefined and disorganized fears. The appearance of anxiety symptoms is correlated with the dose and is the most frequent adverse reaction to the moderate use of smoked cannabis. Inexperienced users are much more likely to experience anxiety symptoms than are experienced users. A 35-year-old white married male who was naïve to cannabis use was given two “joints” by a friend. He smoked the first of the two in the same manner that he normally smoked a cigarette (in about 3 to 5 minutes). Noting no major effects, he

proceeded immediately to smoke the second in the same amount of time. Within 30 minutes, he began to experience rapid heartbeat, dry mouth, mounting anxiety and the delusional belief that his throat was closing up and that he was going to die. That belief induced further panic and the patient was brought to the emergency room in the midst of the experience. Reassurance that he would not die had no effect. He was sedated with diazepam and some of his anxiety diminished. He eventually went to sleep and on awakening in about 5 hours he was asymptomatic with full recall of previous events. Unspecified Cannabis-Related Disorders DSM-5 includes the category unspecified cannabis-related disorders for cannabis disorders that cannot be classified as cannabis use disorder, cannabis intoxication, cannabis intoxication delirium, cannabis withdrawal, cannabis-induced psychotic disorder, or cannabis-induced anxiety disorder. Cannabis intoxication can be associated with depressive symptoms, although such symptoms may suggest long-term cannabis use. Hypomania, however, is a common symptom in cannabis intoxication. When either sleep disorder or sexual dysfunction symptoms are related to cannabis use, they almost always resolve within days or a week after cessation of cannabis use. Flashbacks. There are case reports of persons who have experienced—at times significantly—sensations related to cannabis intoxication after the short-term effects of the substance have disappeared. Continued debate concerns whether flashbacks are related to cannabis use alone or to the concomitant use of hallucinogens or of cannabis tainted with phencyclidine (PCP). Cognitive Impairment. Clinical and experimental evidence indicates that the long-term use of cannabis may produce subtle forms of cognitive impairment in the higher cognitive functions of memory, attention, and organization and in the integration of complex information. This evidence suggests that the longer the period of heavy cannabis use, the more pronounced the cognitive impairment. Nonetheless, because the impairments in performance are subtle, it remains to be determined how significant they are for everyday functioning. It also remains to be investigated whether these impairments can be reversed after an extended period of abstinence from cannabis. Amotivational Syndrome. A controversial cannabis-related syndrome is amotivational syndrome. Whether the syndrome is related to cannabis use or reflects characterological traits in a subgroup of persons regardless of cannabis use is under debate. Traditionally, the amotivational syndrome has been associated with long-term heavy use and has been characterized by a person’s unwillingness to persist in a task— be it at school, at work, or in any setting that requires prolonged attention or tenacity.

Persons are described as becoming apathetic and anergic, usually gaining weight, and appearing slothful. TREATMENT AND REHABILITATION Treatment of cannabis use rests on the same principles as treatment of other substances of abuse—abstinence and support. Abstinence can be achieved through direct interventions, such as hospitalization, or through careful monitoring on an outpatient basis by the use of urine drug screens, which can detect cannabis for up to 4 weeks after use. Support can be achieved through the use of individual, family, and group psychotherapies. Education should be a cornerstone for both abstinence and support programs. A patient who does not understand the intellectual reasons for addressing a substance-abuse problem has little motivation to stop. For some patients, an antianxiety drug may be useful for short-term relief of withdrawal symptoms. For other patients, cannabis use may be related to an underlying depressive disorder that may respond to specific antidepressant treatment. Medical Use of Marijuana Marijuana has been used as a medicinal herb for centuries, and cannabis was listed in the US Pharmacopeia until the end of the 19th century as a remedy for anxiety, depression, and gastrointestinal disorders, among others. Currently, cannabis is a controlled substance with a high potential for abuse and no medical use recognized by the Drug Enforcement Agency (DEA); however, it is used to treat various disorders, such as the nausea secondary to chemotherapy, multiple sclerosis (MS) chronic pain, acquired immune deficiency syndrome (AIDS), epilepsy, and glaucoma. In 1996, California residents approved the California Compensation Use Act that allowed state residents to grow and use marijuana for these disorders: in 2001, however, the U.S. Supreme Court ruled 8 to 0 that the manufacture and distribution of marijuana are illegal under any circumstances. In addition, the Court held that patients using marijuana for medical purposes can be prosecuted; however, as of 2013, 20 states—Alaska, Arizona, California, Colorado, Connecticut, Delaware, Hawaii, Illinois, Maine, Massachusetts, Michigan, Montana, Nevada, New Hampshire, New Jersey, New Mexico, Oregon, Rhode Island, Vermont and Washington—and the District of Columbia have passed laws exempting patients who use cannabis under a physician’s supervision from state criminal penalties. In addition to the Supreme Court ruling, periodically the federal government attempts to prosecute doctors who prescribe the drug for medical use with the threat of loss of licensure or jail sentences. In a strongly worded editorial, the New England Journal of Medicine urged that “Federal authorities should rescind their prohibition of the medical use of marijuana for seriously ill patients and allow physicians to decide which patients to treat.” The editorial concluded by commenting on the role of the physician: “Some physicians will have the courage to challenge the continued proscription of marijuana for the sick. Eventually, their actions will force the courts to adjudicate between the rights of those at death’s door and the absolute power of bureaucrats whose decisions are based more on reflexive ideology and political correctness

than on compassion.” Dronabinol, a synthetic form of THC, has been approved by the U.S. Food and Drug Administration (FDA); some researchers believe, however, that when taken orally, it is not as effective as smoking the entire plant product. In 2006, regulatory officials authorized the first U.S. clinical trial investigating the efficacy of Sativex, an oral spray consisting of natural cannabis extracts, for the treatment of cancer pain. Sativex is currently available by prescription in Canada and on a limited basis in Spain and Great Britain for patients with neuropathic pain, multiple sclerosis, and other conditions. Sativex can be prescribed in the United States only with a special exemption granted by the FDA for use in certain patients. In 2013, a product called Epidiolex which contains cannabidiol was granted orphan drug status for the treatment of certain rare, intractable types of epilepsy in children. REFERENCES Agrawal A, Wetherill L, Dick DM, Xuei X, Hinrichs A, Hesselbrock V, Kramer J, Nurnberger Jr. JI, Schuckit M, Bierut LJ, Edenberg HJ, Foroud T. Evidence for association between polymorphisms in the cannabinoid receptor 1 (CNR1) gene and cannabis dependence. Am J Med Genet. 2009;150B:736. Buckner JD, Silgado J, Schmidt NB. Marijuana craving during a public speaking challenge: Understanding marijuana use vulnerability among women and those with social anxiety disorder. J Behav Ther Exp Psychiatry. 2011;42:104. Carter GT, Flanagan AM, Earleywine M, Abrams DI, Aggarwal SK, Grinspoon L. Cannabis in palliative medicine: Improving care and reducing opioid-related morbidity. Am J Hosp Palliat Care. 2011;28:297. Cohen AS, Buckner JD, Najolia GM, Stewart DW. Cannabis and psychometrically-defined schizotypy: Use, problems and treatment considerations. J Psychiatr Res. 2011;45:548. Crean RD, Crane NA, Mason BJ. An evidence-based review of acute and long-term effects of cannabis use on executive cognitive functions. J Addict Med. 2011;5:1. Crean RD, Tapert SF, Minassian A, MacDonald K, Crane NA, Mason BJ. Effects of chronic, heavy cannabis use on executive functions. J Addict Med. 2011;5:9. Ehlers CL, Gizer IR, Vieten C, Wilhelmsen KC. Linkage analyses of cannabis dependence, craving, and withdrawal in the San Francisco family study. Am J Med Genet. 2010;153B:802. Fridberg DJ, Skosnik PD, Hetrick WP, O’Donnell BF. Neural correlates of performance monitoring in chronic cannabis users and cannabis-naïve controls. J Psychopharm. 2013;27:515. Griffin O, Fritsch AL, Woodward VH, Mohn RS. Sifting through the hyperbole: One hundred year of marijuana coverage in The New York Times. Deviant Behav. 2013;34:767. Hall WD, Degenhardt L. Cannabis-related disorders. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2009:1309. Hurd YL, Michaelides M, Miller ML, Jutras-Aswad D. Trajectory of adolescent cannabis use on addiction vulnerability. Neuropharmacology. 2014;76:416–424. Nickerson LD, Ravichandran C, Lundahl LH, Rodolico J, Dunlap S, Trksak GH, Lukas SE. Cue reactivity in cannabisdependent adolescents. Psychol Addict Behav. 2011;25:168. Pacek LR, Martins SS, Crum RM. The bidirectional relationships between alcohol, cannabis, co-occurring alcohol and cannabis use disorders with major depressive disorder: results from a national sample. J Affect Disord. 2013;148:188. Svrakic DM, Lustman PJ, Mallya A, Lynn TA, Finney R, Svrakic NM. Legalization, decriminalization & medicinal use of