Use, Abuse, and Addiction

Pathology and Psychopathologyl

Acute administration of cannabis produces a pleasant experience in most users, associated with intoxication and the subjective high (see above). However, some individuals with existing psychopathology, particularly in naive individuals who ingest cannabis unknowingly, can experience anxiety and panic reactions. Sometimes these reactions can include paranoia, dysphoria, depersonalization, and psychosis in vulnerable individuals (Box 8.6).

FIGURE 8.11Mean withdrawal scores over 45 days of marijuana abstinence in current marijuana users (n = 18) and ex-users (n = 12). Ranges overall: 0–3. Range for Withdrawal Discomfort: 0–36. The value of the baseline (BL) data point reflects the mean of days 1, 3, and 5. The dotted horizontal line represents the baseline mean score. ∗p < 0.05, significant difference between specific 3 day abstinence periods and baseline mean or between body weight at specific abstinence days and baseline. These data give a comprehensive assessment of the different symptoms of withdrawal from chronic marijuana use in humans. Notice that many of the symptoms are of a motivational nature, such as discomfort, irritability, anxiety, and strange dreams. Notice also that some symptoms, such as discomfort and strange dreams, persist for weeks. [Taken with permission from Budney AJ, Moore BA, Vandrey RG, Hughes JR. The time course and significance of cannabis withdrawal. Journal of Abnormal Psychology, 2003, (112), 393–402.]

Cannabis produces numerous physiological effects in the cardiovascular system, including an increase in heart rate. In vulnerable individuals, this increase can contribute to pathology. Δ9-THC also increases supine blood pressure, produces postural hypotension, and increases cardiac output. Tolerance develops to the increases in heart rate and blood pressure. Although the cardiovascular effects of marijuana are not associated with serious health risks in young healthy users (although occasional cardiac events have been reported), marijuana smoking by people with cardiovascular disease poses health risks.

The adverse effects of smoking cannabis on the respiratory tract may be similar to the effects of tobacco smoking. Firm conclusions in this regard are limited, however, by a lack of animal models, concomitant tobacco use, and the relatively short period of time that marijuana has been smoked in Western society (30–35 years) compared with tobacco. Common untoward respiratory effects reported by abusers include cough, dyspnea, sore throat, nasal congestion, and bronchitis. The long-term effects on the respiratory tract are likely to be similar to those of tobacco because of the similarities in the composition of smoke between cannabis and tobacco (Table 8.11). Although the number of cannabis cigarettes smoked may be less than the number of tobacco cigarettes smoked in a chronic smoker, several characteristics of marijuana smoking are likely to increase the burden of tar and carbon monoxide. Marijuana cigarettes are not usually filtered, and smokers tend to smoke to the very end of the butt length, which increases the total levels of tar, carbon monoxide, and Δ9-THC delivered to the lungs. Marijuana smokers also tend to inhale larger puff volumes, draw more deeply, and hold the smoke longer in their lungs. In subjects with both tobacco and marijuana experience, marijuana smoking was associated with a five-fold greater increase in carboxyhemoglobin levels.

Box 8.5


A 27-year-old male was admitted to a day-treatment program for marijuana dependence. He had been identified at work for being “under the influence” on more than one occasion and was, therefore, referred for treatment. Drug consumption consisted of intermittent cocaine use and daily use of about one marijuana joint. He perceived that he had been “addicted” to marijuana for about 15 years, and that he had skipped marijuana use on very few days during this time. A physical examination was normal except for mild nasal-septum inflammation and a swollen uvula. Urine analysis showed the presence of marijuana metabolite and marijuana plasma analysis by high performance liquid chromatography (HPLC) showed no 11-OH-THC and THC-C to be 8 ng/ml. A 24-hour urine specimen showed secretion of 2-methoxy-4- hydroxy-phenyglycol (MHPG) to be 143.0 MCG/24 hours (normal is 1164 to 2216). Since his continued employment was dependent upon attending the day-care program until his urine was void of all drugs, compliance with treatment and testing procedures was good. Withdrawal medication consisted of desipramine, 25 mg, administered three times per day, and the amino acid, tyrosine. On the third treatment day, his urine still contained metabolite, and his plasma contained 3 ng/ml of THC-C. On the eighth day of attendance, he complained of a flu-like illness consisting of nausea, vomiting, diaphoresis, chills, myalgia, anorexia, and insomnia. The patient did not relate these symptoms temporally to his marijuana use, since he had ceased use eight days previous. Plasma analysis showed no detectable presence of 11-OH-THC or THC-C, but marijuana metabolite was still present in urine at this time. The apparent withdrawal symptoms resolved within 48 hours. Marijuana metabolite remained in his urine until the 34th day of treatment.

From: Tennant FS Jr., The clinical syndrome of marijuana dependence, Psychiatric Annals, 1986, (16), 225–234.

Box 8.6


MV was a 25-year-old male who presented with the complaint that he could not “stop marijuana by myself.” He was a 12-year user having begun marijuana smoking at 13 years of age. He had used marijuana daily for about five years and was using two to three joints per day at the time of admission to outpatient treatment. The patient was married and held a regular job as a warehouse superintendent. He claimed he was having considerable conflicts with his wife and employer. In addition, he had noticed in the two months just prior to admission that he occasionally heard voices that were not real, did not always have total “control over his mind,” and had some thoughts of suicide. He denied use of any other drug or excessive alcohol intake. His treatment admission breath alcohol was negative, and his urine contained marijuana metabolite, but no other abusable drug. The patient was administered desipramine, 25 mg, three times per day and was given weekly psychotherapy for approximately six months. During the first ten days of treatment, he reported insomnia, abdominal cramps, diaphoresis, tachycardia, and anxiety. These symptoms subsided, and he submitted a urine void of marijuana approximately 30 days after admission. Most of the thought disturbances noted above disappeared after about two to six weeks of treatment. He denied any marijuana use during the six months after entering treatment, and he submitted monthly urine tests that showed no marijuana.

From: Tennant FS Jr., The clinical syndrome of marijuana dependence, Psychiatric Annals, 1986, (16), 225–234.

Cannabis use at intoxicating doses impairs psychomotor performance in any situation that requires perceptual, cognitive, and psychomotor functioning, including driving an automobile and flying an airplane. Mental and motor performance, including response speed, physical work capacity, fine hand-eye coordination, complex tracking, divided attention tasks, visual information processing, altered sense of time, and impaired short-term memory are dose-related. Impairment can begin with 5–15 mg, which is equivalent to 4–16 puffs on a 3.55% Δ9-THC cigarette that yields 63–188 ng/ml (Figure 8.12). Automobile driving or flying an airplane in a simulator have shown dose-related deficits, even at doses as low as 5–10 mg, and up to 24 h after smoking (Table 8.12). The actual extent to which cannabis ingestion contributes to road accidents is no longer controversial, and in many countries cannabis is the most common drug detected in individuals involved in reckless driving or traffic accidents with or without alcohol. Significant percentages of impaired drivers or drivers involved in fatal accidents in the United Kingdom, Canada, Europe, New Zealand, and Australia have been reported, with approximately 47% of 1,842 impaired drivers (driving while intoxicated) having cannabis suspected by drug recognition experts, with most of the opinions confirmed by chemical tests. Another study found that 33% of impaired individuals tested positive for marijuana in a group that was not impaired by alcohol. A meta-analysis showed that smoking cannabis increases the probability of an automobile accident two-fold (for further reading, see Ashbridge et al., 2012). These studies suggest that cannabis with or without other sedative hypnotics, like alcohol and benzodiazepines, can contribute to automobile accidents.

TABLE 8.11

Peak Plasma Levels of Δ9-THC After Smoked vs. Oral Administration




Whole smoke



 burning rate

11.6 mm/min/g

5.7 mm/min/g

 pH (3rd to 10th puffs)






Particulate phase



 total particulate (per puff)

1.6 mg

2.4 mg


76.8 _g

39.0 _g


17.9 _g

24.0 _g

 m-cresol + p-cresol

54.4 _g

65.0 _g

 2,4-dimethylphenol + 2,5-dimethylphenol

6.8 _g

14.4 _g


3.0 mg

1.2 mg


75 _g

43 _g


31 _g

22 _g


2.85 mg


820 _g


400 _g


190 _g

Gas phase



 carbon monoxide (per cigarette)

2600 ppm

4100 ppm


228 _g

198 _g

 hydrogen cyanide

532 _g

498 _g


83 _g

310 _g


1.20 mg

0.98 mg


443 _g

578 _g


92 _g

85 _g


132 _g

123 _g


76 _g

67 _g


112 _g

108 _g


75 _g

84 _g


27 _g

30 _g

Taken with permission from Huber GL, First MW, Grubner O. Marijuana and tobacco smoke gas phase cytotoxins. Pharmacology Biochemistry and Behavior, 1991, (40), 629–636.]

FIGURE 8.12 Number of correct responses on a word recall test as a function of list presentation order and placebo, alcohol (0.25, 0.5, and 1.0 g/kg), and marijuana (3.55% Δ9-THC; equivalent to 34 mg). Each data point represents the mean of five measurements taken at 0, 30, 60, 90, and 120 min post-dosing in five subjects. Filled symbols indicate a significant difference from placebo (p < 0.05). These data show that marijuana and alcohol in the moderate intoxication range produced equivalent dose-dependent deficits in word recall memory in humans. [Taken with permission from Heishman SJ, Arasteh K, Stitzer ML. Comparative effects of alcohol and marijuana on mood, memory, and performance. Pharmacology Biochemistry and Behavior, 1997, (58), 93–101.]

TABLE 8.12

Effects of Cannabis that Impair Driving and Piloting Skills

  • Slowed complex reaction time
  • Poor detection of peripheral light stimuli
  • Poor oculomotor tracking
  • Space and time distortion
  • Impaired coordination
  • Brake and accelerator errors
  • Poor speed control
  • Poor judgment
  • Increased risks in overtaking
  • Impaired attention, especially for divided attention tasks
  • Impaired short-term memory
  • Additive effects with alcohol and other drugs

Taken with permission from Ashton CH. Adverse effects of cannabis and cannabinoids. British Journal of Anaesthesia, 1999, (83), 637–649.

Daily or chronic cannabis use at intoxicating doses can lead to chronic impairments in social and occupational functioning, including ineffectiveness in school, sports, work, and learning to initiate and sustain healthy relationships. The state of chronic intoxication increases risk-taking behaviors as a result of disinhibition. Such individuals may participate in unprotected sex, driving while intoxicated, or riding with an intoxicated driver.

Even more remarkable is the lack of motivation, lack of direction, lack of ambition, and inability to hold a coherent conversation. As early as the late 1960s, this configuration of effects was termed “amotivational syndrome” (McGlothlin and West, 1968). Most discussions of this topic recognize this syndrome as a state of chronic intoxication rather than a neurotoxic effect of marijuana itself, because the syndrome disappears when the individual ceases to smoke marijuana. Characterized by diminished goal-directed behavior, apathy, and an inability to master new problems, the “amotivational syndrome” has often been used to explain poor school performance in adolescents, personality deterioration, and a general decrease in function. This syndrome is more likely to occur in high-dose compulsive users than in controlled low-dose users and often remits with the cessation of use.

Acute cannabis intoxication can also lead to an acute transient psychotic episode in some individuals. Such psychotic breaks are characterized by delusions, loosening of associations, and marked illusions. Cannabis can also produce a short-term exacerbation or recurrence of pre-existing psychotic symptoms. Accumulating evidence indicates that cannabis can contribute to the causes of a functional psychotic illness or schizophrenia. Although causality has been difficult to prove, several studies have suggested a causal relationship. Cross-sectional national surveys have found that the rates of cannabis use are approximately two times higher among subjects diagnosed with schizophrenia than among the general population. Daily cannabis use has been shown to double the risk of reporting psychotic symptoms. A series of studies in Sweden, The Netherlands, France, and New Zealand examined cannabis use in adolescence with regard to later adult psychotic symptoms. The results of these studies supported the hypothesis that “cannabis use is an independent risk factor for the emergence of psychosis in psychosis-free persons” (van Os J, Bak M, Hanssen M, Bijl RV, de Graaf R, Verdoux H. Cannabis use and psychosis: a longitudinal population-based study. American Journal of Epidemiology, 2002, (156), 319–327; Table 8.13). The overall risk (odds ratio) for psychosis in cannabis users was 2.8, meaning that cannabis users are almost three times more likely to develop psychosis than non-cannabis users. Such an association between cannabis use in adolescence and psychosis in adulthood persisted even after controlling for numerous social, gender, age, and ethnic group factors. For example, this association was documented as being dose-related in a meta-analysis and a sibling pair analysis nested within a prospective birth cohort (for further reading, see McGrath et al., 2010). Overall, cannabis use conveys a three-fold higher risk for later schizophrenia or schizophreniform disorder. Theoretically, without cannabis use, the general population would have an 8% lower incidence of schizophrenia.

Another insidious toxic effect of cannabis use has been revealed by studies that showed possible adverse effects on executive function in young users, particularly users who begin using cannabis during adolescence. During adolescence, prefrontal areas of the brain continue to develop, and these areas are linked to decision making and executive function (Box 8.7). The adolescent period represents a critical phase of development, characterized by specific progressive neurobiological maturational processes in the prefrontal cortex that include myelination and synaptic pruning. This period of maturation also involves the rearrangement of key neurotransmitter systems, such as glutamate, γ-aminobutyric acid, dopamine, and endocannabinoid systems in the frontal cortex. Changes in these systems are believed to support the emergence of adult cognitive processes. Over the course of adolescence and during early adulthood, individuals show normative growth in planning, preference for delayed rather than immediate rewards, resistance to peer pressure, and impulse control. Many of the brain regions that are undergoing these developmental changes may be particularly affected by alcohol and marijuana use.

Cannabis-dependent adolescents typically have cognitive deficits, characterized by short-term memory and verbal fluency impairments, attentional dysfunction, and poor performance in executive functioning. Memory difficulties are one of the most widely reported and most persistent cognitive deficits associated with extensive marijuana use in adolescents. Functional magnetic resonance imaging studies of adult subjects who abuse marijuana have shown altered activation in prefrontal and insular regions while they performed cognitive tasks, such as those that involve attention, working memory inhibitory control, and decision making during acute marijuana use, chronic marijuana use, and abstinence. Growing evidence suggests that marijuana use during adolescence adversely affects normal physiological maturational processes in the frontal cortex, with reduction of cortical thickness in regions of the prefrontal cortex and insula in adolescents measured by magnetic resonance imaging. Such alterations in normal maturational processes possibly contribute to future problems with impulse control, including substance use disorders. As noted above, accumulating evidence from epidemiological studies suggests that cannabis use is a risk factor for the development of psychosis or schizophrenia.

TABLE 8.13

Longitudinal Studies in the General Population on the Role of Cannabis as a Risk Factor for Schizophrenia

Andréasson S, Allebeck P, Engström A, Rydberg U. Cannabis and schizophrenia: a longitudinal study of Swedish conscripts. Lancet, 1987, (2), 1483–1486.

Arseneault L, Cannon M, Poulton R, Murray R, Caspi A, Moffitt TE. Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. British Medical Journal, 2002, (325), 1212–1213.

Ferdinand RF, Sondeijker F, van der Ende J, Selten JP, Huizink A, Verhulst FC. Cannabis use predicts future psychotic symptoms, and vice versa. Addiction, 2005, (100), 612–618.

Fergusson DM, Horwood LJ, Swain-Campbell NR. Cannabis dependence and psychotic symptoms in young people. Psychological Medicine, 2003, (33), 15–21.

Henquet C, Krabbendam L, Spauwen J, Kaplan C, Lieb R, Wittchen HU, van Os J. Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. British Medical Journal, 2005, (330), 11.

Stefanis NC, Delespaul P, Henquet C, Bakoula C, Stefanis CN, Van Os J. Early adolescent cannabis exposure and positive and negative dimensions of psychosis. Addiction, 2004, (99), 1333–1341.

Tien AY, Anthony JC. Epidemiological analysis of alcohol and drug use as risk factors for psychotic experiences. Journal of Nervous and Mental Disease, 1990, (178), 473–480.

van Os J, Bak M, Hanssen M, Bijl RV, de Graaf R, Verdoux H. Cannabis use and psychosis: a longitudinal population-based study. American Journal of Epidemiology, 2002, (156), 319–327.

Weiser M, Knobler HY, Noy S, Kaplan Z. Clinical characteristics of adolescents later hospitalized for schizophrenia. American Journal of Medical Genetics, 2002, (114), 949–955.

Wiles NJ, Zammit S, Bebbington P, Singleton N, Meltzer H, Lewis G. Self-reported psychotic symptoms in the general population: results from the longitudinal study of the British National Psychiatric Morbidity Survey. British Journal of Psychiatry, 2006, (188), 519–526.

Zammit S, Allebeck P, Andreasson S, Lundberg I, Lewis G. Self-reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1(969), historical cohort study. British Medical Journal, 2002, (325), 1199.

[Table from: Casadio P, Fernandes C, Murray RM, Di Forti M. Cannabis use in young people: the risk for schizophrenia. Neuroscience and Biobehavioral Reviews, 2011, (35), 1779–1787.]

Box 8.7


Definition: Conceptualized as the ability to organize thoughts and activities, prioritize tasks, manage time, and make decisions. Neurobiological substrates include the prefrontal cortex and orbitofrontal cortex.

The ingestion of synthetic cannabinoids like THC produces euphoria and relaxation but also unwanted effects, including tachycardia, anxiety, nausea, agitation, an inability to speak, dystonia, and short-term memory deficits. There are also reports of more severe and dangerous adverse reactions, including elevated blood pressure, tremor, convulsions, hallucinations, and paranoid behavior. Numerous driving-under-the-influence-like impairments have been linked to synthetic cannabinoids (e.g., JWH-019, JWH-122, JWH-210, and AM-2201), indicated by positive chemical/toxicological test results (Box 8.8). Some of the adverse clinical-like effects of “Spice” are listed in Table 8.14 (see “Spice” and Herbal Marijuana Alternatives). Most of these effects reported to date are acute effects. However, new-onset psychosis has been reported in otherwise healthy individuals who smoked synthetic cannabinoids, and at least one incidence of withdrawal syndromes has been described (Boxes 8.9, 8.10; for further reading, see Seeley et al., 2012).

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