The Treatment of Cannabis Use Disorder

Disclosures

Dr. Danovitch has no conflicts of interest to report.

Dr. Gorelick receives royalties from UpToDate for articles about cannabis

Introduction

Cannabis is a flowering plant containing a class of lipophilic hydrocarbons called “cannabinoids.” The stem, leaves, and flowers from cannabis have been cultivated throughout history for therapeutic as well as intoxicating purposes. There are dozens of unique cannabinoid substances in cannabis, only several of which have been well characterized. The primary psychoactive component of cannabis is Δ ⁹ -tetrahydrocannabinol (THC). THC produces an intoxication syndrome and promotes release of dopamine in the nucleus accumbens, one of the cornerstone features of reinforcing drugs. Cannabadiol (CBD), which has been associated with some of the therapeutic effects ascribed to cannabis, may influence the effects of THC but does not itself produce intoxication. Cannabis can be bred to contain varying levels of THC, CBD, and other cannabinoids. For this chapter, the term “cannabis” will refer to THC or cannabis species that are bred predominantly for their intoxicating effects.

Cannabis is the most commonly used illicit substance worldwide. In the United States in 2015, 44% of persons over the age of 12 used cannabis at least once in their lifetime ; 9.5% used within the past year; in 2013, 2.9% met diagnostic criteria for cannabis use disorder (CUD) within the past year. CUD is characterized by loss of control over cannabis use, harmful consequences from use, and excessive time spent buying, using or recovering from cannabis effects (see DSM-5 Table 7.1 ). Among individuals who have ever used cannabis, the lifetime risk of developing CUD is estimated at 8%–12%. This rate is lower than for many other psychoactive substances (both legal and illegal), but is nonetheless significant considering the high prevalence of cannabis use across the population. Children and young adults have greater susceptibility for developing CUD, a concerning notion given increased availability of high potency cannabis and reduced perception of risk from cannabis use over the past decade. In 2013, cannabis was reported as the primary substance of misuse by 17% of admissions to publicly funded addiction treatment programs in the US, with one-third of respondents reporting that cannabis use had started prior to age 14.

TABLE 7.1

DSM5 Cannabis-related Disorders

Cannabis Use Disorder	Cannabis Intoxication	Cannabis Withdrawal
A. A problematic pattern of cannabis use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period: 1. Use in larger amounts or over a longer period than was intended. 2. Persistent desire or unsuccessful effort to cut back 3. A great deal of time is spent in activities necessary to obtain, use, or recover effects. 4. Cravings or persistent desire to use 5. Failure to fulfill major role obligations at work, school, or home. 6. Use despite recurrent social or interpersonal problems 7. Important social, occupational, or recreational activities are given up or reduced 8. Recurrent use in situations in which it is physically hazardous. 9. Persistent use despite knowledge of physical or psychological problems caused or exacerbated by using 10. Tolerance 11. Withdrawal (refer to Criteria A and B of the criteria set for cannabis withdrawal).	A. Recent use of cannabis. B. Clinically significant problematic behavioral or psychological changes (e.g., impaired motor coordination, euphoria, anxiety, sensation of slowed time, impaired judgment, social withdrawal) that developed during, or shortly after, cannabis use. C. Two (or more) of the following signs or symptoms developing within 2 hours of cannabis use: 1. Conjunctival injection. 2. Increased appetite 3. Dry mouth 4. Tachycardia D. The signs or symptoms are not attributable to another medical condition and are not better explained by another mental disorder, including intoxication with another substance.	A. Cessation of cannabis use that has been heavy and prolonged B. Three (or more) of the following signs and symptoms develop within approximately 1 week after Criterion A: 1. Irritability, anger, or aggression. 2. Nervousness or anxiety 3. Sleep difficulty (e.g., insomnia disturbing dreams). 4. Decreased appetite or weight loss. 5. Restlessness. 6. Depressed mood. 7. At least one of the following physical symptoms causing significant discomfort: abdominal pain, shakiness/tremors, sweating, fever, chills, or headache. C. The signs or symptoms in Criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D. The signs or symptoms are not attributable to another medical condition and are not better explained by another mental disorder, including intoxication or withdrawal from another substance.

Epidemiological surveys reveal subtle but significant adverse outcomes associated with CUD. Chronic heavy use is associated with poor educational attainment among youth, an unsurprising association given the fact that chronic cannabis use is associated with cognitive impairment, with earlier age of onset of cannabis use and greater cumulative cannabis use associated with greater impairment. Prospective longitudinal studies suggest that these impairments start resolving after at least 1 month of abstinence. Cannabis use during adolescence carries distinct risk in that, alongside the putative neurobiological consequences of heavy cannabinoid exposure, chronic intoxication may fundamentally alter developmental trajectories. Heavy cannabis use has been linked to school failure, early pregnancy, crime, and progression to further drug use, but some more recent prospective longitudinal studies, which better control for potential confounds, do not demonstrate such associations. Even where these associations are demonstrated in prospective, longitudinal studies that control for baseline (i.e., precannabis use) presence of the adverse outcome and known likely confounds (e.g., other substance use, socioeconomic status, psychiatric comorbidity), it remains possible that the observed associations result from convergent risks, reverse causation, or unmeasured or unknown predisposing factors, as much as from direct effects of cannabis use.

One challenge facing treatment of CUD is the high rate of comorbidity with other major psychiatric disorders. Large-scale, nationally representative epidemiologic surveys of community-dwelling adults in the US suggest that rates of current major psychiatric disorder among those with current CUD are as follows: any mood disorder—30%–33%, any anxiety disorder—23%–24%, posttraumatic stress disorder (PTSD)—12%, any personality disorder—48%. While there are no comparable community-based studies for current schizophrenia (because of low overall-prevalence), large-scale, representative studies in the US and Australia find a 15%–20% prevalence of schizophrenia among hospitalized patients with CUD.

CUD poses distinct challenges for treatment providers. The evolving sociocultural context of use for medical (as opposed to intoxication) purposes, public policy liberalization, and societal normalization has contributed to decrease perceived risk and increase acceptability of use. ^,320 Simultaneously, the comparatively lower “severity” of cannabis-associated consequences, including the absence of a medically serious withdrawal syndrome (compared with other psychoactive substances), makes it more difficult for some users to recognize adverse consequences from their use and to establish an enduring commitment to change.

These factors, plus the reluctance of many treatment-seekers to accept traditional abstinence-based goals, may account for the low proportion of individuals with CUD who seek treatment. A secondary analysis of data on 7278 adults with current (past-year) moderate-severe CUD (cannabis dependence in DSM-IV terms) in the 2005–13 National Surveys on Drug Use and Health (NSDUH) found that only one out of eight (12.87%, 95% CI 11.62–14.23) received any substance use treatment services that year; only 8.18% (95% CI 7.19–9.29) received cannabis-specific treatment. Notwithstanding these challenges, the high prevalence of CUD, its strong association with comorbid mental health problems, and the difficulty of achieving cannabis cessation ensure that most clinicians will encounter patients with CUD. While no pharmacotherapy has been approved for CUD, several promising approaches are in development. Psychotherapy studies are establishing a number of evidence-based models and techniques and innovative technological platforms promise to increase access to effective treatment. This article reviews established and emerging treatment options for CUD.

Pharmacotherapy

Cannabis Intoxication

Cannabis intoxication is a syndrome recognized in DSM-5 and ICD-10, with both psychological/behavioral (euphoria, relaxation, increased appetite, impaired memory, and concentration) and physical (motor incoordination, tachycardia, orthostatic hypotension, conjunctival reddening) manifestations. These manifestations are mediated by THC activation of the cannabinoid CB1 receptor. Intoxication is usually mild and self-limiting, not requiring pharmacological treatment. The most severe effects (anxiety, panic attack, psychosis) are best treated with a benzodiazepine or second-generation (atypical) antipsychotic medication, as appropriate to acutely control symptoms. No medication is currently approved for the treatment of cannabis intoxication by the US Food and Drug Administration (FDA) or any other national regulatory authority.

Several studies have evaluated the impact of the opioid-antagonist naltrexone on cannabis intoxication. Acute pretreatment with single doses of naltrexone actually increases the reinforcing effects of cannabis, while chronic dosing decreases the subjective effects of cannabis.

Human laboratory studies show that antagonists/inverse agonists of the CB1 receptor block the acute effects of cannabis, so might serve as treatment for acute cannabis intoxication. However, all such compounds were withdrawn from the market and from clinical development a decade ago because of psychiatric side-effects such as suicidality and anxiety.

Cannabis Withdrawal

Cannabis withdrawal is a syndrome that develops upon cessation of prolonged cannabis use and is typically characterized by three or more of the following symptoms: irritability, anger or aggression; nervousness or anxiety; sleep difficulty (i.e., insomnia, disturbing dreams); decreased appetite or weight loss; restlessness; depressed mood. Most symptoms begin during the first week of abstinence and resolve after a few weeks. Up to half of patients in treatment for CUD report symptoms of a withdrawal syndrome. Although not usually severe, cannabis withdrawal should be a focus of treatment because it may serve as negative reinforcement for relapse to cannabis use in individuals trying to abstain.

No medications are approved for the treatment of cannabis withdrawal, but several medications have been evaluated in small clinical studies. One approach is cross-tolerant (cannabinoid CB1 receptor) agonist substitution to suppress the withdrawal syndrome (analogous to using an opioid to suppress heroin withdrawal). This approach can be implemented using synthetic THC (dronabinol), which is legally marketed in many countries, including the US (Marinol), as an oral medication for appetite stimulation and suppression of nausea and vomiting due to chemotherapy. Dronabinol has shown efficacy in several human laboratory studies and open-label case series, at doses up to 30 mg tid, with minimal side effects. A controlled clinical trial of dronabinol (20 mg bid), while not showing efficacy for reducing cannabis use (see below), did significantly reduce cannabis withdrawal symptoms. However, a later controlled clinical trial by the same research group found no significant benefit for dronabinol combined with lofexidine (an alpha1-adrenergic receptor agonist found to reduce some cannabis withdrawal symptoms in human laboratory studies).

An alternate cannabinoid agonist approach involves using a combination of THC and CBD (nabiximols) administered as an oromucosal spray. In a two-site controlled trial of nabixomols (maximum daily dose, 86.4 mg THC and 80 mg CBD) for 51 treatment-seeking individuals undergoing inpatient treatment, nabixomols reduced cannabis withdrawal symptoms over 9 days and improved short-term treatment retention, although there was no difference in cannabis use at 28-day follow-up. A smaller (9 subjects) outpatient clinical trial also found that nabiximols reduced cannabis withdrawal symptoms over 5 days, either given as a fixed dose (108 mg THC and 100 mg CBD every hour for 10 hours each day) or self-titrated as needed for withdrawal symptoms.

Lithium, a mood stabilizer used primarily in the treatment of bipolar disorder, has been evaluated in one small open-label clinical study and one randomized controlled trial. In the open-label study, lithium (600–900 mg/day for 6 days) reduced withdrawal symptoms in 4 of the 9 participants, although one of the 4 continued to smoke some cannabis. Abstinence was not verified in the other 8 participants. A placebo-controlled randomized trial of lithium carbonate supplemented with nitrazepam, enrolling 35 treatment-seeking cannabis-dependent adults, showed some improvement on sleep measures but no significant benefit on treatment retention. These results suggest limited therapeutic effect of lithium given during the withdrawal (detoxification) period.

Another approach, which has been evaluated chiefly in human laboratory studies, tries to alleviate symptoms of cannabis withdrawal (e.g., dysphoric mood, disturbed sleep) by influencing the brain circuits that mediate these symptoms, using medications already approved for other psychiatric conditions. In a controlled clinical trial involving 50 treatment-seeking outpatients, the anticonvulsant gabapentin (maximum daily dose 1200 mg/day) significantly reduced cannabis withdrawal symptoms compared with placebo. Human laboratory studies found that the anticonvulsant and mood stabilizer divalproex (1500 mg/day for 29 days) and the antidepressant buproprion (300 mg/day sustained release for 17 days) worsened, rather than improved, some withdrawal symptoms and had no positive effects. A single dose of the antidepressant nefazodone (450 mg/day) decreased some, but not the majority, of cannabis withdrawal symptoms.

Cannabis Use Disorder

Several dozen trials have evaluated pharmacological treatment strategies for CUD. No medication has been shown broadly effective in the treatment of CUD, nor is any medication approved for this condition by any national regulatory authority. The medications that have shown the greatest promise, albeit only in single controlled clinical trials, are the anticonvulsant gabapentin (which increases activity of the inhibitory neurotransmitter GABA) and the amino acid derivative N-acetylcysteine (NAC) (which indirectly increases activity of the excitatory neurotransmitter glutamate).

Gabapentin (peak dose of 1200 mg/day) was evaluated in a 12-week, randomized, double-blind, placebo-controlled study enrolling 50 treatment-seeking adult outpatients with cannabis dependence. Gabapentin was associated with improved performance on cognitive tests and short-term reductions in cannabis use relative to placebo. It was well tolerated, with no significant treatment group differences in side-effects.

NAC (1200 mg bid) was evaluated in an 8-week, randomized, double-blind, placebo-controlled study enrolling 116 treatment-seeking youth (15–21 years old) with cannabis dependence. All participants also received contingency management targeted at treatment adherence and abstinence plus weekly brief drug abuse counseling. NAC was associated with significantly better treatment retention and higher proportion of (weekly) urine tests negative for cannabinoids (40.9% vs. 27.2%). NAC was well tolerated, with no significant treatment group differences in adverse events. A subsequent randomized, double-blind, placebo-controlled 12-week study evaluated the same NAC dose (1200 mg bid) in 302 treatment-seeking adults with CUD. As in the prior youth study, all participants also received contingency management targeted at treatment adherence and abstinence plus weekly brief drug abuse counseling. There was no significant treatment effect on cannabis use.

The anticonvulsant topiramate (which both increases GABA activity and blocks glutamate activity) (titrated up to 200 mg/day over 4 weeks to minimize side-effects) was evaluated in a 6-week, randomized, double-blind, placebo-controlled study enrolling 66 treatment-seeking youth (15–24 years old). All participants also received three sessions of motivational enhancement therapy. Topiramate was associated with significantly more cognitive and neurological side-effects and a higher dropout rate due to side-effects (35% vs. 4%). There was no significant treatment effect on cannabis use.

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