Cannabinoid use disorder (CUD) refers to the continued use of cannabinoids despite negative impacts on psychosocial functioning.¹ CUD includes the use and abuse of natural cannabis as well as synthetic cannabinoids-more potent variations of natural cannabis that have increased in popularity in recent years.² First appearing in the 2000s, synthetic cannabinoids (often referred to as spice, K2, and kush) have since become the fastest-growing psychoactive drug with many new products being developed every year; over 177 new synthetic cannabinoids were developed in 2014.³ These compounds act as full agonists at the CB1 receptor (the main cannabinoid receptor in the central nervous system), whereas THC found in natural cannabis acts as a partial agonist-synthetic cannabinoids thus produce similar but stronger effects as cannabis.³

CUD differs from other substance use disorders because of the widespread misbelief that cannabinoids are harmless and do not cause dependence or withdrawal.^4,5 As cannabis continues to be legalized for medical and recreational purposes, decreased stigma and increased access are possible contributors to increased prevalence of CUD.^1,4,6

Cannabis use disorder

Cannabinoid dependence

Cannabis abuse

Marijuana abuse

CUD

Of an estimated 192 million persons who had used cannabinoids in the previous year, 22.1 million people met criteria for CUD.⁵ In the United States, an estimated 4.2 million people meet criteria for CUD in the past year as of 2015.⁷

Physical findings of recent cannabinoid use (within 2 h) include conjunctival injection, increased appetite, dry mouth, and tachycardia.⁵ One physical finding that can indicate CUD is the presence of cannabinoid withdrawal. Cannabinoid withdrawal symptoms can occur 24 to 48 h after cessation and can include irritability, anxiety, changes in sleep patterns, depressed mood, and at least one physical symptom causing severe discomfort, such as headache, abdominal pain, or fever.⁵ An additional finding that can indicate CUD is cannabinoid hyperemesis syndrome, in which patients present with cyclical vomiting and current or recent history of cannabinoid use.⁵

Cannabinoid use may also cause psychosis (referred to as cannabis-induced psychosis) and other negative psychiatric effects.^5,11 Synthetic cannabinoids in particular are more likely to cause harmful psychiatric symptoms (e.g., psychosis, anxiety, and panic attacks) than cannabis, and thus present a significant public health concern.² This is thought to occur because synthetic cannabinoids lack cannabidiol, a chemical found in natural cannabis that may act as a natural antipsychotic by blocking THC’s binding to the CB1 receptor.²

There are a variety of etiologies for beginning substance use that may lead to substance use disorder. Social influences, such as to conform to peers and for enjoyment or experimentation, are significant reasons for cannabinoid use in adolescents and young adults.¹¹ Others begin using cannabinoids for relaxation or for self-medication of mental illness, including depression, anxiety, and PTSD.¹¹ Additionally, psychosocial risk factors include lack of family/parental support in childhood, negative or traumatic life events, and poor social support increase risk of cannabinoid use.⁵ Once a patient begins using cannabinoids, many genetic, psychosocial, and medical risk factors increase their risk of developing CUD, as stated earlier.

Differential diagnosis may include other substance use disorders; this can be differentiated through a thorough history and laboratory evaluation including toxicology screen and blood alcohol level.¹¹ Additionally, symptoms of CUD such as mood and thought disorder, anxiety, and psychosis may be similar to primary psychiatric disorders including depression, panic disorder, generalized anxiety disorder, or psychotic disorders such as schizophrenia.^5,11 Symptoms of these primary psychiatric disorders are present both before and after initial administration and cessation of cannabinoids, and time course can be obtained through thorough history, including collateral.^5,11

The diagnosis of CUD is primarily a clinical one made through taking a history. CUD history is consistent with persistent cannabinoid use despite negative effects on social life, physical or mental health.⁵ Cannabinoid-specific behavioral changes include impaired motor coordination and judgement, euphoria, anxiety, and social withdrawal.⁵ Additionally, a thorough history can indicate the presence of amotivational syndrome, the presence of apathy and reduced self-efficacy in cannabinoid users.¹² Recent studies have found that cannabinoid use, but not alcohol or tobacco use, is a significant predictor of lower initiative and persistence.¹²

The screening question “In the past year, how often have you used cannabis or other cannabinoids?” may be beneficial for patients with higher baseline risk, including those with a history of incarceration or mental illness.⁵ Diagnosis can be made if a patient meets 2 of 11 The Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria with these symptoms causing impairment in functioning.⁵ The number of these symptoms a patient meets can be used to measure the severity of CUD, with 2 or 3 symptoms classified as mild, 4 or 5 symptoms classified as moderate, and 6 or more classified as severe.⁵

The diagnosis of CUD is made primarily by a thorough history. Although urine or blood testing for the THC metabolite delta-9-tetrahydrocannibinolic acid can indicate whether a patient is currently using cannabis, a positive result is not necessarily indicative of substance use disorder.¹¹ Of note, many synthetic cannabinoids do not result on standard laboratory screens; mass spectroscopy has shown some promise in detecting synthetic cannabinoids but is expensive and may not detect newly developed compounds.³ Laboratory tests to rule out other similarly appearing conditions, including heavy metals, electrolyte levels, and immunologic studies, may be warranted to rule out other causes.¹¹

Imaging is not necessary for diagnosis of CUD, though may be ordered to rule out other similarly appearing conditions.¹¹

Effective nonpharmacologic therapies include cognitive-behavioral therapy (CBT) to teach coping and relapse-prevention skills, motivational-enhancement therapy (MET) to improve patients’ motivation to decrease or stop cannabinoid use, and contingency management (CM) to offer incentives and reinforcement for decreasing or eliminating cannabinoid use.⁹ For adolescent patients, family-based treatment options have the highest efficacy; however, CBT, MET, and brief interventions (such as motivational interviewing) also may be effective.⁹ Technology-driven interventions, involving the these methods delivered via the internet or other technology medium, show similar efficacy for both adults and adolescents with both reduced cost and increased accessibility.⁹

Symptoms of cannabinoid withdrawal tend to present within 1 wk of cessation of use⁷ and can include irritability, anxiety, changes in sleep patterns, depressed mood, decreased appetite, and physical symptoms, including headache, abdominal pain, fever, chills, and tremors.^5,7 Several widely used psychiatric medications may help with withdrawal symptom management in the acute setting, though many are not sufficient on their own for treatment of cannabinoid withdrawal.⁷ Mirtazapine may help with some withdrawal symptoms such as insomnia and decreased appetite but does not prevent relapse or improve mood.⁷ Quetiapine has been found to help with sleep, improve appetite, and prevent weight loss, though it does not prevent relapse (similar to mirtazapine) and may paradoxically increase cravings.⁷ Zolpidem may also assist with sleep difficulties during withdrawal, though the medication itself has abuse and dependence potential.⁷

Administration of cannabinoid agonists represent an alternative approach to treating acute cannabis withdrawal. The oral cannabinoid agonist dronabinol may help with global withdrawal symptoms, including craving, appetite and mood disturbances, and physical symptoms.⁷ Nabilone, another synthetic cannabinoid, has demonstrated benefit in reducing irritability and sleep disturbances during withdrawal.⁷ Nabiximols, a cannabinoid agonist containing both THC and CBD administered via buccal spray, has beneficial effects on a variety of cannabinoid withdrawal symptoms including reducing cravings, irritability, and depression, with minor benefits in sleep and appetite disturbances, restlessness, and other physical symptoms.⁷ In one study, nabiximols was shown to decrease the length of cannabis withdrawal in the inpatient setting by 2 days.⁷

There are currently no FDA-approved pharmacotherapies for CUD, and much research is still in early stages.⁷ Gabapentin has been shown to decrease both cravings and quantity of cannabinoid use in a small pilot study.⁷ Topiramate also has been shown to decrease quantity of cannabinoid use in adolescents, though can be poorly tolerated and slower titration of the medication may be beneficial.⁷ Quetiapine has been shown in one study to decrease the number days of cannabis use per week after 5 wk of treatment, with greater effect seen with longer treatment duration.¹³

Oral cannabinoid agonists represent another approach to chronic cannabis use disorder treatment. Although dronabinol may help with withdrawal symptoms as previously mentioned, it has not been shown to improve abstinence rates.⁷ However, one study has shown a decrease in days of cannabis use per week after 3 wk of treatment with dronabinol (with greater effect seen with longer treatment duration), and this effect is also seen when combined with the alpha-2 agonist lofexidine.¹³ Nabilone, a synthetic cannabinoid with better bioavailability and efficacy, has been shown to decrease cannabinoid use and relapse rates, withdrawal symptoms including irritability and sleep difficulty.⁷ Long-term administration of naltrexone has been shown to decrease cannabis use and positive effects from cannabis, and N-acetylcysteine has shown encouraging data in decreasing cannabis use in adolescents and young adults.⁷ Administration of oxytocin has been shown to augment nonpharmacologic treatment approaches such as motivational enhancement therapy.⁷

Of note, cannabinoids are often used as alternative medicine treatment for a variety of medical conditions. However, because cannabis is classified as a schedule I controlled substance by the FDA, research into the use of cannabis as alternative medicine is minimal and most research has been done with THC alone.¹¹ Medical cannabis as an industry is also significantly less evidence-based and highly regulated than traditional pharmaceuticals; dispensaries often make many decisions about strains used and dosing given based on opinion rather than rigorous clinical data.¹¹ Thus, providers prescribing medical cannabis should be aware that medical cannabis may not always be used as intended.¹¹

The described treatments can be completed either on an outpatient or inpatient basis, depending on patient acuity.⁷ Cannabinoid withdrawal does not pose a serious medical risk, and most people with CUD can be treated outpatient with supportive care.⁵

Behavioral health referral for both medication and psychotherapeutic management is warranted for CUD treatment.¹¹ Because many individuals use cannabinoids as self-medication for pain, referral to neurology or pain management for an adequate and safer pain control regimen may also be warranted.¹¹ Additionally, referral to sleep medicine may be helpful for insomnia and other sleep disorders from chronic use or withdrawal.¹¹

• CUD is much more prevalent than many might assume.
• CUD often co-occurs with other substance use disorders and mental health disorders, but the “gateway” hypothesis has largely been refuted.¹⁰

Although many treatments (pharmacologic and nonpharmacologic) show promise in helping with cannabinoid withdrawal and decreasing or stopping cannabinoid use, there are currently no FDA-approved therapies for CUD and treatment is largely up to provider discretion based on limited data from early-stage research.⁷

• Cannabinoid use is increasing, and the landscape of cannabinoid use and abuse is changing with its destigmatization and legalization. New approaches to CUD prevention and treatment must be developed to adapt to this changing environment.

With rates of adolescent cannabinoid use increasing (and now surpassing rates of tobacco use), effective prevention programs remain an important public health tool.¹⁴ Many previous youth drug prevention campaigns using scare tactics and punishment have not been effective.¹⁴ Instead, programs should provide scientifically accurate data about the risks and consequences of drug use (without overstating risks or equating all use with abuse), move beyond an abstinence-only framework, and contain strategies and information that adolescents find relatable.¹⁴

Recent cannabis legalization in many states provides a new landscape for CUD prevention. One study in Washington State illustrated that although cannabis legalization did not increase cannabis use, rates of current and frequent cannabis use increased in areas of closer proximity to cannabis dispensaries opened after legalization-a similar pattern was illustrated with alcohol and tobacco outlets.¹⁵ Thus density limits for cannabis dispensaries and other policies to decrease cannabis access show promise in decreasing cannabis use that may lead to CUD.¹⁵

With cannabinoid use increasing across many demographics and the widespread belief that cannabis is a harmless drug, patient education is an important tool for prevention of CUD. All patients should be educated about the risks of cannabinoid use, but especially those under the age of 21 who are especially susceptible to CUD and at higher risk of poor long-term outcomes thereof.¹¹ As with all other substances, pregnant patients should be educated about the harmful effects of cannabinoids on the fetus; this is especially important as cannabinoid use during pregnancy is increasing.¹¹

Substance Use Disorder (Related Key Topic)

Synthetic Cannabinoids (Related Key Topic)

Medical Marijuana (Related Key Topic)