Cannabis Use Disorder

Etiology

Reasons for cannabis use vary based on demographics. Research shows college students and young adults most commonly use cannabis to conform socially (42%), experiment (29%), and for “enjoyment” (24%). Twelve percent primarily use the drug to manage stress or relax, consistent with other studies associating its use with depression, anxiety, social anxiety, and post-traumatic stress disorder.[5][6][7][8] During pregnancy, mothers who reported using marijuana say they did so primarily to manage depression, anxiety, and stress (63%); pain (60%); nausea or vomiting (48%); and for recreational purposes (39%).[9] Biologically speaking, impaired inhibition can predispose individuals to substance use disorders. However, clinicians are unsure if this is true for marijuana.[10]

The frequency of use is a major risk factor for the development of cannabis use disorder.[11] However, when using relatively low amounts, specific populations are at high risk of this disorder. According to one study, a significant proportion of marijuana users, particularly adolescents, are at high risk for developing cannabis use disorder at relatively low levels of use.[12]

Epidemiology

Nearly 4% of the global population was using cannabis in 2015.[13] Among teenagers, 8% in the United States and 16% in Europe report use. Nine percent of all users experience addiction, of which nearly a fifth begin to use in adolescence.[14] Limited evidence currently exists for cannabis use among older patients. In the medical profession, first-year psychiatry residents are more likely to have cannabis use disorder and seek out experiences to be disinhibited; these individuals also have a history of sedative use and anxiety.[15]

During pregnancy, 4% of mothers admit to using drugs, most commonly cannabis. A retrospective cohort study of more than 12 million pregnant women revealed nearly a tripling of cannabis abuse or dependence from 1999 through 2003 and a significant association for perinatal complications.[16] Thirty-five percent of mothers who have used marijuana have done so during pregnancy, and 18% used it when breastfeeding.[9] 

As consumption increases among adults, so does the unintended consequence of exposure to children. Between 2005 and 2009, 985 unintentional exposures to children (median age of 1.7 years) were reported. States legalizing marijuana have had a 20-fold increase in calls to poison centers and admissions to critical care units for its exposure.[17] Overall, the trend for cannabis use is increasing over time for most, if not all, demographics.

Pathophysiology

Researchers know that prolonged and heavy cannabis use can alter brain circuitry. However, the specific pathophysiological mechanisms are unclear. In terms of addiction, THC is the primary molecule responsible for the reinforcing properties of marijuana.[18][19][20] Interestingly, the striatal dopamine system is typically involved with substances of abuse, such as alcohol and opioids. Meta-analysis reveals insufficient evidence to support a conclusion about cannabis and suggests that dopamine receptors may not be involved.[21]

At a symptomatic level, heavy use modifies conscious experience by altering the brain’s network for self-awareness. By reducing anxiety and impairing memory, cannabis also affects motivation and personal experience.[22] The botanical provides over 500 active chemical compounds interacting with numerous molecular targets at a molecular level, modulating the transmission of endocannabinoids, gamma-aminobutyric acid, glutamate, and serotonin. Psychoactive effects are primarily derived from THC, which binds cannabinoid receptors CB1 and CB2.

CB1 receptors are located throughout the central nervous system (CNS), lungs, liver, and kidneys. CB2 receptors predominate within the immune hematopoietic cells. Binding these receptors modulates G-protein-coupled inhibition of cyclic adenosine monophosphate, influencing pain, mood, appetite, nausea, and sexual activity.[23] CNS effects are mediated by glial cells, particularly microglia and astrocytes. In vitro studies show microglial cells produce greater endocannabinoids than neurons, and astrocytes may play a role in signaling by regulating endocannabinoid turnover.[24][25] Thus, an influence of the neuropil, not just the neurons, may better describe the CNS changes mediated by cannabis.

Toxicokinetics

Unlike synthetic substances and alcohol, cannabis is a more complex drug. Consumption or inhalation of the botanical exposes the user to hundreds of compounds, including cannabinoids (eg, THC and cannabidiol) and non-cannabinoids (eg, terpenes and flavonoids), many of which are bioactive.[23] Compared to isolated pharmaceutical derivatives (eg, dronabinol and cannabidiol), the sheer complexity of the plant makes a comparison between the two difficult. What is currently known about marijuana is derived from studies of a single active constituent, tetrahydrocannabinol, and less so from the plant itself. This problem is primarily due to the federal status as a Schedule I substance and the prohibition of federal research funds for the study.

THC, the principal psychoactive and addictive component, is most commonly smoked. The substance is rapidly absorbed by the lungs and distributed systemically via perfusion. The rapid influence on the brain contributes to pleasure and abuse potential.[26] Oral ingestion typically follows a more gradual course and delays peak blood concentration. THC is extensively bound to lipoproteins, with only 3% in the free state.[27][28] Metabolism through the liver can produce over 80 metabolites of THC, with the most common pathway involving allylic hydroxylation at the 11-position followed by oxidation to a carboxy derivative. Conjugation occurs with some metabolites. Bioavailability varies greatly amongst individuals depending on their smoking topography, such as number, duration, spacing of puffs, hold time, and inhalation volume.[29] THC remains in the body for extended periods due to lipophilic properties, allowing accumulation and slow release from adipose tissue and further processing via the enterohepatic circulation, which produces active metabolites. 

Chronic daily smokers can produce detectable levels of THC and the metabolites up to 1 month after their last intake.[30] Lipophilic metabolites are suggested to form conjugates, allowing for greater stability and prolonging their metabolism and half-life, so release from adipose tissue is the rate-limiting step.[31][32][33] This high lipophilicity explains why withdrawal from the substance is a slow-onset phenomenon. The pharmacokinetics of THC are further complicated by factors such as its physical or chemical form, route of administration, genetics, and concurrent consumption of alcohol.[34]

History and Physical

The individual’s mental status is a critical part of the exam and can point to the phase of cannabis use. Intoxication can include euphoria, anxiety, uncontrollable laughter, increased appetite, inattentiveness, forgetfulness, restlessness, tachycardia, conjunctival injection, and dry mouth. Less common adverse events may include delusions, hallucinations, and derealization. Prolonged continuous use or withdrawal typically causes a depressed mood characterized by apathy, lack of motivation, irritability, loss of interest in typical activities, difficulty concentrating, and isolation. Cognition can be assessed by testing 3-word recall, asking multi-step math problems, or recalling details from a brief fictional story, as demonstrated on the St. Louis University Mental Status Exam.

In patients with prolonged use or withdrawal, the depressed mood must be differentiated from persistent depressive disorder and major depressive disorder. Substance use and a mood or anxiety disorder are not necessarily mutually exclusive and frequently co-occur. Suicidality and homicidal tendencies can result from dysregulated mood, a recent stressor, or substance use. Differentiation requires an understanding of the intensity and temporality of the symptoms. Persistent symptoms during periods of sobriety can indicate a comorbid primary psychiatric disorder.

Classifying cannabis use disorder in the United States is dictated by the DSM-5. Generally, it can be understood as having acute and chronic phases. The acute phase includes intoxication and withdrawal states, along with secondary complications such as delirium, psychosis, anxiety, and insomnia. Chronic regular use is characterized by disordered behavior. 

History and physical exam findings seen in various cannabis use-associated conditions are outlined below:

Cannabis Intoxication

• A recent use of cannabis can cause intoxication.      
• Intoxication can include clinically significant, problematic, behavioral, or psychological changes (eg, impaired motor coordination, euphoria, anxiety, a sensation of slowed time, impaired judgment, social withdrawal) that developed during or shortly after cannabis use.       
• At least 2 of the following signs develop within 2 hours of cannabis use: conjunctival injection, increased appetite, dry mouth, and tachycardia.        
• The symptoms must not be due to a general medical condition better accounted for by another mental disorder.
• Specify if perceptual disturbances are present: hallucinations with intact reality testing or auditory, visual, or tactile illusions occur in the absence of delirium.   

Cannabis Withdrawal

• This withdrawal accompanies cessation of cannabis use that has been heavy and prolonged (ie, usually daily or almost daily use over at least a few months). Three or more of the following signs and symptoms develop within 1 week after cessation of heavy, prolonged use:           

• Irritability, anger, or aggression          
• Nervousness or anxiety           
• Sleep difficulty (ie, insomnia, disturbing dreams)           
• Decreased appetite or weight loss           
• Restlessness           
• Depressed mood       

• At least 1 of the following physical symptoms are causing significant discomfort: abdominal pain, shakiness or tremors, sweating, fever, chills, or a headache.       
• The signs or symptoms are causing clinically significant distress or impairment in social, occupational, or other important areas of functioning.       
• 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.

Evidence suggests that withdrawal only occurs in a subset of patients. Symptoms usually begin within the first 24 hours, peak by day 3, and last up to 2 weeks.[35] Increased use and more recent use can predict the severity of withdrawal.[36][37]

Cannabis Intoxication Delirium

This diagnosis relies on the definition of delirium and is appropriate when the following 2 symptoms predominate in someone who has taken cannabis:            

• Disturbance in attention (ie, reduced ability to direct focus, sustain, and shift attention) and awareness 
• An additional disturbance in cognition (ie, memory deficit, disorientation, language, visuospatial ability, or perception)

Cannabis-Induced Psychotic Disorder  

• Presence of delusions or hallucinations           
• Evidence from the history, physical examination, or laboratory findings of either one of the following:           

• The symptoms in the first criterion developed during or soon after cannabis intoxication or withdrawal       
• The disturbance was not accounted for by a psychotic disorder that is not substance-induced
• Evidence that the symptoms are accounted for by a psychotic disorder that is not substance-induced might include the following:            
• Symptoms precede the onset of substance use (or medication use)     
• Symptoms persist for a substantial period (eg, about 1 month) after the cessation of acute withdrawal or severe intoxication or are substantially more than what would be expected, given the type or amount of the substance used or the duration of use     
• Other evidence suggests the existence of an independent non–substance-induced psychotic disorder (eg, a history of recurrent non–substance-related episodes)      
• Disturbance does not occur exclusively during delirium    
• Disturbance causes clinically significant distress or impairment in social, occupational, or other areas of functioning 

Cannabis-Induced Anxiety Disorder  

• Panic attacks or anxiety predominate in the clinical picture.           
• Evidence from the history, physical examination, or laboratory findings of either of the following:               
• Symptoms in the first criterion developed during or soon after substance intoxication or withdrawal              
• Disturbance is not better accounted for by an anxiety disorder that is not substance-induced
•  Evidence that the symptoms are better accounted for by an anxiety disorder that is not substance-induced might include the following:     
• Symptoms precede the onset of substance use                 
• Symptoms persist for a substantial period (eg, about a month) after cessation of acute withdrawal or severe intoxication or are substantially more than expected, given the type or amount of the substance used or the duration of use                   
• Other evidence suggests the existence of an independent non–substance-induced anxiety disorder (eg, a history of recurrent non–substance-related episodes)
• Disturbance does not occur exclusively during delirium             
• Disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning     

Cannabis-Induced Sleep Disorder

• A prominent and severe disturbance in sleep          
• Evidence from the history, physical examination, or laboratory findings of both of the following:            
• The symptoms in the first criterion had developed during or soon after the cannabis intoxication or after withdrawal from or exposure to it.          
• The disturbance is not better explained by a sleep disorder that is not substance or medication-induced. Such evidence of an independent sleep disorder could include the following:               
• Symptoms precede the onset of cannabis use         
• Symptoms persist for a substantial period (ie, about a month) after the cessation of acute withdrawal or severe intoxication        
• Other evidence suggests the existence of an independent non-substance or medication-induced sleep disorder (ie, a history of recurrent non-substance or medication-related episodes)      
• Disturbance does not occur exclusively during delirium
• Disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning

Cannabis Use Disorder

Cannabis abuse and dependence were combined in the DSM-5, capturing the behavioral disorder that can occur with chronic cannabis use and named cannabis use disorder defined as:

A problematic pattern of cannabis use leading to clinically significant impairment or distress, as manifested by at least 2 of the following, occurring within 12 months:     

• Cannabis is often taken in more significant amounts or over a longer period than was intended.       
• Persistent desire or unsuccessful efforts are attempted to cut down or control cannabis use.       
• A great deal of time is spent in activities necessary to obtain cannabis, use cannabis, or recover from its effects.       
• A craving or a strong desire or urge to use cannabis exists.       
• Recurrent cannabis use results in failure to fulfill role obligations at work, school, or home.       
• Continued cannabis use, despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of cannabis.       
• Important social, occupational, or recreational activities are given up or reduced because of cannabis use.
• Recurrent cannabis use even in situations in which cannabis is physically hazardous.       
• Cannabis use continues despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by cannabis. 
• The tolerance increases, defined by either (1) a need for markedly increased cannabis to achieve intoxication or desired effect or (2) a markedly diminished effect with continued use of the same amount of the substance.       
• Having a withdrawal, as manifested by either (1) the characteristic withdrawal syndrome for cannabis or (2) cannabis is taken to relieve or avoid withdrawal symptoms.

The criteria have the following specifiers:   

• In early remission, after full criteria for cannabis use disorder were previously met, none of the criteria for cannabis use disorder has been met for at least 3 months but less than 12 months (with an exception provided for craving).   
• In sustained remission, after full criteria for cannabis use disorder were previously met, none of the criteria for cannabis use disorder has been met at any time during 12 months or longer (with an exception provided for craving).
• Severity is graded as mild, moderate, or severe, depending on whether 2 or 3, 4 or 5, or 6+ of the above criteria are present.

Evaluation

Laboratory testing of urine, blood, saliva, or hair can be useful to detect cannabis use, but results should be considered along with a clinical rationale. Assays typically rely on detecting the most common active metabolite, delta-9-tetrahydrocannabinol. The metabolite has been studied thoroughly and has become an established urinary marker of cannabis consumption in forensic, clinical, and environmental analyses.[34] A positive result can indicate usage, but not necessarily a substance use disorder or intoxication, and a negative result does not rule the drug out. Quantifying tolerance is possible by comparing the reported intake of cannabis to blood levels. Heavy or chronic cannabis smokers will take longer to clear THC compared to sporadic or one-time users. Additional tests to rule out related conditions may be beneficial. These include head imaging or laboratory testing for heavy metals, infection, immunological markers, electrolyte disturbances, or hormones.

Treatment / Management

The aim should be to improve the individual’s multiphasic overall function. Supportive treatment may be provided during detoxification. Enabling access to psychiatric services allows the identification of underlying comorbid disorders. Psychological counseling can modify behavior and help develop healthier coping skills for stressors.

As cannabis strains become more potent and accessible, the risk of cannabis use disorder will increase. For individuals with marked intoxication or withdrawal or cannabis use disorder, the goal should be to stop the drug altogether. Unlike abrupt cessation, a gradual decrease is likely to decrease the discomfort of the withdrawal and prevent relapse. Cannabis intoxication most often does not require medical management and will self-resolve. Supportive management, such as a calm, non-stimulating environment, helps patients. Symptomatic treatment can be considered for specific symptoms, such as α-2-adrenergic agonists or β-blockers for tachycardia, benzodiazepines for panic attacks, off-label use of first-generation antihistamines for anxiety and restlessness, and neuroleptics for psychosis. Monitoring psychological symptoms may predict features of withdrawal or continued primary psychiatric illness.

Pharmacologic detoxification is still under investigation. A systematic review indicates most studies are preliminary and cannot statistically support clinical rationale as they are small in size, inconsistent, and have a risk of attrition bias. No medication is FDA-cleared to treat cannabis use disorder. Tetrahydrocannabinol does show some potential in treatment, but more information is needed to demonstrate the validity and inform on the dose, duration, formulation, and adjunct therapies. Gabapentin and N-acetylcysteine are also used but have unclear benefits.[38] Another component of cannabis, cannabidiol, holds promise by modulating the serotonergic, glutamatergic, and endocannabinoid systems.[39](A1)

Differential Diagnosis

The differential may include intoxication syndromes from other substances; these may include:

• Amphetamine intoxication
• Cocaine intoxication
• Benzodiazepine withdrawal
• Anxiety disorder
• Panic attacks

In patients with chronic use, it is imperative to rule out:

• Major depressive disorder
• Bipolar disorder

Toxicity and Adverse Effect Management

Side effects of short-term use of cannabis include impaired short-term memory, which can affect learning, impaired motor coordination in activities such as driving, and an increase in high-risk sexual behaviors.[14] Also, judgment is impaired when tasks are measured, such as the quality of decision-making and executive planning.[40] Children 12 and younger are a separate concern. Their exposure typically occurs via unintentional consumption of edibles, meaning the dosage is not considered. This has led to increased presentations to the emergency department, often for central nervous system depression such as lethargy and somnolence, and rarely for respiratory insufficiency.[41]

Prognosis

The likelihood of continuing cannabis abuse can vary from person to person. Impulsive individuals are more likely to experiment with substances, including cannabis. Using cannabis for experimentation is associated with less use and fewer problems. Factors such as enjoyment, habit, activity enhancement, and altered perception or perspectives are associated with heavier use and more problems.[5] Those more avoidant of punishment, boredom, or unpleasant events are less likely to discontinue use and are at risk for abuse. Individuals who experience withdrawal or those who use cannabis to avoid stressful situations can have perpetuated use.[42]

Complications

Heavy or chronic users are more likely to report a decreased sense of life satisfaction and achievement compared to the general population. Additionally, effects can impair neuropsychiatric, physical, and social domains. These include addiction, altered brain development, cognitive impairment, poor educational outcome, increased likelihood of dropping out of school, and lower intelligence quotient among frequent users during adolescence. In addition, individuals who chronically use cannabis develop cognitive and psychomotor driving impairments.[43][44][45][46] 

Women may be more likely to demonstrate deficits in attentional inhibition.[47] Those with the tendency for chronic psychotic disorders are at increased risk of “unmasking the illness” with prolonged use. THC levels measured in hair among chronic heavy marijuana-only users were predictive of delusions, hallucinations, and organic brain dysfunction. Discontinuation of cannabis did not resolve these symptoms after 3 months, indicating organic neurological dysfunction.[48] Respiratory complications from smoking cannabis can lead to chronic bronchitis.[14] Chronic use may also affect fertility in both sexes.[49]

Perinatal exposure may result in cognitive impairments in the fetus, affecting intelligence, attention, visual-motor coordination, processing speed, visual memory, and interhemispheric transfer of information.[50][51][52][53] Evidence, albeit inconclusive, is apparent for potential risk for preterm delivery, low birth weight, and stillbirth.[54][55][56][57]