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 (e.g., THC and cannabidiol) and non-cannabinoids (e.g., terpenes and flavonoids), many of which are bioactive compounds [21]. The sheer complexity of the plant compared to isolated pharmaceutical derivatives (e.g., dronabinol and cannabidiol) makes a comparison between the two difficult. It is important to establish that what is currently known about marijuana is actually derived from studies of a single active constituent, tetrahydrocannabinol, and less so from the plant itself. This problem is primarily due to its Federal status as a schedule I substance and thus prohibition from federal research funds for its study.

Absorption, distribution, metabolism:

THC, the principal psychoactive and addictive component, is most commonly smoked. It is rapidly absorbed by the lungs and distributed systemically via perfusion. The rapid influence on the brain contributes to its pleasure and abuse potential [24]. Ingestion typically follows a more gradual course and delay to its peak blood concentration. It is extensively bound to lipoproteins with only 3% in the free state.[25][26] Metabolism through the liver can produce over 80 metabolites of delta-9-THC with the most common pathway involving allylic hydroxylation at the 11-position followed by oxidation to a carboxy derivative [27]. Conjugation occurs with some metabolites, but it is not a major step [27]. Bioavailability varies greatly amongst and between individuals pending on their smoking topography such as number, duration, and spacing of puffs; hold time; and inhalation volume [28]. It remains in the body for extended periods due to its lipophilic properties, allowing it to accumulate and slowly release from adipose tissue, along with its further processing via the enterohepatic circulation, which produces active metabolites as well [27]. Chronic daily smokers can produce detectable levels of THC and its metabolites one month after its last intake [29]. It is suggested that its lipophilic metabolites can form conjugates, allowing for greater stability, thereby prolonging its metabolism, and thus half-life, so that release from adipose tissue is the rate-limiting step of THC[30][31][32]. This high lipophilicity explains why withdrawal is a slow onset.

It is worth noting that the pharmacokinetics of THC is further complicated with multiple factors such as its physical/chemical form, route of administration, genetics, and concurrent consumption of alcohol [27].

Upon evaluation, the patient history should investigate substance use, mental health, family history for substance use and mental health disorder, medical history, medications, use of substances amongst social circle (particularly in adolescents), and environmental stressors.

The mental status of the individual is a critical part of the exam and can point at the phase of cannabis use. Intoxication can include euphoria, anxiety, uncontrollable laughter, increased appetite, inattentiveness, forgetfulness, restlessness, tachycardia, conjunctival injection, and dry mouth. And less commonly may include delusions, hallucinations, and derealization. Prolonged continuous use or withdrawal typically causes depressed mood characterized by apathy, lack of motivation, irritability, loss of interest in typical activities, difficulty concentrating, and isolation. (Side note: Cognition can quickly be assessed by testing three-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.) This depressed mood can also include on the differential persistent depressive disorder and major depressive disorder. Substance use and a mood or anxiety disorder are not necessarily mutually exclusive and frequently co-occur.  Even suicidality and homicidal tendency can be a result of dysregulated mood, a recent stressor, or substance use. Differentiation requires an understanding of the symptoms intensity and temporality; persistent symptoms during periods of sobriety can indicate a comorbid primary psychiatric disorder.

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

Pending on the setting (i.e., Emergency Department, office visit, or rehabilitation program), different effects of cannabis may be of focus. The diagnostic criteria of the varying effects of cannabis are listed below, as defined by the DSM-5.    

Cannabis Intoxication        

1. Recent use of cannabis        
2. Clinically significant problematic behavioral or psychological changes (e.g., impaired motor coordination, euphoria, anxiety, a sensation of slowed time, impaired judgment, social withdrawal) that developed during, or shortly after, cannabis use        
3. At least two of the following signs, developing within 2 hours of cannabis use: conjunctival injection, increased appetite, dry mouth, tachycardia.        
4. Symptoms not due to a general medical condition and not better accounted for by another mental disorder.
5. 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         

1. Cessation of cannabis use that has been heavy and prolonged (i.e., usually daily or almost daily use over a period of at least a few months). Three or more of the following signs and symptoms develop within approximately 1 week after cessation of heavy, prolonged use:            
   1. Irritability, anger or aggression           
   2. Nervousness or anxiety            
   3. Sleep difficulty (i.e., insomnia, disturbing dreams)            
   4. Decreased appetite or weight loss            
   5. Restlessness            
   6. Depressed mood        
2. At least one of the following physical symptoms causing significant discomfort: abdominal pain, shakiness/tremors, sweating, fever, chills, or a headache.        
3. The signs or symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.        
4. 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.

It should be noted that evidence suggests that withdrawal only occurs in a subset of patients[33]. Symptoms usually begin within the first 24 hours, peak by day 3, and can last for up to 2 weeks[33]. Increased use and more recent use can predict the severity of withdrawal [34][35].      

Cannabis intoxication delirium

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

1. Disturbance in attention (i.e., reduced ability to direct focus, sustain, and shift attention) and awareness (reduced orientation to the environment)
2. An additional disturbance in cognition (i.e., memory deficit, disorientation, language, visuospatial ability, or perception).

Cannabis-induced psychotic disorder            

1. Presence of delusions or hallucinations.            
2. Evidence from the history, physical examination, or laboratory findings of either one of the following:           
1. The symptoms in the first criterion developed during or soon after cannabis intoxication or withdrawal.            
2. The disturbance is not accounted for by a psychotic disorder that is not substance induced.
3. Evidence that the symptoms are accounted for by a psychotic disorder that is not substance induced might include the following:            
1. The symptoms precede the onset of substance use (or medication use).      
2. The symptoms persist for a substantial period (e.g., about a 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.      
3. Other evidence suggests the existence of an independent non–substance–induced psychotic disorder (e.g., a history of recurrent non–substance–related episodes).      
4. The disturbance does not occur exclusively during delirium.    
5. The disturbance causes clinically significant distress or impairment in social, occupational, or other areas of functioning. 

Cannabis-induced anxiety disorder            

1. Panic attacks or anxiety predominate in the clinical picture.            
2. Evidence from the history, physical examination, or laboratory findings of either of the following:                
   1. The symptoms in the first criterion developed during or soon after substance intoxication or withdrawal.                
   2. The 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:                    
   3. The symptoms precede the onset of substance use.                    
   4. The symptoms persist for a substantial period (e.g., 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.                    
   5. Other evidence suggests the existence of an independent non–substance–induced anxiety disorder (e.g., a history of recurrent non–substance–related episodes).                
   6. The disturbance does not occur exclusively during delirium.               
   7. The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.      

Cannabis-induced sleep disorder            

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

The chronic effects: Cannabis Use Disorder

Cannabis abuse and dependence were combined in the DSM-5 into a single entity capturing the behavioral disorder that can occur with chronic cannabis use and named Cannabis Use Disorder, it is defined as:        

1. 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:       
2. Cannabis is often taken in larger amounts or over a longer period than was intended.        
3. There is a persistent desire or unsuccessful efforts to cut down or control cannabis use.        
4. A great deal of time is spent in activities necessary to obtain cannabis, use cannabis, or recover from its effects.        
5. Craving, or a strong desire or urge to use cannabis.        
6. Recurrent cannabis use results in failure to fulfill role obligations at work, school, or home.        
7. Continued cannabis use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of cannabis.        
8. Important social, occupational, or recreational activities are given up or reduced because of cannabis use.
9. Recurrent cannabis use in situations in which it is physically hazardous.        
10. 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. 
11. Tolerance, as 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.       
12. Withdrawal, as manifested by either (1) the characteristic withdrawal syndrome for cannabis or (2) cannabis is taken to relieve or avoid withdrawal symptoms.

It has 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 three 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 either Mild, Moderate, or Severe pending if 2-3, 4-5, or 6+ of the above criteria are present.

Laboratory testing of urine, blood, saliva, or hair can be useful to detect cannabis use, but results should be considered along with clinical rationale. Assays typically rely on detection of the most common active metabolite- delta 9 -tetrahydrocannibinolic acid. It has been studied thoroughly, and this abundant acid metabolite has become an established urinary marker of cannabis consumption in forensic, clinical, and environmental analyses [27]. A positive result can indicate usage but not necessarily a substance use disorder or intoxication, and a negative result does not rule it out. It is possible to quantify tolerance 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.

Also, other tests to rule out additional conditions may be of benefit. These include head imaging, or laboratory testing of heavy metals, infection and immunological markers, electrolyte disturbances, or hormones.

The aim should be to improve the individual's overall function which is multiphasic and multifactorial. Supportive treatment may be provided during detoxification; enabling access to psychiatric services allows addressing underlying disorders; psychological counseling can modify behavior, develop healthier coping skills in the face of stressors, and enlighten them as to their temperament.

As cannabis strains become more potent and accessible, the risk will increase for frequency and severity of serious adverse reactions. For individuals with marked intoxication or withdrawal, or cannabis use disorder, the goal should be a cessation of the drug altogether. A gradual decrease as opposed to abrupt cessation 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 alpha-2-adrenergic agonists or beta-blockers for tachycardia, benzodiazepines for panic attacks, off-label use of first-generation antihistamines for anxiety and restlessness, and neuroleptics for psychosis. It is important to monitor psychological symptoms which may be features of the withdrawal or part of the patient’s primary psychiatric illness - which may not have been previously identified.

Pharmacologic detoxification is still under investigation. A systematic review indicates most studies are preliminary and cannot statistically support clinical rationale as they are small sizes, inconsistent, and have a risk of attrition bias [36]. 

There is no medication that is FDA approved to treat cannabis use disorder. Tetrahydrocannabinol does show some potential in treatment, but more information is needed to demonstrate the validity and inform on dose, duration, formulation, and adjunct therapies [36]. Gabapentin and N-acetylcysteine are also used but have unclear benefits [36]. Another component of cannabis, cannabidiol, holds promise by modulating the serotonergic, glutamatergic, and endocannabinoid systems [37].

Cannabis Intoxication, Cannabis Withdrawal, and Cannabis Use Disorder: the differential for these may include intoxication syndromes from other substances. These may include amphetamine or cocaine intoxication, withdrawal from benzodiazepines or hypnotics, atrial tachycardia, an anxiety disorder, and panic attacks. A thorough medical history, psychiatric history, substance use history, family psychiatric and medical history, medication review, toxicology screen, and blood alcohol level are needed. Endogenous psychiatric disorders such as Generalized Anxiety Disorder or Panic Disorder or a primary psychotic disorder such as the Schizophrenia Spectrum Disorder will typically demonstrate symptomology before and long after cessation of cannabis. Collateral sources, typically from family members, long-standing friends, or other providers, can be of help.

Side effects for short-term use of cannabis include impaired short-term memory, which can affect learning, impaired motor coordination as required for driving, and increased high-risk sexual behaviors [4]. Also, judgment is impaired on tasks measuring the quality of decision-making and executive planning [38].

Children aged less than twelve are a separate concern. Their exposure is typically via unintentional consumption of edibles meaning the dosage of THC taken in is not considered. This has lead to increased presentations to the ED, often for central nervous system depression such as lethargy and somnolence, and rarely for respiratory insufficiency[39].

The likelihood of continuing cannabis abuse can vary from person to person. Impulsive individuals are more likely to experiment with substances, including cannabis [40]. Using cannabis for experimentation is associated with less use and fewer problems [5]. 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 [40]. Also, those experiencing withdrawal or who are avoidant of stressful situations can perpetuate usage [40].

Heavy or chronic users are more likely to report a decreased sense of life satisfaction and achievement in comparison to the general population [4]. 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 IQ among those who were frequent users during adolescence [4]. In addition to acute users, also chronic users demonstrate cognitive and psychomotor driving impairments [41][42][43][44]. Females may be more likely to demonstrate deficits in attentional inhibition (i.e., ignoring irrelevant features in a situation)[45]. Those with the tendency for chronic psychotic disorders are at increased risk of "unmasking the illness" with prolonged use[4]. THC levels measured in hair amongst chronic heavy marijuana-only users were found to be predictive of delusions, hallucinations, and organic brain dysfunction [46]. Discontinuation of cannabis did not lead to a resolution of these symptoms even after three months, indicating organic neurological dysfunction [46].

Also at risk is the respiratory system as the byproducts of combustion and heated smoke can result in chronic bronchitis with inhaled use [4]. Chronic use may also affect fertility in both sexes may [47].

The risk is not only restricted to the user. Extensive evidence of perinatal cannabis exposure reveals the future child to be at risk for a broad array of cognitive impairments including intelligence, attention, activity, restraint, visual-motor coordination, processing speed, visual memory, and interhemispheric transfer of information as late as adolescence [48][49][50][51]. There is evidence, albeit inconclusive, for a potential risk for preterm delivery [52][53][54][55][14], low-birth-weight [52][56][14], and stillbirth[57]; wherever the truth may lie, it should not be considered a harmless substance.

Consultation for cannabis use disorder includes involving Behavioral Health for substance use disorder and psychopathology management. Neurology or Pain Management for chronic pain interventions and sleep professionals for insomnia if needed. All specialties including emergency providers should also include the primary care provider as they are best suited for long term monitoring and most accessible for early interventions.

It is important for providers to educate patients, especially those under the age of 21 who are a higher risk for long term, potentially irreversible, cognitive impairments. With the increased access to misinformation about cannabis being safe with no risks, it is important to bring evidence to the discussion. Pregnant patients should be counseled,  if they admit to usage or not, on the potential impact of cannabis on the fetus. Adults should be informed that if they desire to use, cannabis and its paraphernalia should be kept in a locked and hidden location to prevent pediatric intoxication. Despite the legalization of medical marijuana in many states, employers can still enforce their company policies and terminate workers who present to work intoxicated or test positive for cannabis.

It is important for providers across all specialties to familiarize themselves with the effects of cannabis use. It is increasingly becoming ubiquitous in our society. The evidence for supporting the use of marijuana for specific conditions is limited and most often derived from pharmaceutical preparations of isolated THC. Researchers struggle to gain funding for these studies given that it is a schedule I controlled substance with the Food and Drug Administration. Providers should be aware that providing permission to access medical marijuana for a given symptom does not restrict that patient to its limited usage. The dispensary’s employees can influence the strain, dosing, formulation, and its indications used on the basis of an opinion. Also, it should be stressed that continuous and/or heavy use of cannabis can increase the risk of intoxication or withdrawal requiring medical attention, and long term complications which may be irreversible. Despite its paler comparison to an opiate, benzodiazepine, and alcohol use, it is still a substance with potential for ill health effects and marked impairment on social and occupational functioning. With the expansion of evidence-based uses, it is important to separate the abuse of marijuana from use with a thorough history taking. Differences in state regulations governing medical indications for cannabis should be considered. And providers should not forget that Medical Marijuana is a not product of the tightly regulated and scientifically back pharmaceutical industry - it is a product produced by growing operations without similar oversight and indicated for conditions mostly not based on rigorous medical or scientific evidence required for products they prescribe, as opposed to a permitted use.

Deterring patients from substance use is often best supported by a team effort with the goal to relieve the underlying cause. A non-judgemental approach to understanding the reasons for use are best. Amongst children, cannabis use can indicate coping with home or school stressors. Counseling, particularly cognitive behavioral therapy and Multidimensional Family Therapy should be provided at school, home or an outpatient clinic to improve behavioral issues in both environments[58] - Level 1b evidence. Assessment by psychiatry for mental health disorders is important. Among adults, a similar strategy may be utilized with counseling and psychiatry. There is a longitudinal relationship between reductions in cannabis use and improvements in anxiety, depression, sleep quality, but not the quality of life [59] - Level 3 evidence. Peer Network Counseling-txt (PNC-txt), a 4-week, automated text-delivered cannabis treatment that focuses on close peer relations was able to decrease usage and relationship problems [60]-Level 1b evidence. Also, intensive outpatient programs for substance use disorders can be beneficial. For chronic pain, pain management or neurology can be involved. For insomnia, sleep studies are useful. Providers should know that a patient with a history of substance use disorder is more likely to misuse controlled substances, and tools for monitoring of controlled prescriptions should be utilized if available.