# Cannabis Use Disorder and Cannabinoid Hyperemesis

## Epidemiology and Changing Landscape

Most commonly used illicit substance worldwide; ~48 million US users (2022) Cannabis use disorder prevalence: ~6% of past-year users meet DSM-5-TR criteria (~3 million Americans) Legalization expanding rapidly: recreational use legal in 24+ US states; medical use in 38+ states. THC potency has increased dramatically: average THC content ~3-4% in the 1990s to ~15-25% currently; concentrates can exceed 80-90%. Decreasing perception of harm, especially among adolescents and young adults. CBD:THC ratio in modern cannabis strains has decreased, reducing potential protective effects of CBD.

## Pharmacology

### Endocannabinoid System

Two main receptors: CB1 (primarily CNS -- cortex, hippocampus, basal ganglia, cerebellum, amygdala) and CB2 (primarily immune cells and peripheral tissues) Endogenous ligands: anandamide and 2-arachidonoylglycerol (2-AG) Functions: modulation of neurotransmitter release, pain, appetite, mood, memory, immune function. THC (delta-9-tetrahydrocannabinol): partial agonist at CB1 and CB2; primary psychoactive compound. CBD (cannabidiol): complex pharmacology; low affinity for CB1/CB2; modulates THC effects; may have anxiolytic, antipsychotic, and anti-inflammatory properties.

### THC Pharmacokinetics

Highly lipophilic: accumulates in adipose tissue. Onset: seconds (inhaled) vs. 30-90 minutes (oral) Duration: 2-4 hours (inhaled) vs. 6-8 hours (oral) Half-life of elimination: 1-3 days for single use; up to 30 days for chronic heavy users (fat stores) Metabolized by CYP2C9 and CYP3A4; active metabolite 11-OH-THC; inactive metabolite THC-COOH (detected in urine drug screens) Urine detection window: 3-5 days (occasional use) to 30+ days (chronic heavy use)

## Cannabis Use Disorder

### DSM-5-TR Criteria

Same 11-criterion framework as other substance use disorders. >= 2 criteria within 12 months. Tolerance and withdrawal are now recognized (previously debated) Important: regular cannabis use does NOT automatically equal CUD -- must have impaired control, social impairment, risky use, or pharmacological indicators causing distress or impairment.

### Cannabis Withdrawal Syndrome

Recognized in DSM-5-TR; occurs in ~50% of daily users who abruptly stop. Onset: 1-2 days after cessation; peak: days 2-6; duration: 1-2 weeks. Symptoms: irritability, anxiety, insomnia, decreased appetite, restlessness, depressed mood, physical symptoms (abdominal pain, shakiness, sweating, fever, chills, headache) Not life-threatening but can drive relapse. No FDA-approved pharmacotherapy for cannabis withdrawal; supportive measures, gabapentin and NAC studied.

### Risk Factors for CUD

Early onset of use (before age 16) -- strongest predictor. Frequency of use (daily or near-daily) High-potency products. Genetic vulnerability (heritability ~50-60%) Concurrent mental health disorders (anxiety, depression, ADHD)

## Cannabis and Psychosis

### Evidence for Association

Dose-response relationship: daily use of high-potency cannabis increases psychosis risk 5-fold (Di Forti et al., 2019, *Lancet Psychiatry*) Meta-analyses show ~40% increased risk of psychotic disorders among cannabis users. Earlier onset of first psychotic episode in cannabis users (by ~2.7 years) Strongest risk in adolescents (developing brain, ongoing myelination and synaptic pruning) Gene-environment interaction: AKT1 and COMT polymorphisms modulate vulnerability.

### The Causality Debate

**Arguments for causal role:** dose-response relationship, temporal precedence, biological plausibility (dopamine modulation via CB1), stronger association with high-potency THC. **Arguments against:** shared genetic vulnerability, reverse causation (prodromal psychosis leads to cannabis use), confounding variables. Current consensus: cannabis is a "component cause" -- it significantly increases risk in vulnerable individuals but is neither necessary nor sufficient to cause psychosis. Clinical implication: counsel ALL patients at risk for psychosis (family history, prodromal symptoms) to avoid cannabis entirely.

### Cannabis-Induced Psychosis vs. Primary Psychotic Disorders

| Feature | Cannabis-Induced Psychosis | Primary Psychotic Disorder |
|---------|---------------------------|---------------------------|
| Onset | During or shortly after heavy cannabis use | Insidious or acute, not necessarily linked to substance use |
| Resolution | Typically resolves within days to weeks of abstinence | Chronic/relapsing course |
| Symptoms | Paranoia, visual/auditory hallucinations, agitation | Full range of positive/negative/cognitive symptoms |
| Negative symptoms | Absent or minimal | Often prominent |
| Insight | May return quickly with abstinence | Often persistently impaired |
| Conversion risk | ~50% convert to primary psychotic disorder within 3-5 years | N/A |
| Cannabis use history | Heavy, daily, high-potency use | May or may not be present |
| Management | Abstinence + short-term antipsychotic | Long-term antipsychotic treatment |

Cannabis-induced psychosis: onset during or shortly after heavy use; typically resolves with abstinence within days to weeks. However, up to 50% of patients with cannabis-induced psychosis convert to a primary psychotic disorder (schizophrenia or bipolar disorder) within 3-5 years -- the highest conversion rate of any substance-induced psychosis. Follow these patients longitudinally; do not assume resolution.

## Cannabinoid Hyperemesis Syndrome (CHS)

### Clinical Features

Cyclic episodes of severe nausea, vomiting, and abdominal pain in chronic cannabis users. Pathognomonic behavior: compulsive hot bathing/showering (provides temporary relief via TRPV1 receptor activation) Three phases: prodromal (nausea, abdominal discomfort), hyperemetic (intractable vomiting, dehydration), recovery (resolution with cannabis cessation) Episodes recur with resumed cannabis use. Often misdiagnosed as cyclic vomiting syndrome, leading to extensive unnecessary workup.

### Pathophysiology

Poorly understood; paradoxical given THC's known antiemetic properties. Hypotheses: chronic CB1 agonism in the gut leads to paradoxical gastroparesis and emesis; disruption of the endocannabinoid tone in the emetic centers; TRPV1 receptor involvement (explains hot water relief)

### Management

**Definitive treatment:** cannabis cessation (only intervention that prevents recurrence) **Acute management:** IV fluids, antiemetics (ondansetron has limited efficacy; haloperidol 5 mg IV has shown benefit in case series) **Topical capsaicin (0.075%):** applied to the abdomen; stimulates TRPV1 receptors (same mechanism as hot showers); increasingly used in EDs. Avoid opioids and anticholinergics (worsen gastroparesis) Patient education is critical: most patients are unaware cannabis is the cause.

## Treatment of Cannabis Use Disorder

### Psychotherapy

**CBT:** identifies triggers, develops coping strategies; moderate effect sizes. **Motivational enhancement therapy (MET):** brief intervention addressing ambivalence about change; often combined with CBT (MET + CBT is the most studied combination) **Contingency management:** voucher-based reinforcement for negative UDS; effective but less studied than for stimulant use disorders. Adolescents: multidimensional family therapy (MDFT) and brief strategic family therapy have evidence.

### Pharmacotherapy

No FDA-approved medications for CUD. **Agents under investigation:**. NAC (N-acetylcysteine): most promising in adolescents; modulates glutamate; positive RCT in youth (Gray et al., 2012) but negative in adults. Gabapentin: may reduce withdrawal symptoms and craving. Dronabinol/nabilone (synthetic THC): agonist replacement strategy; reduces withdrawal but mixed evidence for reducing use. Nabiximols (THC:CBD oromucosal spray): available in some countries; being studied for CUD.

## The Medical Marijuana Controversy

Tension between expanding legalization and psychiatric risks. Conditions with reasonable evidence for medical cannabis: chronic noncancer pain, chemotherapy-induced nausea, spasticity in MS, refractory epilepsy (CBD-specific: epidiolex) Psychiatric conditions: NO strong evidence supports cannabis for anxiety, depression, PTSD, or insomnia; some evidence suggests worsening of these conditions with chronic use. Psychiatrists should counsel patients that "medical" marijuana is not regulated like other medications (no standardized dosing, formulation, or quality control in most states)

<image>
A diagram illustrating the dose-response relationship between cannabis use and psychosis risk. Show an x-axis of cannabis use frequency/potency (never, occasional, weekly, daily, daily high-potency) and a y-axis of relative risk for psychotic disorder. Plot the epidemiological data points showing increasing risk, with daily high-potency use conferring a 5-fold increase. Include genetic modifiers (AKT1, COMT) as risk-modifying factors. Note that up to 50% of cannabis-induced psychosis converts to a primary psychotic disorder. Epidemiology education style.
</image>

<image>
An infographic on cannabinoid hyperemesis syndrome. Show the three phases (prodromal, hyperemetic, recovery) on a timeline. Include hallmark features: compulsive hot bathing, severe cyclic vomiting, chronic daily cannabis use. Show the treatment approach: acute (IV fluids, haloperidol, topical capsaicin) and definitive (cannabis cessation). Include the pathognomonic feature of hot showers and the TRPV1 receptor mechanism. Note common misdiagnosis as cyclic vomiting syndrome. Clinical education format.
</image>

<image>
A treatment algorithm for cannabis use disorder. Start with "Cannabis use disorder diagnosed." Assess severity (mild, moderate, severe). For all: motivational enhancement therapy. For moderate-severe: MET + CBT, consider contingency management. For adolescents: add family-based therapy (MDFT). Pharmacotherapy: note no FDA-approved options; consider NAC (especially adolescents), gabapentin for withdrawal symptoms. Assess for comorbid psychosis risk and counsel accordingly. Include monitoring with urine drug screens. Flowchart format.
</image>

## Clinical Pearls

Cannabis potency has increased 5-10 fold over two decades -- the cannabis of today is not the cannabis of the 1970s; counsel patients accordingly. Daily use of high-potency cannabis increases psychosis risk 5-fold; counsel all patients with psychotic disorder risk factors to avoid cannabis entirely. Cannabis-induced psychosis has the highest conversion rate to primary psychotic disorder (~50% within 3-5 years) -- follow these patients longitudinally. Cannabinoid hyperemesis syndrome is commonly missed; ask about compulsive hot bathing in any chronic cannabis user presenting with cyclic vomiting; topical capsaicin is an effective acute treatment. Cannabis withdrawal is real, recognized in DSM-5-TR, and occurs in ~50% of daily users -- irritability, insomnia, and decreased appetite are most prominent. There are no FDA-approved pharmacotherapies for CUD; psychotherapy (MET + CBT) remains the mainstay of treatment. "Medical marijuana" lacks the regulatory rigor of FDA-approved medications -- no standardized dosing, no consistent formulations, and no strong evidence for psychiatric indications.

## References

- Di Forti M, et al. The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI). *Lancet Psychiatry*. 2019;6(5):427-436.
- Gray KM, et al. A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents. *Am J Psychiatry*. 2012;169(8):805-812.
- Sorensen CJ, et al. Cannabinoid hyperemesis syndrome: diagnosis, pathophysiology, and treatment. *J Emerg Med*. 2017;52(4):544-551.
- Volkow ND, et al. Adverse health effects of marijuana use. *N Engl J Med*. 2014;370(23):2219-2227.
- Connor JP, et al. Cannabis use and cannabis use disorder. *Nat Rev Dis Primers*. 2021;7(1):16.