Recreational cannabis use: Pleasures and pitfalls

CANNABINOID HYPEREMESIS SYNDROME

First reported in 2004,²⁸ cannabinoid hyperemesis syndrome is a recurrent disorder, the pathophysiology of which is poorly understood. It has three phases.

The first phase is a prodrome that may last months or years and is characterized by morning nausea, fear of vomiting, and abdominal discomfort. During this phase, the patient maintains normal eating patterns and may well increase his or her cannabis use due to its well-known antiemetic effects.

The second phase is the hyperemetic phase, characterized by intense, incapacitating emesis with episodes of vomiting throughout the day. These symptoms can be relieved only with frequent hot baths, a feature that distinguishes cannabinoid hyperemesis syndrome from other vomiting syndromes. Hot-water bathing is reported to be a compulsive but learned behavior in which the patient learns that only hot water will provide relief. The extent of relief depends on the temperature of the water—the hotter, the better. Symptoms recur as the water cools.²⁸ Patients often present to the emergency department repeatedly with recurrent symptoms and may remain misdiagnosed or subjected to repeated extensive evaluation including laboratory testing and imaging, which are usually not revealing. If the patient has not been accurately diagnosed, there may be reported weight loss of at least 5 kg.

The third phase, recovery, may take several months to complete, possibly because of the prolonged terminal elimination time of cannabinoids. Complete cessation of cannabis use, including synthetic cannabinoids, is usually necessary.²⁹

Diagnostic criteria for cannabinoid hyperemesis syndrome have been suggested, based on a retrospective case series that included 98 patients.³⁰ The most common features of these affected patients were:

• Severe cyclical vomiting, predominantly in the morning
• Resolution of symptoms with cessation of cannabis use
• Symptomatic relief with hot showers or baths
• Abdominal pain
• At least weekly use of cannabis.

Interestingly, long-term cannabis use has been cited as a critical identifying feature of these patients, with the duration of cannabis use ranging from 10 to 16 years.^31,32 Other reports show greater variability in duration of cannabis use before the onset of cannabinoid hyperemesis syndrome. In the large study noted above,³⁰ 32% of users reported their duration of cannabis use to be less than 1 year, rendering this criterion less useful.

How can cannabis both cause and prevent vomiting?

The body controls nausea and vomiting via complex circuitry in the brain and gut that involves many neurotransmitters (eg, dopamine, serotonin, substance P) that interact with receptors such as CB1, 5-HT_1–4, alpha adrenergic receptors, and mu receptors. Interestingly, cannabis use has antiemetic properties mediated by CB1 with a still unclear additional role of CB2 receptors. Data point to the existence of an underlying antiemetic tone mediated by the endocannabinoid system.

Unfortunately, the mechanism by which cannabinoid hyperemesis syndrome occurs is unknown and represents a paradoxical effect against the otherwise antiemetic effects of cannabis. Several theories have been proposed, including delayed gastric emptying, although only a third of patients demonstrated this on scintigraphy in one study.³⁰ Other theories include disturbance of the hypothalamic-pituitary axis, a buildup of highly lipophilic THC in the brain, and a down-regulation of cannabinoid receptors that results from chronic exposure.³⁰ Given that this syndrome has been recognized only relatively recently, one author has suggested the cause may be recent horticultural developments.⁵

Treating cannabinoid hyperemesis syndrome is difficult

Treatment of cannabinoid hyperemesis syndrome is notoriously difficult, with many authors reporting resistance to the usual first-line antiemetic drugs. Generally, treatment should include hydration and acid-suppression therapy because endoscopic evaluation of several patients has revealed varying degrees of esophagitis and gastritis.²⁹

Antiemetic therapy should target receptors known to mediate nausea and vomiting. In some cases, antiemetic drugs are more effective when used in combination. Agents include the serotonergic receptor antagonists ondansetron and granisetron, the dopamine antagonists prochlorperazine and metoclopramide, and even haloperidol.^33,34 Benzodiazepines may be effective by causing sedation, anxiolysis, and depression of the vomiting center.^34,35 Two antihistamines—dimenhydrinate and diphenhydramine—have antiemetic effects, perhaps by inhibiting acetylcholine.³⁴

Aprepitant is a neurokinin-1 antagonist that inhibits the action of substance P. When combined with a corticosteroid and a serotonin antagonist, it relieves nausea and vomiting in chemotherapy patients.^34,36

Corticosteroids such as dexamethasone are potent antiemetics thought to inhibit prostaglandin synthesis.³⁴

Capsaicin cream applied to the abdomen has also been reported to relieve symptoms, possibly through an interaction between the TRPv1 receptor and the endocannabinoid system.^37,38

DIAGNOSTIC TESTING

Cannabinoids are detectable in plasma and urine, with urine testing being more common.

Common laboratory methods include the enzyme-multiplied immunoassay technique (EMIT) and radioimmunoassay. Gas chromatography coupled with mass spectrometry is the most specific assay; it is used for confirmation and is the reference method.

EMIT is a qualitative urine test that detects 9-carboxy-THC as well as other THC metabolites. These urine tests detect all metabolites, and the result is reported as positive if the total concentration is greater than or equal to a prespecified threshold level, such as 20 ng/mL or 50 ng/mL. A positive test does not denote intoxication, nor does the test identify the source of THC (eg, cannabis, dronabinol, butane hash oil). EMIT does not detect nabilone. The National Institute on Drug Abuse guidelines for urine testing specify a test threshold concentration of 50 ng/mL for screening and 15 ng/mL for confirmation.

Many factors affect the detection of THC metabolites and their presence and duration in urine: dose, duration of use, route of exposure, hydration status, urine volume and concentration, and urine pH. THC metabolites have been detected in urine using gas chromatography-mass spectrometry for up to 7 days after smoking one marijuana cigarette.⁷ Chronic users have also been reported to have positive urine EMIT tests for up to 46 days after cannabis cessation.³⁹ Detection may be further complicated in chronic users: in one study, users produced both negative and positive specimens over 24 days, suggesting that diet and exercise may influence clearance.⁴⁰ Also, many factors are known to produce false-positive and false-negative results for these immunoassays (Table 1).^39,41

In the United States, penalties for driving under the influence of cannabis vary from state to state, and laws specify plasma testing for quantitative analysis. Some states use a threshold of 5 ng/mL in plasma to imply driving under the influence, whereas others use any detectable amount. Currently, there are no generally accepted guidelines for storage and testing of blood samples, despite the known instability of analytes.⁴²

Saliva, hair, and sweat can also be used for cannabinoid testing. Saliva is easy to collect, can be tested for metabolites to rule out passive cannabis exposure, and can be positive for up to 1 day after exposure. Calculating a blood or plasma concentration from a saliva sample is not possible, however.

Hair testing can also rule out passive exposure, but THC binds very little to melanin, resulting in very low concentrations requiring sensitive tests, such as gas chromatography with tandem mass spectrometry.

Only one device is commercially available for sweat testing; further work is needed to elucidate sweat excretion pharmacokinetics and the limitations of the collection devices.⁴³

CLINICAL MANAGEMENT IS GENERALLY SUPPORTIVE

Historically, clinical toxicity from recreational cannabis use is rarely serious or severe and generally responds to supportive care. Reports of cannabis exposure to poison centers are one-tenth of those reported for ethanol exposures annually.⁴⁴ Gastrointestinal decontamination with activated charcoal is not recommended, even for orally administered cannabis, since the risks outweigh the expected benefits. Agitation or anxiety may be treated with benzodiazepines as needed. There is no antidote for cannabis toxicity. The ever-increasing availability of high-concentration THC preparations may prompt more aggressive supportive measures in the future.

SYNTHETIC MARIJUANA ALTERNATIVES

Available since the early 2000s, herbal marijuana alternatives are legally sold as incense or potpourri and are often labeled “not for human consumption.” They are known by such brand names as K2 and Spice and contain blends of herbs adulterated with synthetic cannabinoid chemicals developed by researchers exploring the receptor-ligand binding of the endocannabinoid system.

Clinical effects, generally psychiatric, include paranoia, anxiety, agitation, delusions, and psychosis. There are also reports of patients who arrive with sympathomimetic toxicity, some of whom develop bradycardia and hypotension, and some who progress to acute renal failure, seizures, and death. Detection of these products is difficult as they do not react on EMIT testing for THC metabolites and require either gas chromatography-mass spectrometry or liquid chromatography with tandem mass spectrometry.^45–48