Continuing Education Activity

Cannabis, also known as marijuana, is commonly sought out by patients for various conditions. Conversely, many providers are uncomfortable prescribing marijuana due to a paucity of clinical trials and a lack of awareness regarding the potential risks and benefits of the substance. This activity reviews the current indications and contraindications for medical marijuana. In addition, it highlights the role of the interprofessional team in caring for patients who use or are considering using medical marijuana.

Objectives:

• Identify the mechanism of action of marijuana.
• Describe the adverse effects of marijuana.
• Describe the current clinical use of marijuana.
• Describe interprofessional team strategies to educate patients on potential clinical benefits and adverse effects of medical marijuana to improve patient outcomes.

Indications

The major medical indications of marijuana are to relieve symptoms rather than cure disease. Medical marijuana is not approved by the US Food and Drug Administration (FDA) to treat any medical condition. However, cannabidiol is the first FDA-approved drug that contains a purified drug substance derived from marijuana. Additionally, the FDA has approved analogs of marijuana as follows.[1]

FDA-approved Analogs of Marijuana

• Cannabidiol

• Dronabinol

• Nabilone

Cannabidiol 

• Cannabidiol(CBD) oral solution is approved for treating seizures associated with severe forms of epilepsy in patients ≥1 year of age in the following conditions.

• Lennox-Gastaut syndrome[2]

• Dravet syndrome[3]

• Tuberous sclerosis[4]

Dronabinol

• Treatment of anorexia associated with weight loss in patients with AIDS[5]

Nabilone

• Refractory chemotherapy-induced nausea and vomiting[6]

Off-label Clinical Uses(Marijuana)

• TCH(tetrahydrocannabinol) has been shown to decrease intraocular pressure, yet no major ophthalmology organizations support medical cannabis use for glaucoma at this time.

• Improvement in muscle spasms and pain related to multiple sclerosis and spinal cord injuries. The use of cannabis and cannabinoids for chronic pain is controversial, but it is commonly used for this purpose.[7][8]

• Marijuana is used to treat neuropathic pain, spasticity related to Parkinson disease, nausea and vomiting related to chemotherapy, anxiety disorder, sleep disorder, Tourette syndrome, and Crohn disease.

• To increase appetite in AIDS or AIDS-related wasting and psychiatric disorders such as posttraumatic stress disorder.[9]

Mechanism of Action

Marijuana is a complex of more than 400 compounds, including flavonoids, terpenoids, and cannabinoids. Cannabinoids are the active ingredients and appear to have individual interactive effects that contribute to the net effect of marijuana. Cytochrome p450 enzymes metabolize cannabinoids in the liver. The principal cannabinoid is tetrahydrocannabinol(THC), responsible for both the psychoactive effects sought by recreational users and the drug's therapeutic effects. Although the mechanism of action is still being researched, it is known that there are widespread cannabinoid receptors in the brain and peripheral tissues known as the endocannabinoid system. The endocannabinoid system regulates metabolism, appetite, blood pressure, glycemic control, immune response, and sense of reward. Although the receptors are located throughout the body, the central nervous system interactions arise from the most prominent effects. Since it has a high lipid-soluble profile, it circulates through the body efficiently and causes various effects based on the receptors and dosage.[10]

The primary action is on the cannabinoid receptors, which are G-protein-linked receptors(GPCR). There are two known cannabinoid receptors: CB1 and CB2. The CB1 receptor is found in the central nervous system. It modulates the release of several neurotransmitters such as norepinephrine, dopamine, serotonin, and gamma-aminobutyric acid(GABA). The CB2 receptor is located in the immune system. Therefore, it is assumed that it performs a function in the modulation of immune and inflammatory responses. However, CB2 expression is highly inducible on the microglia in the CNS following inflammation.[11][12]

Administration

Marijuana can be administered in many different ways - orally, sublingually, or topically. It can also be smoked, mixed into foods, and brewed as tea.

• Typically cannabis is smoked, which has the advantage of rapid onset and easy titration and rapidly delivers it to the brain and circulation. However, smoked cannabis has had difficulty being approved for medical use for multiple reasons, an important one being the variable mixture of THC, other cannabinoids, carcinogens, and other toxic substances to the lungs. 

• When ingested orally, the pharmacokinetics vary greatly. The onset of action is delayed with maximum blood levels reaching up to six hours post-ingestion and a half-life of 20-30 hours.[13]

• The topical route, such as making it into a liniment, has been used for arthritic pain with varying success.

• Routes such as lozenges, sublingual tablets, skin patches, or suppositories have been attempted for medical purposes but have had difficulty obtaining standardized effects. In addition, the combinations of cannabinoids in each preparation can vary substantially, which makes precise dosing difficult.[14]

Adverse Effects

The most common emergency caused by marijuana ingestion is a panic attack.[15] The most common adverse effects include dizziness, dry mouth, nausea, disorientation, euphoria, confusion, sedation, increase heart rate, and breathing problems.[16][17][18][19]

• Marijuana use has also been linked to acute reversible psychotic reactions and 24% of new psychosis cases in adolescents. Marijuana use has also been linked to acute reversible psychotic reactions and 24% of new psychosis cases in adolescents. It has also been shown to increase the risk of psychotic disorders and exacerbate or relapse symptoms in those with psychotic disorders.[20]

• Some studies suggest an increased risk of lung cancer from inhalation of marijuana, as well as an association between inhalational marijuana and spontaneous pneumothorax. It is also linked to bullous emphysema and COPD complications, such as increased wheezing, cough, and phlegm production.[21]

• Long-term use has also been associated with periodontal disease, pre-term birth if used at 20 weeks gestation, and more frequent pain crises in sickle cell patients.[22]

• Approximately one in 10 adult users of marijuana develop an addiction, with higher rates reported in adolescents.[23]

• Studies have shown that adolescents who used marijuana were significantly less likely than their non-using peers to finish high school or obtain a degree and were more likely to develop dependence, use other drugs, or attempt suicide. Marijuana has also been shown to worsen verbal memory, some cases of depression, anxiety disorders, and pre-existing schizophrenia.[24]

• Chronic use has also been well documented as a cause of cannabinoid hyperemesis syndrome(CHS), first described in Australia by Allen et al. in 2004. This syndrome is characterized by recurrent episodes of nausea and vomiting relieved by hot showers.[25] 

• There have also been complications linked to the abrupt cessation of marijuana after chronic use. Cannabis withdrawal typically requires no treatment. Symptoms may include irritability, poor sleep, poor appetite, and restlessness.[26][27]

• Impaired spermatogenesis[28]

Contraindications

There is minimal information available about contraindications with cannabis-derived pharmaceuticals and medical cannabis. Known contraindications to dronabinol, a synthetic THC and DEA schedule 3 drug, include hypersensitivity to the drug, allergy to cannabinoids/propylene glycol/peppermint oil, as well as concomitant use of ritonavir, which may lead to potential toxicity.[29]

Medical contraindications are cardiovascular disease, arrhythmias, poorly controlled hypertension, severe heart failure, history of psychotic disorder, patients under eight years old, pregnant women, or nursing women.[30]

One study showed that marijuana could worsen preexisting heart disease, resulting in up to a five-fold increase in heart attacks one hour after smoking marijuana.[31][32]

Monitoring

Clinicians can detect marijuana use up to 2–5 days after exposure for infrequent users and up to 1-15 days for chronic or heavy users.  Those with high body fat may have positive tests from 1 to 30 days. The actual detection times vary based on many factors, including the method of use, metabolism, and volume of distribution.  It also depends on the type of THC metabolite being tested for. False positives have been triggered by several medications and materials, although more detailed and expensive tests can differentiate further if necessary.

Assess ALT, AST, and total bilirubin before initiating treatment, with dose changes or the addition of or changes in hepatotoxic medications.[33]

Marijuana is classified as a Schedule I substance by the FDA, and therefore is not accepted for medical use and has a high abuse potential from a federal point of view. As a result, doctors cannot prescribe marijuana, but doctors may certify its use in states that allow its use to treat medical conditions.  Both dronabinol (synthetic THC) and nabilone (a synthetic cannabinoid receptor antagonist) are individual oral agents registered for use in the US available commercially but have been difficult to titrate to receive therapeutic effects. As of now, it is not known to what extent a physician who certifies a patient for medical marijuana is liable for negative outcomes or whether medical insurance will cover liability.[34][35]

Toxicity

Clinical Features

• Tachycardia

• Postural hypotension

• Tachypnea

• Nystagmus

• Ataxia

• Euphoria/dysphoria

• Conjunctival injection 

• Hypotonia

• Seizures(associated with ingestion of cocaine)

• Impaired cognition[36]

• Respiratory depression[37]

• Coma[37]

Management

• Maintain airway, breathing, and circulation.

• Administer benzodiazepines (e.g., lorazepam or midazolam) for seizures.

• Administer intravenous fluid, antiemetics (e.g., ondansetron) for cannabis hyperemesis syndrome. In refractory cases, consider using haloperidol.[38]

• Following stabilization, psychiatry consultation is necessary for patients with cannabis use disorder.

Enhancing Healthcare Team Outcomes

There is a vast amount of literature on marijuana and its health benefits. Unfortunately, the majority of these are anecdotal reports. Without clinical trials and a lack of a universal formula for marijuana, there appear to be significant controversies in the clinical benefits of marijuana. All healthcare workers, including nurse practitioners and pharmacists, should educate patients that marijuana may not be the panacea for all medical disorders. To date, marijuana has been shown to improve appetite and reduce mild nausea. Until data from randomized clinical trials are available, the prescription of marijuana should be limited as more evidence seems to indicate that this product may not be entirely safe for long-term consumption.[39][40][41]

In acute intoxication, triage nurses and emergency department physicians should maintain patent airway breathing and circulation. Psychiatrists should evaluate for the signs of psychosis and administer proper treatment. Similarly, critical care physicians should take care of the patient while in ICU. Finally, clinicians should refer patients with cannabis dependency to social workers. As depicted above, clinicians(MDs, DOs, NPs, PAs), pharmacists, specialists, nurses, and other healthcare providers are involved in taking care of the patient and an interprofessional team approach will minimize the risk of substance use disorder. [Level 5]