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ORLANDO -- As more patients seek cannabis products for pain relief and other indications, clinicians' knowledge of the products, risks, and benefits becomes paramount in guiding safe and effective use, a primary care practitioner in pain management said here.

As many as 80% of patients who seek medical cannabis want it for pain, and about 40% of also use cannabis. Many clinicians, however, aren't ready for the role. A of medical residents and fellows showed that 90% felt unprepared to prescribe cannabis, only a third expressed confidence in their ability to answer patients' questions about cannabis, and fewer than 10% of medical studies included cannabis clinical content in their curricula.

"Even if we're not prescribing it, we want to be able to answer questions," said Megan Filoramo, APRN-C, of Altair Health in Morristown, New Jersey, during the American Association of Nurse Practitioners meeting. "I work in pain management, and I answer questions all the time. I certainly refer them back to the right people, but I want to have some basis of knowledge of whether I even think they need to go back and ask the questions of the right people."

Cannabis has been associated with several potential benefits, including decreased pain, reduced reliance on other medications, improved function, improved sleep, and decreased spasticity. One showed a 64% reduction in self-reported use of opioids in association with cannabis treatment, which was associated with fewer side effects and adverse reactions and improved quality of life. Other researchers have documented reduced use of antidepressants, mood stabilizers, and benzodiazepines in association with cannabis use, said Filoramo.

Cannabinoid Science

Cannabinoids promote the release of neurotransmitters involved in sleep regulation, mood, pain perception, appetite, and memory, she continued. The substances exist endogenously and can be produced from plants and chemically synthesized. Phytocannabinoids (plant derived) include delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). More recently, delta-8 THC has become available and has primarily psychogenic effects.

Two cannabinoid receptors (CB1 and CB2) account for the varied biologic effects. CB1 is primarily in the central and peripheral nervous system, heart, lungs, adrenals, kidneys, pancreas, testes, liver, colon, and prostate. The receptor helps mitigate anxiety, stress, pain and inflammation, depression, post-traumatic disorders, multiple sclerosis (MS) symptoms, and symptoms of other neurodegenerative disorders.

CB2 is found in the brain, peripheral nervous system, peripheral immune cells, lungs, uterus, brainstem neurons, and microglia. The receptor is involved in mitigating inflammation, mental health disorders, and neurologic conditions.

"You'll notice there are very few receptors in the brainstem or cardiorespiratory system," said Filoramo. "This means you are not going to overdose on [cannabinoids] when you take them with opioids. I'm not saying everybody should mix everything together and have a cocktail. The point is that you might get dizzy, you might have balance issues, but you're not going to stop breathing."

Benefits and Risks

A long list of potential health benefits has been attributed to cannabis, but there is strong supporting evidence of benefit only for the following:

• Chemotherapy-induced nausea and vomiting

• AIDS anorexia

• Chronic pain

• MS-related spasticity

• The epileptic disorders Lennox-Gastaut syndrome and Dravet syndrome where the CBD product Epidiolex is approved

Filoramo displayed a list of two dozen other conditions with anecdotal or case evidence of benefits, ranging from Sjogren's syndrome to psoriasis to ulcerative colitis.

Medical use of cannabis products is not risk-free, she cautioned. Several "barriers to safety" can complicate decision making and use of cannabis:

• Lack of product standardization

• The wide range of terminology and jargon

• Variation in regulatory authorities' packaging requirements

• Patient belief that "natural" means "safe"

• Lack of knowledge among many providers about cannabis products, limiting the ability to evaluate product quality and safety

Real and potential risks include drug interactions, risk of product contamination, side effects, and concern about a possible association with cancer. THC and CBD are both metabolized via the cytochrome P450 (CYP450) pathway, as are a majority of pharmaceuticals, creating a risk of drug-drug interactions, said Filoramo. Because of the common metabolic pathway, cannabis products have the potential to affect opioid levels and analgesia.

"That doesn't mean people can't take it," she said. "If we only let people have one drug that went through the cytochrome P450 system, we'd have a lot less polypharmacy, but we'd also have a lot fewer patients. It's just important to remember to weigh the benefit and risk for each patient."

Chronic and/or heavy use of cannabis does carry a risk of addiction or dependence in the form of cannabis use disorder. The DSM-5 describes the disorder as a "problematic pattern of cannabis use leading to clinically significant impairment or distress" associated with at least the two conditions or circumstances from a list of 11 possibilities, each step reflecting increased use and dysfunction leading to tolerance and withdrawal.

In general, studies of cannabis use and cancer risk have turned up no associations. The one exception is nonseminomatous germ cell testicular cancer. A National Academies of Sciences, Engineering, and Medicine turned up "modest evidence" of an association between cannabis use and that subtype of testicular cancer.

Special Populations

Immunocompromised patients have a higher risk of infection if they use contaminated cannabis products. CBD might also interact with the calcineurin inhibitor tacrolimus. Preliminary evidence suggests that THC can inhibit lymphocyte proliferation and suppress the activity of CD8+ T cells and cytotoxic T lymphocytes. In theory, CBD and THC might interfere with cancer immunotherapy, but no formal studies of drug interaction have been conducted, said Filoramo.

The evidence regarding adverse effects in adolescents is more compelling. Studies have linked to learning deficiencies. Other studies showed that adults who used cannabis in adolescence had impaired cognitive function related to alertness and self-conscious awareness, as well as impaired learning and memory.

"If you have an adolescent patient who has a medical diagnosis and is not doing well, maybe the risk/benefit ratio is worthwhile," said Filoramo. "But in general, it's not great for adolescents or for adults who used cannabis as adolescents."

Cannabis use in vulnerable populations also carries certain risks. In patients with bipolar disorder, cannabis use has been shown to have a significant association with exacerbation or onset of manic episodes. High THC concentrations may increase seizure frequency in people with a history of seizures. Cannabis should be used with caution by patients who have severe liver or kidney disease because of possible adverse effects related to cannabinoid metabolism. Cannabis also should be used with caution by suicidal patients, although data on the issue are contradictory.

Studies have identified several risks related to fertility and pregnancy, including failed embryo implantation, impaired spermatogenesis, a risk of birth defects with cannabis use during pregnancy, and low birth weight. Additionally, THC is secreted in breast milk at levels that may be detectable for as long as 6 days after cannabis use.

Clinicians and patients should educate themselves about the manufacturers and distributors of cannabis products to determine the content and safety of products, said Filoramo. Get information from company websites, search for reviews, read package labels carefully, and seek information about the type of product and its source.

The legal and regulatory status of cannabis varies from state to state and remains in flux. Filoramo noted that New Jersey legalized cannabis for medical use a few years ago but only recently legalized recreational use. Clinicians and patients should make a concerted effort to learn about a given state's position on cannabis use.

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