The Emerging Risks of Modern Cannabis

The rapid evolution of cannabis content and laws surrounding cannabis, along with the explosion of hemp-derived synthetics, has transformed the therapeutic and recreational landscape. Products approved by the FDA are evidence-based, and randomized, controlled trials have emerged in favor of using some non-FDA-approved products for certain indications.¹ However, many who use those products are unaware of possible harms.

Pharmacists may be intimately involved as dispensary consultants (or in other roles) or completely uninvolved in the regulation of this space, depending upon their state’s laws. Regardless, pharmacists now face potent, variably regulated products, complex drug interactions, and rising cannabis-related syndromes in emergency and outpatient settings.

Cannabis 2.0: Potency, Products, and Policy Shifts

Although there are more than 125 known cannabinoids from the Cannabis sativa plant, Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) remain the best studied and characterized.² Acting as a partial agonist on cannabinoid 1 receptors in the central nervous system, THC exerts psychoactive effects. CBD is thought to act indirectly on the endocannabinoid system and is not psychoactive.

THC potency has risen dramatically over the past decade to well over 20% in most state-regulated nonmedical retail markets.³ One study’s findings showed that daily THC intake among those with cannabis-related disorders has risen from 20 mg to 40 mg.⁴ While a typical smoked product contains 18 mg to 32 mg of THC, some edibles can have as much as 400 mg of THC.

Increased THC concentration has driven an increase of cannabis-related disorders over the past decade, but that is not the only problem. The 2018 Agricultural Improvement Act removed hemp and derivatives of cannabis with less than 0.3% THC from Schedule I, which led to the biosynthesis of intoxicating hemp-derived cannabinoids. CBD has been converted to intoxicating, psychoactive products now commonly sold in gas stations and vape stores under various product names. Many of them contain “novel” cannabinoids such as Δ-8-THC, THC-H, THC-B, and THC-P. Δ-8-THC has half the psychoactive potency of THC; however, the latter 3 listed are up to 33 times the potency of THC.

Youth are often targeted in the marketing of these products. Since tracking began of Δ-8-THC in 2021, calls to state poison control centers have grown exponentially. More than half of the exposures in one study were children, with 1 in 3 being younger than 6 years old.⁵

Pharmacology and Drug-Drug Interactions

Both THC and CBD share metabolic pathways (CYP3A4, CYP2C9, CYP2C19) with many prescription drugs, creating a potential for clinically meaningful drug-drug interactions. These potential interactions have not been largely studied. However, systematic reviews of real-world cases highlight interactions with narrow therapeutic index agents such as warfarin, tacrolimus, valproate, clobazam, and other antiepileptics.^6,7 Adverse events such as bleeding, altered mental status, anesthetic difficulties, and gastrointestinal problems have been reported. The CYP3A4 inhibitor ketoconazole has been shown to double THC and CBD concentrations.

Other such inhibitors like ritonavir, erythromycin, and diltiazem may theoretically increase cannabinoid concentrations, although clinical evidence is lacking at this time. Evidence is also lacking with other common medications metabolized by CYP2C19, such as clopidogrel, proton pump inhibitors, benzodiazepines, and tricyclic amines; however, THC and CBD could theoretically increase plasma concentrations of these medications.

Additive effects have been shown when cannabis is combined with sympathomimetics and anticholinergics, with increased tachycardia. Increased drowsiness and ataxia can be experienced when combined with alcohol and opioids.⁸

Clinical Syndromes: Hyperemesis, Withdrawal, and Use Disorder

High-dose, long-term cannabis exposure can lead to distinct clinical syndromes now routinely encountered across care settings. Cannabinoid hyperemesis syndrome (CHS) presents with cyclic vomiting, abdominal pain, and compulsive hot bathing, mostly when previously inexperienced individuals begin daily or near-daily cannabis use for 1 to 2 years.⁹ Symptoms typically start abruptly within 24 hours of last cannabis use. Stopping cannabis use completely is the most effective long-term solution for CHS. However, suddenly stopping cannabis use completely can result in withdrawal symptoms (Table 1¹⁰) and high rates of relapse.

The diagnostic criteria for cannabis use disorder (CUD) encompass several factors, including earlier age of use and rapid progression to frequent/daily use (Table 2). Alcohol or tobacco use, comorbidities of depression or anxiety, and social isolation are other common associated factors. The prevalence of lifetime CUD among United States adults is 6.35%; however, only 13.2% of these receive professional treatment.¹¹ Urine screens or other biological screening can detect use of cannabis but not necessarily CUD.

A structured interview asking, “In the past year, how often have you used cannabis or marijuana?” could help identify CUD. Any answer of “more than once” or more often than this is highly associated with detecting CUD.¹² Most young adults and those with mild CUD often exhibit a desired goal of harm reduction rather than total abstinence. Reducing frequency of use is associated with greater improvement than decreasing quantity.

Almost 50% of those with heavy and/or prolonged cannabis use who stop abruptly experience cannabis withdrawal syndrome (CWS).¹³ Treatment of CUD is usually in the outpatient setting, with inpatient treatment reserved for those with multiple substance use disorders or comorbidities of depression, psychosis, or suicidality. Research shows treatment to be most effective by a clinician experienced in cognitive behavior therapy (CBT), even when the patient has moderate or severe CUD.¹⁴ CBT identifies and manages thoughts, behaviors, and emotions, helping the patient identify external triggers, develop coping skills, and implement healthy alternatives. Of interest, while gabapentin, topiramate, and varenicline have been studied, no medication therapy has been shown to decrease the severity of CUD or produce sustained abstinence.¹⁵

Practical Roles for Pharmacists

Pharmacists are encouraged to keep abreast of the literature favoring cannabis products for certain conditions, but the scope of this article is to increase awareness of the possible risks. As community practice clinicians, pharmacists are perfectly aligned in the health care spectrum for cannabis care risk assessment, interaction management, and patient education. The pharmacokinetic and pharmacodynamic complexity of cannabinoids, combined with widespread polypharmacy, argues for a “start low, go slow” approach with close monitoring for efficacy and neurocognitive changes.¹⁶ Systematic reviews and clinical case series repeatedly emphasize the need for open communication about cannabis use—including CBD oils, Δ-8-THC, other intoxicating hemp products, and vapes—to preempt unrecognized drug-drug interactions and adverse events.⁶ Pharmacists recognizing patterns consistent with clinical syndromes (CHS, CUD, and CWS) should refer to behavioral treatment clinicians in their area who use cognitive behavior therapy for the best results.

Conclusion

Modern cannabis comprises high-potency plant products, dispensary products, unregulated intoxicating hemp products, and complex formulations that challenge traditional assumptions of safety. Evidence is emerging to document clinically important drug-drug interactions, distinct cannabis-related syndromes, and a substantial burden of under-treated CUD. Pharmacists, as accessible medication experts, are central to navigating this landscape: identifying at-risk patients, mitigating interactions, counseling on product risks, and promoting evidence-based pathways to reduce harm and support recovery.

About the Author

Justin J. Sherman, PharmD, MCS, is an associate professor of pharmacy practice at the University of Mississippi School of Pharmacy.

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