Chronic noncancer pain

Currently, multiple studies and clinical guidelines suggest cannabis or cannabinoids may yield benefit as third‑line treatment for chronic pain. In addition to activating cannabinoid receptors 1 and 2 (CB1; CB2), cannabinoids are considered to reduce pain by interacting with multiple other G protein‑coupled receptors to produce analgesic and anti‑inflammatory effects.^15,16

In a systematic review and meta‑analysis of 32 randomized controlled trials (RCTs) with a total of 5174 patients, moderate‑to‑high certainty evidence (as assessed by the Grading of Recommendations, Assessment, Development and Evaluations approach) shows that noninhaled preparations of cannabis or cannabinoids resulted in small improvements in pain relief and physical functioning in patients with chronic pain, with a modelled risk difference of 10%.¹⁷ For chronic neuropathic pain, δ-9‑tetrahydrocannabinol (THC) and cannabidiol (CBD)—the 2 most studied cannabinoids—have demonstrated some promise in both animal models and clinical trials.¹⁸ Utilizing data from the 2017 German Pain Practice Registry, a study of 800 patients using THC and CBD oromucosal sprays for 12 weeks as add‑on treatment found that refractory chronic, especially neuropathic, pain was reduced in intensity—as assessed by the 7‑item validated Pain Detect questionnaire—and that the treatment was well tolerated overall.¹⁹ In total, 67.5% of the patients reported a reduction in pain by over 50%, with 94.8% of the patients experiencing neuropathic pain reduction by over 50%. As assessed by the visual analog scale for pain, the study participants reported a median 64% decline in pain intensity at the end of 12 weeks.¹⁹

Cannabis and cannabinoids are recommended for chronic pain by clinical guidelines developed through a systematic review of 70 articles by Bell et al.²⁰ In 2025, the American College of Physicians released clinical guidelines detailing that patients with chronic, noncancer neuropathic pain may experience small improvements to pain severity with cannabis use.²¹ Bell et al²⁰ advise that THC (not CBD) formulations demonstrate the strongest evidence for reduction of chronic pain symptoms and minimization of adverse effects. It is important, however, to consider therapeutic cannabis for patients with chronic pain only after failure of first- and second‑line pain management options, such as nonsteroidal inflammatory drugs, antidepressants, and antiepileptics.^21-23

Insomnia

Cannabis has also been considered to treat insomnia, and is often marketed accordingly due to its psychotropic and sedative effects.^24,25 Sleep disorders have been ranked among the top 5 conditions for which medical cannabis is used, according to an international survey carried out across 31 countries.²⁶ Despite the widespread commercialization of cannabis for sleep, the current understanding of cannabinoid mechanisms of action on sleep architecture is relatively nascent. Studies on sleep and cannabinoids vary in design, with many outcomes tied to subjective reports of sleep quality, instead of electroencephalography or polysomnography data.^27,28 Furthermore, participants who chronically use cannabis often have poorer baseline sleep quality, which may result from cannabis withdrawal and be reflected in data from these groups.^29-32

As research on cannabis and sleep advances, there is renewed focus on endocannabinoids, which modulate synaptic transmission and may regulate the sleep‑wake cycle.^25,33 Preclinical and clinical studies illustrate that endocannabinoid levels fluctuate throughout the day, and that wakefulness can be modulated with temporal administration of CBD.^34,35 Both THC and CBD have dose‑dependent effects on sleep latency, and the heterogeneity of compounds in cannabis underscores the need to evaluate components in isolation. THC has a sedative effect at low doses, though higher doses can be stimulating or cause symptoms of psychosis that disrupt sleep.³⁶ THC has also been shown to have mixed effects on sleep latency, and its use correlates with decreased rapid eye movement sleep.^29,37 Studies on the isolated effects of CBD are mixed, and dose‑dependent trends require further investigation.³⁶ Findings from the combined administration of THC and CBD suggest that CBD can be activating and counter THC‑induced sedation.^36,37 Nonetheless, existing studies employ a wide range of THC and CBD concentrations and combinations, making direct comparison of findings challenging. Further research, ideally RCTs, is needed to strengthen clinical applicability.

Psychiatric disorders

There is also a dearth of supportive evidence for cannabis or cannabinoids as a treatment for depression, post‑traumatic stress disorder (PTSD), psychosis, attention deficit‑hyperactivity disorder, or Tourette syndrome. Cannabinoids have demonstrated modest efficacy in treating anxiety disorders, as multiple studies have reported a reduction in anxiety symptoms, though the risk of adverse effects limits the feasibility of use.^38-40 While the mechanism of action is not yet fully understood, increased activation of the CB1 and CB2 receptors is associated with decreased anxiety‑like behaviors. THC is a partial agonist at both receptors, while the mechanism of action of CBD is less well characterized.⁴¹

Some research suggests that cannabis use may worsen PTSD symptoms. In an observational study of 2276 veterans with PTSD, cannabis use was associated with increased PTSD symptom severity, and cannabis cessation was associated with significant symptom reduction.⁴² In a systematic review of 47 studies, cannabis use was linked to the exacerbation of symptoms in bipolar disorder and PTSD, with unclear impact on depression and anxiety.⁴³ Despite a lack of supportive evidence, PTSD is a qualifying condition for medical cannabis use in several US states.⁴⁴ The 2023 Clinical Practice Guideline from the US Veterans Affairs and the Department of Defense recommends strongly against cannabis and cannabinoids as treatment for PTSD.⁴⁵ As psychiatric disorders present with a constellation of symptoms, with variable responses to cannabis, there is a need for further research on the effect of cannabis or cannabinoids on these conditions.

Opioid use disorder

Studies report mixed results on the effects of cannabis or cannabinoids on patients with opioid use disorder (OUD). While some research suggests that cannabinoids can reduce cue‑induced cravings in individuals with OUD,^46-48 others report no significant or even adverse effects.^49,50 CB1 receptors are co‑localized with opioid µ receptors, resulting in potentially synergistic analgesic effects, and stimulation of CB2 receptors in mice was associated with inhibition of cocaine and alcohol self‑administration.^51,52

In a cohort study of 8165 patients receiving long‑term opioid therapy for chronic pain, medical cannabis was associated with a reduction in opioid dosage.⁵³ Similar observations were found in a systematic review of 11 studies with 5330 participants, where cannabis or cannabinoid use was associated with alleviation of opioid withdrawal symptoms.⁵⁴ Other studies, however, are less promising. An online national survey of 450 patients with chronic pain and active opioid prescriptions correlated opioid and cannabis co‑use with severe opioid dependence.⁵⁵ Olfson et al⁵⁶ analyzed data from the National Epidemiological Survey on Alcohol and Related Conditions, and identified a correlation between cannabis use and the subsequent onset of OUD and nonmedical opioid use. Overall, cannabis and cannabinoids are not considered evidence‑based interventions for OUD and should not be used in place of treatment approved by the Food and Drug Administration. While individual patients may report therapeutic benefits, current research is unable to support cannabis or cannabinoid therapy for OUD.^49,57

Neurological disorders

There is limited evidence supporting the use of cannabis or cannabinoids for treatment of dementia, including Alzheimer and Parkinson diseases. A review of 4 RCTs including a total of 126 participants with dementia found inconsistent or very modest positive effects of cannabinoids, as compared with placebo.⁵⁸ Conversely, long‑term cannabis use is associated with reduced hippocampal volume, a risk factor for dementia.⁵⁹

For patients with Parkinson disease, potential symptomatic benefits of cannabinoids include reduction in dystonia, pain, spasticity, lack of appetite, dyskinesia, and tremor. Activation of the CB2 receptor is neuroprotective for dopaminergic neurons in mice.⁶⁰ In a retrospective chart review of 69 patients with Parkinson disease, 87% reported improvement in 1 or more symptoms after starting medical cannabis treatment, and 28% reported worsening of 1 or more symptoms.⁶¹ Other clinical trials investigating cannabis use and Parkinson disease reported no improvement in motor symptoms, but potential benefit in reducing anxiety and increasing sleep quality.^62,63 More high‑powered clinical trials are required to support clinical relevance, and further pharmacological research is needed to understand the benefit‑risk tradeoff of treating older patients, who are more sensitive to adverse effects of cannabinoids.

Cannabis use disorder and other substances

As cannabis use becomes more common globally, cannabis use disorder (CUD) is also increasing for most demographics. It is estimated that approximately 35% of all individuals who use cannabis will experience addiction, with increased vulnerability in adolescents; the overall percentage of adult users meeting criteria for CUD has increased considerably.⁶⁴ CUD is described broadly as persistent use despite negative consequences, and the Diagnostic and Statistical Manual of Mental Disorders (March 2022 edition) details the problematic pattern of use with more specificity.^65,66 Additionally, research has suggested that medical cannabis use is not linked with lower addiction risk when compared with nonmedical cannabis use.⁶⁴

Moreover, exposure to THC starting in adolescence has been associated with increased sensitivity to cocaine, heroin, and cannabinoids in adulthood.⁶⁷ Young adults who report use of high‑potency cannabis are more likely to also report use of other illicit drugs, tobacco dependence, and alcohol use disorder.⁶⁸

Developmental harm in adolescents

Human brain development, especially of the prefrontal cortex responsible for executive function, continues until the mid‑20s.⁶⁹ Multiple studies have shown that chronic cannabis use, particularly starting in adolescence, may decrease neurocognitive performance, brain activation, and brain volume at specific regions, as well as increase addiction susceptibility to other substances.^67,70,71 Some effects may be long‑term, as cessation of cannabis does not lead to full recovery of cognitive deficits.^70,71

In a cohort study of 799 adolescents aged 12–15 years across 8 European sites, a dose‑dependent, negative association was observed at 5‑year follow‑up between cannabis use and cortical thickness. Thinning in the right prefrontal cortices was associated with increased attentional impulsiveness.⁷² Numerous studies suggest that cannabis use may result in deficits in working memory, decision‑making, executive functioning, intelligence quotient, inhibitory processes, and flexibility. Adolescents are particularly vulnerable to the negative effects of cannabis use; less intensive use results in similar cognitive deficits in comparison with adults, and these deficits are less reversible.^71,73

Cannabis use is prevalent among adolescents, despite a decreasing trend in recent years. Given the heightened risk of adverse effects with early‑onset cannabis use, efforts to delay the age of onset are valuable in minimizing harm.^74,75

Cannabinoid hyperemesis syndrome

Cannabinoid hyperemesis syndrome (CHS) is a subtype of cyclical vomiting syndrome, associated with chronic and heavy use of cannabis. The clinical presentation consists of recurring episodes of severe nausea, vomiting, and abdominal pain. These symptoms typically present within 24 hours of last cannabis use. A diagnosis of CHS can be made in patients with 3 or more annual episodes of nausea, vomiting, and abdominal pain lasting less than 1 week, who have used cannabis more than 4 days a week on average for over a year, and who experience resolution of symptoms after cannabis cessation for over 6 months.^76,77 While the pathophysiology is not fully understood, vagal control of gut motor functions, such as nausea and vomiting, involves CB1 and CB2 receptors; overstimulation can result in increased vagal nerve discharges, leading to vomiting.^76,78

Despite limited evidence supporting a consensus treatment protocol, acute symptoms of CHS are currently treated with intravenous fluids, antinausea medications (such as topical capsaicin and ondansetron), short‑term benzodiazepines, and antipsychotics (such as haloperidol and olanzapine). Chronic care involves counseling to support cannabis use cessation and administration of tricyclic antidepressant medication (such as amitriptyline). Although the overall prevalence of CHS is unknown and likely underreported, emergency department visits for CHS have doubled in the US and Canada between 2017 and 2022.^77,79 Use of high‑potency cannabis products, particularly with high THC concentrations, daily use, and onset of cannabis use before the age of 16 years are predisposing risk factors for CHS. Although CHS is a well‑characterized adverse effect of cannabis use, more research is needed to provide empirical treatment and management recommendations for clinicians.

Psychosis

Cannabis use has been associated with an increased risk of acute psychotic symptoms, with a higher risk of converting to a psychotic disorder. In observational studies, it is estimated that 19.4% of participants experience psychotic symptoms associated with cannabis use, although the rate of psychosis associated with medical cannabis is much lower, at 1.5%.⁸⁰ Young individuals with pre‑existing mental health conditions and individuals using high‑potency cannabis appear to be especially sensitive to these adverse effects.^68,80,81

A case‑control study of 901 patients aged 18–64 years across 11 sites in Europe and Brazil found that daily cannabis use was associated with increased odds of psychotic disorder, as compared with individuals who had never used it, and that this increase was nearly 5‑fold for those who reported daily use of high‑potency cannabis.⁸² Additionally, a cohort study of 61 participants observed that individuals with cannabis use disorder had a higher neuromelanin signal on magnetic resonance imaging in brain areas associated with the expression of psychosis, providing a potential explanation for this association.⁸³ Multiple studies have reported a relationship between cannabis use and schizophrenia in cases where cannabis use preceded psychosis.⁸⁴ While there is ongoing discussion regarding if the link between cannabis use and psychosis risk is due to neurobiological changes, a shared vulnerability for cannabis use and psychosis, self‑medication of psychotic symptoms, or an alternative explanation, psychotic symptoms and disorders are still considered a potential risk of cannabis use.⁸⁵

Pregnancy and lactation

The prevalence of cannabis use among pregnant individuals has increased in recent years, with the highest rate being in the first trimester.⁸⁶ The self‑reported prevalence of cannabis use in the US states with legalized medical and recreational use during pregnancy was found to be 5.7%.⁸⁷ Though multiple states have approved cannabis for nausea and vomiting, including during pregnancy, the American College of Obstetricians and Gynecologists recommends against cannabis use during pregnancy and breastfeeding.⁸⁸

In‑utero exposure to cannabis has been associated with an increased risk of gestational hypertension, preeclampsia, low birth weight, small‑for‑gestational‑age birth, stillbirth, and spontaneous pre‑term birth, though conflicting evidence has been reported.^89-91 Cannabis exposure may disrupt placental function, as the endocannabinoid system is involved with placental implantation.⁹² Additionally, THC crosses the placenta and is detectable in breast milk.⁹³ It is estimated that cannabis use among breastfeeding individuals is 5%.⁸⁷ Limited data have suggested other potential risks, including impaired infant motor development, decreased secretory immunoglobulin A levels in milk, and dysregulated serum prolactin levels that potentially decrease milk supply.⁹⁴

Cardiovascular and pulmonary risk

Cannabis use has been associated with increased risk of cardiovascular and pulmonary diseases.⁶⁶ Activation of the CB1 receptors affects the cardiovascular system by decreasing heart rate, blood pressure, and myocardial contractility, in addition to increasing coronary dilation.⁸⁷ In a systematic review of 24 studies, cannabis or cannabinoid use was positively associated with major adverse cardiovascular events, such as stroke, acute coronary syndrome, and cardiovascular mortality.⁹⁵ Although evidence regarding cannabis use and adverse cardiovascular outcomes remains inconclusive, a 3.3‑fold risk of stroke in frequent cannabis users has been reported.⁸⁷

Cannabis and cannabinoids have also been linked to chronic bronchitis symptoms and reduced forced expiratory volume in 1 second / forced vital capacity ratios. There is inconsistent evidence regarding how cannabis use may affect the risk of chronic obstructive pulmonary disease and asthma, and these data are often complicated by concomitant smoking of tobacco.^96,97 Due to these confounding factors, the prevalence of pulmonary adverse effects due to cannabis use remains unclear.

Motor vehicle accidents and falls

Acute cannabis use can impair motor and cognitive function, and it is associated with an increased risk of falls and motor vehicle accidents.^66,98 Bidwell et al⁹⁹ conducted an observational cohort study of 121 participants and identified moderate balance impairment lasting 1 hour in the participants after cannabis use. They suggested using a balance measure to identify impaired drivers, similar to the field testing tools for alcohol intoxication. In a double‑blind and placebo‑controlled RCT of 191 participants, cannabis use was associated with worsened driving performance lasting 4 to 5 hours after use. However, the participants reported feeling safe to drive around 1.5 hours after use, suggesting that a false sense of safety may contribute to a higher motor vehicle crash risk.¹⁰⁰ In 2018, the Centers for Disease Control and Prevention found that 4.7% of US residents over the age of 16 years reported driving under the influence of marijuana.¹⁰¹ More research regarding predisposing risk factors for motor impairment at older age and use of high‑THC concentration products is needed.