Pain Relief with CBD Roll-On Cream Lavender 100 mg by Elixicure

LIKELY EFFECTIVE

• Epilepsy. A specific prescription cannabidiol product, Epidiolex (GW Pharmaceuticals), is FDA-approved for use in Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. It is unclear if other cannabidiol products are beneficial for these conditions. Details: Research into the use of cannabidiol for the treatment of epilepsy has primarily been conducted with a specific oil-based solution, Epidiolex. This product is FDA-approved for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex in patients 1 year of age and older (99613). Prescription cannabidiol is typically used as an adjunctive treatment to conventional anti-epileptic medicines such as clobazam, valproic acid, lamotrigine, levetiracetam, and rufinamide. A meta-analysis of clinical studies in patients with Dravet syndrome and Lennox-Gastaut syndrome shows that cannabidiol daily for 14 weeks must be used by 4 patients taking antiepileptic treatment regimens with clobazam, and 8 patients taking antiepileptic regimens without clobazam, to result in one additional patient achieving a 50% greater reduction in seizures (103037). Research suggests that Epidiolex maintains efficacy when used long-term (105495,106631,106633). A prospective open-label study in adults and children with treatment-resistant epilepsy suggests that taking Epidiolex for 2 years results in sustained seizure reduction when compared with baseline (105495). For patients with Dravet syndrome or Lennox-Gastaut syndrome, reduced seizure frequency tends to occur within 2-4 weeks of starting treatment with Epidiolex (97017,97979,97980,106632). Clinical research in children 2-18 years of age with refractory Dravet syndrome shows that taking Epidiolex 20 mg/kg daily for 14 weeks reduces total convulsive seizure frequency by 39%, compared to 13% with placebo (97017). Up to 50% of patients with Dravet syndrome experience at least a 50% reduction in convulsive seizures after taking Epidiolex for 12-14 weeks. An open-label extension study shows similar reductions in total convulsive seizure frequency sustained through 156 weeks of treatment at a mean modal dose of 22 mg/kg daily, with more than 45% of patients experiencing at least a 50% reduction in convulsive seizures at each 12-week visit window (106633). Epidiolex seems to be effective at daily doses of 10 mg/kg and 20 mg/kg, but lower doses seem to be better tolerated (97017,97022,103038,106633). Clinical research in patients 2-43 years of age with refractory Lennox-Gastaut syndrome shows that taking Epidiolex for 14 weeks reduces the frequency of drop seizures by up to 43%, which is significant when compared with placebo (97979,97980). An open-label extension study in these patients shows similar reductions in drop seizures sustained through 156 weeks of treatment at a mean modal dose of 24 mg/kg daily (106631). A clinical trial in patients with tuberous sclerosis complex (TSC) shows that taking Epidiolex 25 mg/kg or 50 mg/kg daily for 16 weeks reduces seizure frequency by 30% or 29%, respectively, when compared with placebo (104888). An open-label extension study in these patients shows seizure frequency reductions of 54% to 68% sustained through 48 weeks of treatment at a mean modal dose of 27 mg/kg daily, with more than 53% of patients experiencing at least a 50% reduction in seizures (107327). Other cannabidiol products also have been evaluated for use in the treatment of developmental and epileptic encephalopathy, including Dravet and Lennox-Gastaut syndromes. A small, nonrandomized, open-label clinical study in children and adolescents 3-18 years of age with developmental and epileptic encephalopathy receiving a stable antiseizure regimen shows that application of a cannabidiol 4.2% gel, delivering cannabidiol 125-500 mg twice daily decreases monthly seizure frequency by 12% when compared with baseline. Seizure types demonstrating the greatest response included focal impaired awareness seizures (previously called complex partial seizures) and tonic-clonic seizures (106630). The validity of this finding is limited by the lack of a comparator group. Cannabidiol has also been evaluated for its effects on interictal epileptiform activity in children with treatment-resistant epilepsy. A small clinical study shows that taking cannabidiol, either as Epidiolex or another pharmaceutical grade formulation of synthetic cannabidiol, 20 mg/kg daily for 3 months reduces the rate of interictal epileptiform discharges from 37 per minute to 20 per minute when compared with baseline (107330). The validity of these findings is limited by the lack of a comparator group. Epidiolex has also been evaluated for use in other forms of epilepsy such as Sturge-Weber syndrome, febrile infection-related epilepsy syndrome (FIRES), and epileptic encephalopathy of genetic origin; however, the available research is limited, and it is not approved for these uses (97019,97020,97022,97025,99603,99604,100883,100889,103034). Limited research has also evaluated pharmaceutical-grade, synthetically-derived cannabidiol products. One open-label observational study in children and adults with refractory epilepsy has found that taking a specific synthetic cannabidiol product (THC Pharm GmbH) for 3 months reduces median motor seizure frequency by 40% and median seizure frequency per month by 10.5 when compared with baseline (102323). Another small, observational open-label study in children 6-36 months of age with refractory infantile spasms shows that taking a specific synthetic cannabidiol product (Insys Development Company) for 14 days does not reduce spasms when compared with baseline (102324). The effect of a topical cannabidiol product has also been investigated in adults with drug-resistant focal seizures. One clinical study shows that topical application of cannabidiol 97.5 mg or 195 mg twice daily for 12 weeks is no more effective than placebo for reducing seizure frequency. However, in an open-label extension, doses of 195 mg or 390 mg twice daily resulted in about 61% of patients achieving a seizure reduction of at least 50%; benefits were maintained for at least 18 months (109173).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Anxiety. It is unclear if cannabidiol is beneficial for reducing test-related or other forms of anxiety. Details: Preliminary clinical research in college students who self-reported moderate to severe test anxiety shows that taking a single dose of cannabidiol 150 mg, 300 mg, or 600 mg does not reduce symptoms when compared with placebo (109185). This study may have been underpowered to detect a difference between groups. Other preliminary clinical research in patients with treatment-resistant anxiety shows that taking cannabidiol titrated from 200 mg daily up to 800 mg daily for 12 weeks reduces the severity of anxiety by 43% from baseline. There were also modest improvements in symptoms of depression. However, benefits were not maintained at a 6-month follow-up, and the validity of these findings is limited by the lack of a control group (109177). Additionally, the patients in this study were heterogenous, with almost 50% having social anxiety alone, and 40% having social anxiety in combination with other types of anxiety such as generalized anxiety disorder and/or panic disorder. Sublingual cannabidiol has also been investigated. A small, preliminary clinical trial in patients with moderate to severe anxiety shows that sublingual use of a solution providing cannabidiol 9.97 mg three times daily for 4 weeks modestly improves symptoms of anxiety, as well as sleep, quality of life, and some measures of cognition when compared with baseline. All patients responded to treatment. This product also contained low levels of delta-9-tetrahydrocannabinol (THC), providing a total of 0.69 mg daily, as well as cannabichromene, cannabigerol, and cannabinol (110245).
• Athletic performance. It is unclear if oral cannabidiol is beneficial for improving athletic performance. Details: A very small crossover study in endurance trained males undergoing a 60-minute run followed by a run to exhaustion suggests that taking a single dose of cannabidiol 300 mg (GD Cann®-C; GD Pharma Pty Ltd) 90 minutes before exercise does not improve athletic performance, and may increase oxygen consumption, when compared with placebo (108557). However, this study may not have been adequately powered to detect a difference between groups. Additionally, the washout period of 7 days may have been insufficient, as most individuals had detectable CBD levels during the crossover portion of this study.
• Atopic dermatitis (eczema). It is unclear if topical cannabidiol is beneficial for reducing eczema symptoms. Details: A small observational study in adults with eczema has found that applying a gel containing cannabidiol 1% in dimethicone and polysilicone-11 for 14 days modestly reduces overall symptoms and pruritus severity when compared with baseline (105498). This study is limited by its observational nature, short duration, and the lack of a control group.
• Bipolar disorder. Although there has been interest in using cannabidiol for bipolar disorder, there is insufficient reliable information about the clinical effects of cannabidiol for this purpose.
• Cachexia. Oral cannabidiol has only been evaluated as a component of a cannabis extract; its effect when used alone is unclear. Details: One clinical study in patients with cancer-related anorexia-cachexia syndrome shows that using a cannabis extract standardized to contain delta-9-tetrahydrocannabinol (THC) 2.5 mg and cannabidiol 1 mg twice daily for 6 weeks does not increase appetite when compared with placebo (61785). However, the substantial placebo effect and dropout rate in this study limits the reliability of these findings.
• Cancer-related fatigue. More research is needed to determine if non-inhaled cannabidiol is beneficial in patients with cancer-related pain that is not adequately controlled with standard treatment. Details: A small and preliminary clinical trial shows that taking cannabidiol (GD-Cann C, Norwood, South Australia) for 2 weeks does not improve tiredness or drowsiness when compared with placebo. The dose of cannabidiol started at 50 mg once daily and was titrated every third day up to a maximum of 200 mg three times daily (110247).
• Cancer-related pain. More research is needed to determine if non-inhaled cannabidiol is beneficial in patients with cancer-related pain that is not adequately controlled with standard treatment. Details: In 2021, the British Medical Journal published a clinical practice guideline for the use of medical cannabis and cannabinoids for chronic pain. This guideline states that the evidence weakly supports a trial of cannabinoids in conjunction with standard pain management in individuals with moderate to severe chronic pain and insufficient pain relief. Trials should begin with a low dose of cannabidiol titrated to effect, followed by the gradual addition of delta-9-tetrahydrocannabinol (THC), with a maximum daily dose of cannabidiol 40 mg and THC 40 mg (108698). This recommendation is based on evidence from four systematic reviews of research conducted in patients with various forms of chronic pain, including cancer-related pain, which suggest that using non-inhaled THC or cannabidiol for 1-4 months may modestly improve pain, physical function, and sleep, but not emotional, role, or social functions, when compared with standard treatment alone (108674). However, a meta-analysis of 5 clinical studies in patients with chronic, cancer-related pain receiving prescription opioids shows that using a specific oromucosal cannabis spray (Sativex, GW Pharmaceuticals), standardized to contain cannabidiol 2.5 mg and THC 2.7 mg per spray, for 2-5 weeks does not improve prescribed opioid consumption, sleep, or pain, and actually increases nausea and vomiting by 43% and 50%, respectively, when compared with opioids alone (108676). All studies instructed patients not to alter the prescribed opioid dose, which may have increased the risk for adverse effects such as nausea and vomiting. A small and preliminary clinical trial shows that taking cannabidiol (GD-Cann C, Norwood, South Australia) alone for 2 weeks does not reduce pain or opioid use when compared with placebo. The dose of cannabidiol started at 50 mg once daily and was titrated every third day up to a maximum of 200 mg three times daily (110247). More research is needed on the effect of cannabidiol alone.
• Cannabis use disorder. It is unclear if oral cannabidiol is beneficial for reducing cannabis use in patients with cannabis use disorder. Details: A small clinical study in patients with moderate cannabis use disorder shows that taking synthetic cannabidiol oil (STI Pharmaceuticals) 400 mg or 800 mg in two divided doses daily for 4 weeks seems to reduce overall cannabis consumption, as measured by 11-nor-9-carboxy-tetrahydrocannabinol (THC-COOH) urine levels, when compared with placebo. The 400 mg dose, but not the 800 mg dose, also seems to increase self-reported abstinence from cannabis by about 0.5 days per week when compared with placebo. A 200 mg daily dose demonstrated no effect (104500). An observational study in a small number of patients with cannabis use disorder has found that vaping cannabidiol daily for 12 weeks is associated with an approximately 50% reduction in daily cannabis use from baseline in 30% of patients. The mean amount of inhaled cannabidiol was 215.8 mg daily; however, dosing was increased at each visit based on withdrawal symptoms and cravings. All patients also used nicotine 6 mg/ml due to co-consumption of tobacco (109175). However, this study was small and uncontrolled and more than 50% of patients were lost to follow-up by 10 weeks.
• Chemotherapy-induced nausea and vomiting (CINV). It is unclear if a cannabis oromucosal spray or oral cannabis extract, providing standard doses of cannabidiol in combination with other ingredients, is beneficial for the prevention of CINV. Details: A small clinical study in patients receiving moderate-to-high emetogenic chemotherapy and still experiencing CINV despite conventional antiemetic prophylaxis shows that taking a cannabis extract (TN-TC11M) containing cannabidiol 2.5 mg and delta-9-tetrahydrocannabinol (THC) 2.5 mg three times daily during chemotherapy days 1-5 prevents CINV in 25% of patients, compared with 14% of patients receiving usual care. This means that 9 patients must be treated with this extract in order to prevent one case of CINV (104489). Limited research has also evaluated a cannabis oromucosal spray (Sativex, GW Pharmaceuticals) standardized to contain cannabidiol 2.5 mg and THC 2.7 mg per actuation. A very small clinical study shows that, when used in addition to a standard antiemetic regimen, 1-3 sprays after each daily chemotherapy infusion and then up to 8 sprays every 4 hours as needed for 4 days, prevents delayed CINV in 71% of patients, compared with only 22% of patients in the placebo group. There was no between-group difference in the occurrence of acute CINV, which was low in both groups (96814). This study is limited due to its small size and non-standardized treatment regimens. The effect of pure cannabidiol alone is unclear.
• Cocaine dependence. It is unclear if oral cannabidiol is beneficial for reducing anxiety in patients with cocaine use disorder. Details: An exploratory study in adults with severe cocaine use disorder, most of whom have an additional substance use disorder, shows that taking up to 800 mg of cannabidiol daily for 12 weeks does not improve overall anxiety, cortisol levels, or anxiety after a stressful cocaine-cue exercise when compared with placebo (108561). The validity of this finding is limited due to the high dropout rate of participants (36%); additionally, other substances such as cannabis, alcohol, opioids, and other stimulants were used by patients during the study period.
• Cognitive function. It is unclear if oral, sublingual, or inhaled cannabidiol improves cognitive function in healthy adults. Details: Most clinical research shows that cannabidiol does not improve cognitive function. However, the evidence is mixed, and most studies are small. A small clinical trial in patients with cannabis use disorder shows that taking cannabidiol 400 mg or 800 mg daily for 4 weeks does not improve most measures of cognitive function when compared to placebo (110251). Also, another small clinical trial in young, healthy adults shows that taking a single dose of cannabidiol 300 mg (Zatural, Eden, Idaho) does not improve most measures of cognition after 2 hours when compared with placebo (110250). Sublingual cannabidiol has also been investigated. A small, preliminary clinical trial in patients with moderate to severe anxiety shows that sublingual use of a solution providing cannabidiol 9.97 mg three times daily for 4 weeks modestly improves some measures of cognition when compared with baseline. This product also contained small amounts of delta-9-tetrahydrocannabinol (THC), providing a total of 0.69 mg daily, as well as small amounts of cannabichromene, cannabigerol, and cannabinol (110245). An observational study has found that working memory performance is similar among users and non-users of cannabidiol (107335). The effect of inhaled cannabidiol has also been investigated. A small clinical study in healthy young adults shows that vaping a single dose of cannabidiol 5% over 15 minutes for a total dose of 12.5 mg modestly improves episodic memory performance, but not attention or working memory performance, when compared with placebo (107326).
• Coronavirus disease 2019 (COVID-19). A small clinical study suggests that oral cannabidiol is not beneficial in patients with mild to moderate COVID-19. Details: A clinical study in patients with mild to moderate COVID-19 shows that taking cannabidiol 300 mg daily for 14 days has no effect on clinical deterioration when compared with placebo. Additionally, the median time to symptom resolution was 12 days in those receiving cannabidiol, compared with 9 days in those receiving placebo (107331).
• Crohn Disease. It is unclear if oral cannabidiol is beneficial for Crohn disease. Details: A small clinical study in adults with Crohn disease shows that taking cannabidiol oil 10 mg twice daily for 8 weeks does not alter disease activity or C-reactive protein levels when compared with placebo (97026). An additional small clinical study in patients with mild to moderate Crohn disease shows that using a cannabis oil containing cannabidiol 16% and delta-9-tetrahydrocannabinol (THC) 4% , titrated gradually to satisfactory response to a maximum of cannabidiol 160 mg twice daily before meals for 8 weeks, in conjunction with standard care such as corticosteroids, improves patient satisfaction and some symptoms such as abdominal pain and number of daily bowel movements, but does not improve disease activity scores or endoscopic findings, when compared with placebo (108678).
• Dementia. Oral cannabidiol has only been evaluated as a component of cannabis oil; its effect when used alone is unclear. Details: Preliminary clinical research in patients with dementia shows that taking cannabis oil (Avidekel, Tikun-Olam Cannbit Pharmaceuticals) providing cannabidiol 295 mg/mL and THC 12.5 mg/mL three times daily for 16 weeks results in a clinically significant reduction in agitation in 50% of patients, compared with only 15% of those taking placebo. Cannabidiol was titrated from one drop to 21 drops per administration over the first 6 weeks; the average intake of cannabidiol during the final 10 weeks of the study was 527.5 mg daily (109187).
• Diabetes. A small clinical study suggests that cannabidiol is not beneficial for improving glycemic control. Details: A small clinical study in adults with type 2 diabetes shows that taking cannabidiol 100 mg twice daily for 13 weeks does not improve plasma lipid levels, glycemic parameters, or markers of inflammation when compared with placebo (97021).
• Dyspepsia. It is unclear if oral cannabidiol is beneficial for dyspepsia. Details: A small clinical trial in patients with functional dyspepsia and normal gastric emptying shows that taking cannabidiol 10 mg/kg twice daily for 4 weeks does not reduce symptoms or improve gastric function when compared with placebo. Dosing started at 1.25 mg/kg twice daily and increased by daily doses of 2.5-5 mg/kg every other day, to a final total daily dose of 20 mg/kg (109176).
• Dystonia. It is unclear if oral cannabidiol is beneficial for dystonia of various etiologies. Details: A very small clinical study shows that taking cannabidiol 100-600 mg daily for 6 weeks improves dystonia by 20% to 50% when compared to baseline in patients with Meige syndrome, levodopa-induced dystonia, or primary dystonia (89700). However, the lack of a comparator group limits the validity of these findings.
• Essential tremor. It is unclear if oral cannabidiol is beneficial in adults with this condition. Details: A small clinical study in patients with essential tremor shows that taking a single oral dose of cannabidiol 300 mg does not reduce the severity of upper limb tremors at 60 or 210 minutes after ingestion when compared with placebo (104887).
• Exercise-induced muscle damage. It is unclear if oral cannabidiol helps to reduce muscle damage from exercise in untrained males. Details: A small clinical study in healthy, untrained males shows that taking cannabidiol oil 150 mg (Green Roads) in two divided doses daily for 4 days prior to performing maximal-strength muscle contractions does not affect muscle soreness, peak torque, arm circumference, or hanging joint angle when compared with placebo (104499). Also, a small clinical crossover study in 24 well-trained females shows that taking cannabidiol does not benefit performance or fatigue at 4 and 48 hours after strenuous eccentric exercise when compared with placebo. Cannabidiol 5 mg/kg was taken 2 hours prior, immediately after, and 10 hours after exercise (109180). Another small clinical crossover study in 16 healthy, trained athletes shows that taking a single cannabidiol dose of 60 mg after intensive strength training attenuates increases in creatine kinase and myoglobin levels and improves recovery of squat performance, but not countermeasure jump and reach test performance, after 72 hours when compared with placebo (106634).
• Fibromyalgia. Inhaled cannabidiol has only been evaluated as a component of a cannabis extract; its effect when used alone is unclear. Details: A small clinical study in female adults with fibromyalgia and chronic pain shows that a single vapor inhalation of cannabis containing cannabidiol 17.8 mg and delta-9-tetrahydrocannabinol (THC) 13.4 mg does not improve pain, electrical pain thresholds, or spontaneous pain scores when compared with placebo (101420).
• Fragile X syndrome. It is unclear if topical cannabidiol is beneficial in children with this condition. Details: A small clinical study in children with fragile X syndrome shows that applying cannabidiol gel to the skin twice daily for 12 weeks, titrated from a daily dose of 50 mg up to 250 mg, improves anxiety and behavioral symptoms such as hyperactivity, compulsiveness, and social avoidance when compared to baseline (100880). The validity of these results is limited by a lack of comparator group. A more recent clinical trial in children with fragile X syndrome given standard care shows that applying this product to the skin for 12 weeks does not improve social avoidance-related behavior when compared with placebo. However, in a sub-group of children at risk of the most severe symptoms, social and disruptive behaviors were modestly improved. The dose was 250 mg daily, or 500 mg daily for those over 35 kg (110243).
• Graft-versus-host disease (GVHD). It is unclear if cannabidiol prevents or delays GVHD. Details: A small prospective cohort study in adults receiving allogeneic bone marrow transplant has found that taking cannabidiol oil 150 mg twice daily, starting 7 days before transplantation and continuing for 30 days thereafter, in conjunction with standard GVHD prophylaxis, is associated with delayed development of grades II-IV GVHD prior to day 100, but not 12 months, when compared to historical controls. The median time to onset of GVHD was 60 days for those receiving cannabidiol and 20 days for the control group. All patients in this study had a 10/10 Human Leukocyte Antigen (HLA)-matched or 1-antigen-mismatched related or unrelated donor (97024).
• Huntington disease. It is unclear if oral cannabidiol is beneficial for this condition. Details: Preliminary clinical research in patients with Huntington disease shows that cannabidiol 10 mg/kg daily for 6 weeks does not improve chorea severity or other symptoms when compared with placebo (61832).
• Hypertension. Oral cannabidiol has only been evaluated as a component of a cannabis extract; its effect when used alone is unclear. Details: A very small study in older adults with hypertension shows that taking cannabis oil containing 2% to 20% cannabidiol and 1% to 10% delta-9-tetrahydrocannabinol (THC) , for an average total daily dose of about 21 mg of each cannabinoid, seems to modestly reduce blood pressure when compared with baseline (104480). The validity of this finding is limited by the lack of a control group and the non-standardized formulations and dosing used.
• Insomnia. Sublingual cannabidiol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical trial in patients with self-reported insomnia shows that using an investigational drug (ZLT-101; Zelira Therapeutics) containing cannabidiol 1 mg/mL, delta-9-tetrahydrocannabinol (THC) 20 mg/mL, and cannabinol (CBN) 2 mg/mL, taken as 0.5-1 mL sublingually one hour before sleep for 2 weeks, improves symptom severity and total sleep time when compared with placebo (108677). The validity of this finding is limited by the short duration of treatment.
• Irritable bowel syndrome (IBS). It is unclear if oral cannabidiol is beneficial for improving pain in IBS. Details: A small clinical study in adults with IBS shows that chewing gum containing cannabidiol 50 mg for at least 30 minutes while experiencing moderate to severe pain, as needed but not exceeding 6 times daily, over 3 weeks does not reduce abdominal pain when compared with a placebo gum (105558). This study is limited by small size and low reported use of the gum intervention due to the difficulty of chewing for the minimum required duration of 30 minutes.
• Multiple sclerosis (MS). A small clinical study suggests that oral cannabidiol improves pain and spasticity in patients with MS. Details: A small clinical study in patients with MS suggests that administering a sublingual cannabidiol spray, delivering cannabidiol 2.5 mg per actuation, as needed for 7 days, with a maximum daily dose of 120 mg, seems to improve self-reported pain and muscle spasm severity, but not other neurogenic symptoms, when compared with placebo (61720). The validity of this finding is limited by small study size and a lack of outcome adjustment for multiple comparisons.
• Neuropathic pain. It is unclear if oral cannabidiol is beneficial for neuropathic pain. Details: Clinical research shows that taking cannabidiol up to 50 mg alone or with delta-9-tetrahydrocannabinol (THC) up to 25 mg in two divided doses daily for 8 weeks does not reduce neuropathic pain of various etiologies or use of analgesics, when compared with placebo (110249).
• Obesity. It is unclear if an oral cannabidiol-rich hemp oil extract helps to improve weight loss. Details: A small clinical study in healthy overweight adults shows that taking a specific hemp oil extract (PlusCBD Extra Strength Hemp Extract) as 60 mg, providing 15 mg cannabidiol, daily for 6 weeks, does not reduce weight or body mass index when compared with placebo (103805). This study is limited due to its exploratory nature and because it did not control for dietary changes.
• Opioid withdrawal. It is unclear if cannabidiol is beneficial for reducing cravings associated with heroin use disorder. Details: A small clinical study in drug-abstinent adults with heroin use disorder shows that taking a specific oil-based solution (Epidiolex, GW Pharmaceuticals) of cannabidiol 400 or 800 mg daily for 3 days reduces cue-induced craving and anxiety acutely and for 7 days after the last cannabidiol dose when compared with placebo (99491). This study was limited by its small sample size and subjective primary outcomes. Furthermore, it is not clear if cannabidiol can prevent heroin use disorder relapse.
• Osteoarthritis. It is unclear if oral or topical cannabidiol is beneficial for improving pain in patients with osteoarthritis. Details: A clinical study in adults with joint disease, including hand osteoarthritis, and moderate pain intensity shows that adjunctive therapy with synthetic cannabidiol 20-30 mg daily for 12 weeks does not improve pain intensity in the previous 24 hours when compared with placebo (106635). However, a small clinical crossover trial in patients with thumb basal joint arthritis shows that topical cannabidiol 6.2 mg in shea butter twice daily for 2 weeks modestly improves pain and disability, but not strength, when compared with a shea butter placebo (109183).
• Pain (acute). Small clinical studies suggest that a single dose of oral cannabidiol does not reduce acute pain. Details: A clinical trial in adults presenting to the emergency department with acute low back pain shows that taking a single dose of cannabidiol (GD Pharma) 400 mg in a 4 mL oil solution, in addition to the standard treatment of acetaminophen 1000 mg with ibuprofen 400 mg, does not reduce pain, length of hospital stay, or need for rescue analgesia with oxycodone over 2 hours when compared with placebo (105492). Single doses of cannabidiol also do not seem to reduce experimentally-induced acute pain. Small clinical studies in healthy volunteers shows that taking a single dose of cannabidiol 800-1600 mg as an oil-solution 30-60 minutes prior to electrically-induced pain does not reduce acute pain intensity, hyperalgesia, or allodynia when compared with placebo (105500,108560). Another small clinical trial in healthy volunteers shows that taking a single dose of cannabidiol 200 mg, 400 mg, or 800 mg does not reduce pain severity or improve pain tolerance while submerging the left hand in cold water every hour for 8 hours when compared with placebo (105595).
• Pain (chronic). It is unclear if oral cannabidiol is beneficial for chronic pain. Details: A small observational cohort study has found that taking cannabidiol for 8 weeks is associated with reduced opioid use, as well as improved chronic pain and sleep quality (104498). However, due to the observational nature of the study, it is unclear if this is a direct result of cannabidiol use. Recent clinical practice guidelines for the use of cannabis and cannabinoid-based medicines for the management of chronic pain strongly recommend the use of cannabinoid-based medicines alone and/or as adjunct treatment for improvement of pain and in individuals with chronic pain not responsive to, or intolerant of, non-pharmacologic treatment. The guidelines indicate that cannabidiol-dominant products can be used in combination with delta-9-tetrahydrocannabinol (THC) in order to reduce adverse events; however, the strongest evidence of benefit comes from oral or inhaled formulations rich in THC, not cannabidiol. The evidence related to cannabidiol-predominant formulations for this purpose is unclear (110321).
• Parkinson disease. It is unclear if cannabidiol is beneficial for improving symptoms or reducing psychosis in adults with this condition. Details: A small clinical study in adults with Parkinson disease shows that taking a single dose of cannabidiol 300 mg attenuates anxiety and reduces tremor during a simulated public speaking test when compared with placebo (102328). Another very small study in adults with Parkinson disease and psychosis shows that taking flexible-dose cannabidiol starting at 150 mg daily for 4 weeks improves psychotic symptoms when compared to baseline (89689). Also, a small clinical study shows that taking cannabidiol (Epidiolex) titrated from 5 mg/kg to 20-25 mg/kg daily for 10-15 days reduces disease severity by 18% and movement disorders by 25% when compared with baseline (104884). The lack of comparator groups limits the validity of these findings.
• Peripheral neuropathy. It is unclear if oral cannabidiol is beneficial for neuropathic pain. Details: Clinical research in patients with neuropathic pain, mainly peripheral neuropathy, shows that taking cannabidiol up to 50 mg daily alone or with delta-9-tetrahydrocannabinol (THC) up to 25 mg daily in two divided doses daily for 8 weeks does not reduce pain or use of analgesics, when compared with placebo (110249). A small clinical study in adults with peripheral neuropathy of various etiologies shows that applying a specific emu oil product (Theramu Relieve, Theramu) containing cannabidiol, camphor, and eucalyptus leaf oil to symptomatic areas for 4 weeks modestly improves intense pain, sharp pain, and cold and itchy sensations when compared with a placebo emu oil (102329). It is possible that any benefit of this product is due to camphor. Camphor is approved by the US Food and Drug Administration (FDA) for topical use as an analgesic and anesthetic (272).
• Postoperative pain. Small clinical studies suggest that oral or topical cannabidiol may not significantly affect postoperative pain. Details: Clinical research in patients undergoing arthroscopic rotator cuff repair shows that taking a buccally-absorbed cannabidiol (Oravexx; Orcosa) in a weight-based dose for 14 days postoperatively modestly reduces pain the day after surgery, but not on postoperative days 2, 7, or 14, when compared with placebo. Opioid intake was low and not significantly different between groups. Patients who weighed less than 80 kg received cannabidiol 25 mg three times daily; others received cannabidiol 50 mg three times daily (109174). Topical cannabidiol has also been investigated. A clinical study in adults undergoing unilateral total knee arthroplasty shows that applying a topical formulation containing cannabidiol 120 mg per ounce three times daily around the knee, beginning on the day of surgery and continued for 2 weeks, does not improve pain, opioid consumption, or sleep scores when compared to patients applying a topical formulation containing arnica and wintergreen (108559). Additionally, an analysis of 6-week postoperative survey data among patients having undergone total hip or knee arthroplasty shows that self-directed cannabidiol use has no effect on pain satisfaction in the perioperative period when compared with patients who did not use cannabidiol (106636).
• Psoriatic arthritis. It is unclear if oral cannabidiol is beneficial for improving pain in patients with psoriatic arthritis. Details: A clinical study in adults with joint disease, including psoriatic arthritis, and moderate pain intensity shows that adjunctive therapy with synthetic cannabidiol 20-30 mg daily for 12 weeks does not improve pain intensity in the previous 24 hours when compared with placebo (106635).
• Psychological well-being. It is unclear if an oral cannabidiol-rich hemp oil extract improves psychological well-being in healthy patients. Details: An open-label clinical study in frontline hospital workers in Brazil during the COVID-19 pandemic shows that taking cannabidiol (PurMed Global) 150 mg, provided in 1 mL of medium-chain triglyceride oil, twice daily for 28 days in conjunction with standard care modestly reduces emotional exhaustion within 14 days of treatment, as well as symptoms of depression and anxiety within 7 days of treatment, when compared with standard care alone. Standard care included motivational and instructional videos and weekly meetings with a behavioral health provider (105696). The validity of these findings is limited by the lack of blinding and placebo control. Also, a small clinical study in healthy overweight adults shows that taking a specific hemp oil extract (PlusCBD Extra Strength Hemp Extract) as 60 mg, providing 15 mg cannabidiol, daily for 6 weeks seems to improve ability to cope with stress and general enjoyment of life when compared with placebo (103805). The validity of this study is limited by its exploratory nature.
• Psychosis. It is unclear if inhaling cannabidiol is beneficial in patients with acute psychosis. Details: A small open-label study in patients hospitalized with acute psychosis who have either schizophrenia or other psychotic disorders, as well as concomitant tobacco use disorder, shows that smoking cigarettes containing cannabidiol 20 mg and tobacco for 4 weeks as add-on therapy has no effect on positive and negative syndrome scale (PANSS) scores, subjective well-being, depressive symptoms, violence prediction assessment, or antipsychotic drug use when compared with smoking cigarettes containing tobacco only (107332).
• Post-traumatic stress disorder (PTSD). It is unclear if oral cannabidiol is beneficial in patients with PTSD. Details: A small study in patients with PTSD shows that taking high purity cannabidiol 300 mg attenuates cognitive impairment, but not anxiety, alertness, or discomfort, associated with recall of traumatic events when compared with placebo. Effects on cognitive impairment were sustained for at least 1 week after treatment (107334). It should be noted that patients receiving cannabidiol had more psychiatric comorbidities (e.g., depressive and/or anxiety disorders) at baseline.
• Rapid eye movement sleep behavior disorder (RBD). It is unclear if oral cannabidiol is beneficial for the management of Parkinson disease-related RBD. Details: One small clinical study in patients with RBD due to Parkinson disease shows that taking cannabidiol 75 mg nightly for one week, 150 mg nightly for the second week, and 300 mg nightly for the next 10 weeks does not reduce RBD behaviors or improve sleep when compared with placebo (105494).
• Rheumatoid arthritis (RA). It is unclear whether an oromucosal cannabis spray containing cannabidiol and delta-9-tetrahydrocannabinol (THC) improves RA symptoms. Details: A small clinical study in adults with RA shows that using a specific oromucosal cannabis spray (Sativex, GW Pharmaceuticals), containing cannabidiol 2.5 mg and THC 2.7 mg per actuation, daily for 5 weeks may help decrease morning pain and improve quality of sleep, but not joint stiffness or total pain intensity, when compared with placebo (61762). The effects of cannabidiol alone are unclear.
• Schizophrenia. Small clinical studies suggest that oral cannabidiol may modestly reduce symptoms and improve wellbeing in patients with schizophrenia or schizophreniform psychosis. Details: A small clinical trial in patients with acute paranoid schizophrenia or schizophreniform psychosis shows that taking cannabidiol 400 mg four times daily for 4 weeks modestly improves psychotic symptoms and cognition when compared to baseline and seems to be no better than taking the antipsychotic amisulpride 600-800 mg daily (89680,105497). Another small exploratory clinical trial in patients with schizophrenia shows that adding cannabidiol 1000 mg daily (as 10 mL of a 100 mg/mL solution) for 6 weeks to standard treatment modestly improves positive symptoms and wellbeing when compared with adding placebo to standard treatment (104014).
• Smoking cessation. It is unclear if cannabidiol helps to reduce cravings for cigarettes in patients attempting to quit smoking. Details: A small clinical study in cigarette smokers wishing to quit suggests that inhaling one spray of cannabidiol 400 mcg when craving a cigarette reduces the number of cigarettes smoked during one week by 40% when compared to baseline (89684). The validity of this finding is limited by small sample size, short study duration, and a lack of statistical comparison to the placebo group.
• Social anxiety disorder. It is unclear if oral cannabidiol is beneficial for reducing overall anxiety or anxiety during public speaking; the available research is conflicting. Details: A small clinical study in Japanese adolescents with social anxiety disorder shows that taking cannabidiol 300 mg daily for 4 weeks improves anxiety when compared with placebo (102326). However, other preliminary clinical research in patients with social anxiety disorder or panic disorder shows that taking cannabidiol (STI pharmaceuticals, UK or THC Pharm) 300 mg about 2 hours prior to each of eight separate cognitive behavioral therapy sessions does not improve symptoms when compared with placebo (109184). Research on the use of cannabidiol for anxiety associated with public speaking has yielded conflicting results. Small clinical studies demonstrate that taking CBD 300-600 mg as a single dose tends to reduce overall anxiety, but this reduction was noted only before or after, and not during, the speech in some subjects (89675,89909,99602). These differences may be due to small study size, baseline anxiety severity, and the use of non-standardized products. Also, cannabidiol does not seem to reduce speaking anxiety in patients at higher risk for psychiatric complications. One small clinical study in adults at high risk for psychosis shows that taking cannabidiol 600 mg daily for 8 days does not reduce anxiety during a simulated public speaking test when compared with placebo (102325).
• Temporomandibular disorders (TMD). A small clinical study suggests that topical cannabidiol may reduce TMD pain. Details: A small clinical study in adults with TMD shows that applying a 20% cannabidiol ointment topically over the masseter muscles twice daily for 14 days improves nerve activity as measured by surface electromyography when compared with placebo. The ointment also seems to reduce pain in the masseter muscle when compared with baseline. However, the validity of this finding is limited by the lack of statistical comparison to the placebo ointment (102327). More evidence is needed to rate cannabidiol for these uses.

(Read more about CANNABIDIOL (CBD))

LIKELY EFFECTIVE

• Irritable bowel syndrome (IBS). Oral enteric-coated peppermint oil is conditionally recommended by the American College of Gastroenterology (ACG) for the relief of global IBS symptoms, such as abdominal pain. Details: The ACG conditionally recommends the use of peppermint for the relief of global IBS symptoms. This recommendation is based on an available meta-analysis of generally low-quality clinical research (105124). Several clinical trials and meta-analyses show that taking enteric-coated peppermint oil 1-2 capsules orally two to four times daily reduces abdominal pain, distention, flatulence, and bowel movements in patients with IBS. Each capsule provides approximately 0.2 mL of peppermint oil or 180-225 mg peppermint oil. Most trials have used specific products (Colpermin, Tillotts Pharma; Mintoil, Cadigroup; Ibgard, IM HealthScience, Tempocol) (3802,3803,4469,11778,11779,17681,17682,68467,68515,68522)(68603,68604,68605,96360,99493,109980). The most recent meta-analysis to date shows that four patients would need to take peppermint oil to prevent one patient from having persistent IBS symptoms, and seven patients would need to take peppermint oil to prevent one patient from having abdominal pain. However, the individual studies included in the analysis lasted no more than 12 weeks (109980); any long-term effects are unclear. Although most studies have shown benefit for reducing symptoms, some older studies have found no significant effect (11777,11789) or only short-term benefits (68620). Also, a well-designed study shows that taking peppermint oil capsules designed for either small intestinal release (enteric-coated) or ileocolonic release does not increase the number of people with at least a 30% decrease in abdominal pain over a period of 4 weeks, although symptoms are modestly reduced when compared with placebo (102602). Another clinical trial in patients with moderate to severe IBS shows that taking a specific enteric-coated formulation of peppermint oil (Pepogest; Nature's Way) 180 mg three times daily for 6 weeks does not further improve symptom severity when compared with placebo. However, both groups experienced a large improvement on the IBS-Severity Scoring System (IBS-SSS) and the IBS Global Improvement Scale (107955). The validity of these findings is limited due to lost data and inconsistent follow-up; additionally, adverse effects occurred more frequently in the peppermint oil group. The reasons for these negative findings are unclear but may include short treatment durations and the use of different formulations; additionally, IBS is comprised of various subtypes and symptoms that can range in severity and presentation, which may alter treatment response. Some clinical research has also evaluated a specific combination product (Atrantil, KBS Research) containing peppermint leaf, red quebracho extract, and conker tree extract. Taking this product as needed for 2 weeks seems to reduce constipation and bloating when compared to baseline in patients with constipation-predominant IBS (95429,95430). It is unclear if the effects of this product are due to peppermint, the other ingredients, or the combination.

POSSIBLY EFFECTIVE

• Barium enema-related colonic spasm. Rectal peppermint, as part of barium enema preparations, seems to reduce colonic spasms during examination. Oral peppermint also seems to be beneficial. Details: Rectal use of peppermint oil, added as an ingredient in barium enema preparations, seems to relax the colon during barium enema examination and reduce the percentage of patients who experience colonic spasms by about 25% to 30% (6739,6749,12009). Adding peppermint oil to the barium enema seems to be at least as effective as using systemic scopolamine (Buscopan). Adding peppermint oil to the barium solution also does not seem to impair image quality (12009). Some clinical research also shows that taking peppermint oil orally before the start of a double-contrast barium enema examination decreases spasms and might also increase diagnostic quality (14467).
• Chemotherapy-induced nausea and vomiting (CINV). Oral and inhaled peppermint seem to reduce nausea and vomiting in patients with CINV. Details: Clinical research shows that adding peppermint oil, 40 drops in 20 mL water, every 8 hours following chemotherapy treatment to treatment with standard antiemetics reduces the severity of nausea, vomiting, and anorexia by moderate to large amounts over 48 hours when compared with a plain water placebo (105123). The use of peppermint oil aromatherapy has also been investigated. Clinical research shows that adding 2 drops of peppermint oil to a cool, damp washcloth for use on the neck as aromatherapy for about 30 minutes helps relieve chemotherapy-induced nausea by a small amount when compared with a washcloth without peppermint oil (102603). Additional clinical research in patients receiving standard antiemetics after chemotherapy shows that applying one drop of peppermint oil below the nose three times daily for 5 days reduces the severity of nausea and the frequency of nausea, vomiting, and retching by a moderate to large amount when compared with the antiemetics alone. These parameters were not improved following treatment with cisplatin (105122). In children with acute leukemia, a small clinical study shows that aromatherapy with 2 drops of peppermint oil and 3 drops of lemon oil in 80 mL of water diffused 30 minutes prior to and 2 and 4 hours after chemotherapy once weekly for 4 weeks decreases the severity of nausea, vomiting, and retching, and improves quality of life scores when compared with diffused water or no intervention (112015). The validity of these findings is limited by the use of patient-reported outcomes.
• Dyspepsia. Oral peppermint, in combination with caraway and possibly other ingredients, seems to reduce symptoms of dyspepsia. It is unclear if oral peppermint alone is beneficial. Details: Some clinical research shows that taking specific products containing peppermint and caraway oil (Enteroplant, Dr Willmar Schwabe Pharmaceuticals; Menthacarin, Dr Willmar Schwabe GmbH & Co.) improves quality of life and reduces symptoms of dyspepsia, including feelings of fullness, pain, and mild gastrointestinal spasms (6740,6741,10075,96344,102600). A meta-analysis of three of these clinical studies shows that taking this combination product 2-3 times daily for 4 weeks modestly reduces abdominal pain when compared with placebo (110091). Taking this combination twice daily for 4 weeks also improves postprandial distress syndrome and epigastric pain syndrome, two subtypes of dyspepsia, when compared with placebo (96344). The combination of enteric-coated peppermint oil 90 mg and caraway oil 50 mg appears to be comparable to cisapride for relieving dyspepsia when taken 2-3 times daily for up to 4 weeks (6740,6741,10075). However, most trials investigating this combination are small and/or of overall low quality (102600). A specific combination product containing peppermint leaf (Iberogast, Steigerwald Arzneimittelwerk GmbH) also seems to improve symptoms of dyspepsia. The combination includes peppermint leaf plus clown's mustard plant, German chamomile, caraway, licorice, milk thistle, angelica, celandine, and lemon balm (7049). A meta-analysis of studies using this combination product shows that taking 1 mL orally three times daily over a period of 4 weeks reduces the severity of acid reflux, epigastric pain, cramping, nausea, and vomiting when compared with placebo (13089). A similar combination product containing extracts from peppermint leaf, clown's mustard plant, German chamomile flower, caraway, licorice root, and lemon balm (STW 5-II, Steigerwald Arzneimittelwerk GmbH) 1 mL taken three times daily for up to 8 weeks eliminates gastrointestinal symptoms in 40% more dyspepsia patients when compared with placebo (12724).
• Endoscopy-associated adverse effects. Intraluminal peppermint seems to reduce spasticity during an endoscopy. It is unclear if oral peppermint is beneficial for reducing adverse effects related to endoscopy. Details: A meta-analysis of four clinical trials show that peppermint oil, administered orally or intraluminally, reduces the incidence of spasticity by about 41% when compared with placebo in patients undergoing endoscopy, with severe spasticity occurring at about 30% the rate of those taking placebo. However, there was no effect on subjective pain (102604). Individual clinical studies show that intraluminal peppermint oil can reduce both pain and spams in patients undergoing endoscopy (18220,68371,68395,68445,68532). However, there are limitations with this form of administration, including cost and practicality, which has led to interest in the use of oral formulations (104221). Studies evaluating oral extended-release peppermint have been conflicting. While one study shows that a specific extended-release peppermint oil product (Colpermin) 187 mg or 0.2 mL taken orally 4 hours prior to a colonoscopy reduces procedure time, pain, and spasticity (68532), a study using another specific extended-release peppermint oil (IBGard) did not show an effect on colonic spasms, procedure time, or adenoma detection rate when compared with placebo (104221). These differing outcomes may be due to timing of administration. The study that showed benefit administered the treatment 4 hours prior to endoscopy, whereas the study showing no benefit administered the treatment only 1 hour prior. This suggests that extended-release peppermint may need to be administered at least 4 hours prior to the procedure to allow for adequate colonic release (68532,102604,104221).
• Nipple fissures. Topical peppermint seems to reduce cracked skin and pain in the nipples due to breastfeeding. Details: Clinical research shows that topical application of peppermint oil in gel or water reduces cracked skin and pain in the nipple area from breastfeeding when compared with using placebo, lanolin, or the expressed breast milk technique (68454,68462). Other research shows that applying peppermint oil in cream immediately after breastfeeding for 2 weeks decreases pain and trauma in the nipple area similarly to the topical application of dexpanthenol or lanolin (96365).
• Pressure ulcers. Topical peppermint seems to reduce the risk of pressure ulcers. Details: Clinical research in bedridden patients shows that prophylactic application of a topical gel containing peppermint oil 0.2% three times daily for up to 14 days results in pressure injuries in about 23% of patients compared with 77% of those given a placebo gel (102605).
• Tension headache. Topical peppermint seems to relieve tension headaches. Details: Clinical research shows that topical application of peppermint oil 10% relieves tension headaches when compared with placebo (3801,6190).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Abdominal pain. Although there has been interest in using oral peppermint for abdominal pain, there is insufficient reliable information about the clinical effects of peppermint for this condition.
• Anxiety. It is unclear if inhaled peppermint oil is beneficial for reducing anxiety. Details: A clinical trial in patients presenting to the emergency department for an acute coronary syndrome event shows that placing 3 drops of peppermint oil on a cotton ball and inhaling for 1 hour improves anxiety and respiratory rate when compared with baseline or placebo (107958). Due to the single-dose nature of this study, the effects of repeated inhalation of peppermint oil are unclear.
• Breast cancer-related hot flashes. It is unclear if topical peppermint is beneficial for reducing hot flashes in patients with breast cancer. Details: Preliminary clinical research shows that using a spray containing a combination of peppermint and neroli hydrolat does not alleviate hot flashes in most patients receiving chemotherapy for breast cancer when compared with using a plain water spray (68481).
• Cognitive function. It is unclear if inhaled peppermint oil is beneficial for improving cognitive function. Details: Preliminary clinical research shows that inhalation of peppermint oil slightly improves memory and the performance of cognitive tasks such as typing, alphabetization, and ordering, but not attention and speed of task completion, when compared with control (56954,68416,68466).
• Common cold. Although there has been interest in using oral, topical, or inhaled peppermint for the common cold, there is insufficient reliable information about the clinical effects of peppermint for this condition.
• Dental plaque. Topical peppermint has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that rinsing the mouth for one minute with 10 mL of a specific combination product (HiOra, Himalaya Herbal Healthcare) containing peppermint oil and numerous other ingredients twice daily for two days reduces plaque index or plaque area when compared with placebo; however, it was not as effective as chlorhexidine 0.2% solution (68530). It is unclear if these effects are due to peppermint oil, other ingredients, or the combination.
• Diffuse esophageal spasm. It is unclear if oral peppermint oil is beneficial for diffuse esophageal spasm. Details: A small exploratory study in adults with diffuse esophageal spasm shows that drinking a solution of peppermint oil, 5 drops in 10 mL of water, can resolve esophageal contractions when compared with baseline (13415). The validity of this finding is limited by the lack of a comparator group.
• Dysmenorrhea. It is unclear if oral peppermint oil is beneficial for reducing menstrual pain. Details: Preliminary clinical research shows that taking three capsules of peppermint oil (Colpermin; Tillotts Company or Razak company) daily for 3 days, starting on the first day of menstruation, is as effective as mefenamic acid 250 mg three times daily for reducing pain, and more effective for reducing nausea and vomiting, associated with dysmenorrhea. However, mefenamic acid was more effective for reducing bleeding and analgesic use (105125).
• Fatigue. It is unclear if inhaled peppermint oil improves fatigue in patients with cardiac disease. Details: A clinical trial in hospitalized patients with various forms of cardiac disease shows that placing 3 drops of peppermint oil on a cotton ball and inhaling for 20 minutes nightly for 7 days improves fatigue scores when compared with placebo. These improvements were similar to those seen with lavender oil inhalation. Fatigue scores decreased by 24 and 21 points in the peppermint and lavender groups, respectively, compared with a 2-point reduction in the placebo group (107959). The validity of these findings is limited due to the short duration of treatment.
• Halitosis. Peppermint has only been evaluated in combination with other ingredients as a mouthwash; its effect when used alone is unclear. Details: Preliminary clinical research shows that rinsing the mouth with a specific combination of tea tree oil, peppermint, and lemon essential oil once for three minutes improves breath smell when compared with placebo or benzydamine hydrochloride (19177).
• Insomnia. It is unclear if inhaled peppermint oil is beneficial for insomnia. Details: Preliminary clinical research in cancer patients shows that receiving aromatherapy as three drops of peppermint oil applied to a cotton ball and attached to the collar for 20 minutes at bedtime for one week improves sleep when compared with baseline. However, it seems to be no better than using lavender oil aromatherapy or using a control of lavender oil 1% (103063).
• Menopausal symptoms. Although there has been interest in using inhaled peppermint oil for menopausal symptoms, there is insufficient reliable information about the clinical effects of peppermint for this condition.
• Migraine headache. It is unclear if intranasal peppermint oil is beneficial for migraine headache. Details: Preliminary clinical research shows that using 1-2 doses of intranasal peppermint oil 1.5% (Poursina Company) at the start of migraine pain is as effective as intranasal lidocaine 4%, and more effective than placebo, for reducing migraine headache intensity. Approximately 42% of those using peppermint oil indicated a high level of headache reduction, compared with 42% of those using lidocaine and 5% of those using placebo. Also, pain relief was felt within 5 minutes in more patients using peppermint than placebo (105126). However, it is unclear if participants were truly blinded to the use of peppermint oil.
• Mosquito repellent. Although there has been interest in using topical peppermint oil as a mosquito repellent, there is insufficient reliable information about the clinical effects of peppermint for this purpose.
• Myalgia. Although there has been interest in using topical peppermint oil for myalgia, there is insufficient reliable information about the clinical effects of peppermint for this condition.
• Oral mucositis. Topical peppermint has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in adults undergoing stem cell transplantation shows that using an oral rinse containing peppermint oil and German chamomile three times daily, in addition to standard treatment with sodium chloride and chlorhexidine, reduces the duration and severity of mucositis and the use of narcotic analgesics when compared with placebo and standard treatment. However, this oral rinse does not reduce or delay the occurrence of mucositis or affect the duration of hospitalization (96363). Another small clinical study in adults with head and neck cancers undergoing radiation shows that rinsing with 5 mL of a polyherbal mouthwash containing peppermint oil, German chamomile, aloe vera, and honey for 1 minute 3 times daily for 6 weeks reduces oral mucositis incidence, severity, and pain when compared with chlorhexidine 0.2% and placebo (111291). Clinical research in adults receiving treatment with 5-fluorouracil shows that using an oral rinse containing peppermint, sage tea, and thyme in addition to basic oral care, starting on the first day of chemotherapy and continuing for 14 days, delays the onset of mucositis, but not the rate or severity of mucositis, when compared with basic oral care alone (96364). It is unclear if these effects are due to peppermint oil, other ingredients, or the combinations.
• Osteoarthritis. Although there has been interest in using topical peppermint oil for osteoarthritis, there is insufficient reliable information about the clinical effects of peppermint for this condition.
• Pain (acute). It is unclear if inhaled peppermint oil is beneficial for acute pain. Details: Preliminary clinical research in cardiac patients shows that peppermint oil aromatherapy reduces pain associated with intravenous catheterization by a small amount when compared with a distilled water control (102601).
• Postherpetic neuralgia. Although there has been interest in using topical peppermint oil for postherpetic neuralgia, there is insufficient reliable information about the clinical effects of peppermint for this condition.
• Postoperative ileus. It is unclear if oral peppermint oil is beneficial for the prevention of postoperative ileus. Details: Clinical research shows that taking a specific peppermint oil product (Colpermin, Tillotts Pharma) as two capsules three times daily for 5 days after routine gynecological surgery does not prevent postoperative abdominal distension and dyspepsia when compared with placebo (68602). Conversely, a small clinical study in patients undergoing elective cesarean section shows that taking 20 drops of peppermint oil 4 hours after surgery and then hourly for a total of three doses reduces the time to first bowel sounds by around 3.3 hours, first flatulence by 4.4 hours, and first stool by 5 hours when compared with placebo (110092).
• Postoperative nausea and vomiting (PONV). Some preliminary clinical studies suggest that inhaled peppermint may be beneficial for PONV. However, it is unclear if the benefit is due to aromatherapy or improved breathing patterns. Details: Some preliminary clinical research shows that using peppermint aromatherapy helps relieve postoperative nausea (3804,13415,68524,104219,104220). Inhaling peppermint oil 10% and 30% as aromatherapy reduces the severity of nausea when compared with placebo, with no significant difference between concentrations (104220). Small clinical trials show improvement in PONV within the first 4 hours after surgery. However, this effect diminishes beyond 4 hours (104219). Other preliminary clinical research shows that peppermint oil aromatherapy is no more effective for reducing postoperative nausea than inhaling isopropyl alcohol or saline (13416,68529). It is possible that any relief of postoperative nausea observed with peppermint aromatherapy results from improved breathing patterns after surgery rather than peppermint oil itself (13416,90512). One small study shows that inhaling peppermint oil while practicing controlled breathing does not appear to relieve PONV better than practicing controlled breathing alone (90512). Some preliminary clinical research shows that inhaling vapors from a mixture of peppermint, ginger, spearmint, and cardamom essential oils reduces symptoms of postoperative nausea in approximately 15% more patients when compared with inhaling ginger essential oils alone, and in approximately 43% more patients when compared with inhaling saline (89888). However, it is not clear if the effect is due to peppermint, the other oils, or the combination.
• Pre-procedural anxiety. It is unclear if inhaled peppermint oil is beneficial for reducing anxiety prior to a medical procedure. Details: Preliminary clinical research in cardiac patients shows that peppermint oil aromatherapy does not reduce anxiety associated with intravenous catheterization when compared with a distilled water control (102601).
• Pregnancy-induced nausea and vomiting. Inhaled peppermint oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that aromatherapy with a mixture of 5% lemon and 5% peppermint essential oils modestly reduces the intensity of nausea and vomiting on days 2-4, but not day 1, when compared with placebo aromatherapy. When nauseated, patients placed three drops of the essential oil mixture (Barij Essence Co.) onto a cotton ball held 3 cm from the nose. This action could be repeated after 5 minutes if needed (105121).
• Pruritus. Some preliminary clinical studies suggest that topical peppermint oil improves itching of various etiologies. Details: Preliminary clinical research in adults with renal, hepatic, or diabetic pruritus shows that topical application of peppermint oil 5% in petrolatum twice daily for 2 weeks improves symptoms of pruritus when compared with petrolatum alone (96361). Preliminary clinical research in patients with severe or intractable pruritus secondary to burn scars shows that applying a specific product (Chongqing No.1, CQ-01, MJ Medical Gel Systems Ltd.) containing peppermint oil 3.6%, menthol 1.4%, and methyl salicylate 2.5%, covered with gauze for 24 hours, reduces the severity of pruritus for up to 7 days after application when compared with hydrogel covered with gauze or with gauze alone (96362). Preliminary clinical research in females experiencing itchy skin due to intrahepatic cholestasis of pregnancy also shows that applying peppermint oil 0.5% in sesame oil twice daily for 2 weeks reduces pruritus severity approximately 1.8-fold when compared with sesame oil alone (89478).
• Small intestinal bacterial overgrowth (SIBO). Although there has been interest in using oral peppermint for SIBO, there is insufficient reliable information about the clinical effects of peppermint for this condition.
• Stress. It is unclear if inhaled peppermint oil is beneficial for stress. Details: Clinical research shows that peppermint aromatherapy decreases physical and perceived levels of stress when compared with baseline (68422,68517). A small clinical study in adults undergoing a virtual reality (VR) driving scenario to test road rage shows that exposure to peppermint oil (Pure Essential Oil of Peppermint, Tisserand Aromatherapy) 5 drops via fan diffuser improves aggressive driving behavior scores but does not seem to improve self-reported stress, aggression, alertness, happiness, or calmness when compared with controls that did not receive aromatherapy during the VR session (112017).
• Toothache. Although there has been interest in using topical peppermint oil for toothache, there is insufficient reliable information about the clinical effects of peppermint for this condition.
• Urticaria. Although there has been interest in using topical peppermint oil for urticaria, there is insufficient reliable information about the clinical effects of peppermint for this condition. More evidence is needed to rate peppermint for these uses.

(Read more about PEPPERMINT)

POSSIBLY EFFECTIVE

• Back pain. Oral willow bark extract has been evaluated for the treatment of back pain, with promising results. Details: Clinical research in patients with chronic low back pain shows that taking a standardized willow bark extract providing salicin 120 mg or 240 mg daily for 4 weeks reduces lower back pain and decreases the need for rescue analgesia when compared with placebo. Salicin 240 mg appears to be more effective than salicin 120 mg, and significant pain relief may be observed after 1 week of high-dose use (6456). Additional research suggests that taking willow bark extract providing salicin 240 mg daily for 4 weeks is as effective as rofecoxib (Vioxx) for lower back pain (12804).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Ankylosing spondylitis. Although there has been interest in using oral willow bark for pain associated with ankylosing spondylitis, there is insufficient reliable information about the clinical effects of willow bark for this purpose.
• Common cold. Although there has been interest in using oral willow bark for common cold symptoms, there is insufficient reliable information about the clinical effects of willow bark for this purpose.
• Dysmenorrhea. Although there has been interest in using oral willow bark for dysmenorrhea, there is insufficient reliable information about the clinical effects of willow bark for this purpose.
• Gout. Although there has been interest in using oral willow bark for gout, there is insufficient reliable information about the clinical effects of willow bark for this purpose.
• Headache. Although there has been interest in using oral willow bark for headache, there is insufficient reliable information about the clinical effects of willow bark for this purpose.
• Influenza. Although there has been interest in using oral willow bark for pain and fever associated with influenza, including swine flu, there is insufficient reliable information about the clinical effects of willow bark for this purpose.
• Joint pain. Oral willow bark has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with joint pain shows that taking capsules of a specific combination product (Instaflex Joint Support, Direct Digital) containing glucosamine sulfate 500 mg, methylsufonlylmethane 167 mg, white willow bark extract 83 mg, ginger root concentrate 17 mg, boswellia extract 42 mg, turmeric root extract 17 mg, cayenne 40 m H.U. 17 mg, and hyaluronic acid 1.3 mg three times daily for 8 weeks reduces joint pain severity by 37% compared to only 16% with placebo. However, the specific combination product does not appear to significantly improve joint stiffness or function when compared with placebo (89560). It is unclear if these findings are due to willow bark, other ingredients, or the combination.
• Myalgia. Although there has been interest in using oral willow bark for myalgia, there is insufficient reliable information about the clinical effects of willow bark for this purpose.
• Obesity. Oral willow bark has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research suggests that willow bark in combination with ephedra and cola nut might cause modest weight loss in overweight and obese people. Willow bark 600 mg daily (containing 90 mg salicin) in divided doses given for 3 months in combination with these central nervous system stimulants might cause a 2 kg reduction in weight (12811). However, this combination may not be appropriate due to safety concerns associated with ephedra. Ephedra is banned in the US due to severe adverse effects (10055).
• Osteoarthritis. Small clinical studies suggest that oral willow bark extract may improve symptoms of osteoarthritis, although some conflicting evidence exists. Details: Some preliminary clinical research in patients with osteoarthritis shows that taking willow bark extract standardized to contain 240 mg of salicin daily for 2 weeks produces moderate analgesic activity when compared with placebo (12474,86490). Additional research shows that taking a specific willow bark extract (Optovit actiFLEX, Hermes Arzneimittel GmbH) standardized to contain salicin 120-240 mg daily for 6 weeks improves swelling, tenderness, and physical function similarly to conventional non-steroidal anti-inflammatory drugs (NSAIDs) (91406). However, other research shows that taking willow bark extract standardized to 240 mg of salicin daily for 6 weeks does not improve pain, stiffness, or physical function when compared with placebo (12475).
• Rheumatoid arthritis (RA). It is unclear if oral willow bark is beneficial in patients with RA. Details: Clinical research in a small number of patients with RA shows that willow bark extract standardized to 240 mg of salicin daily for 6 weeks does not improve pain when compared with placebo (12475). However, it is possible this study was underpowered to detect a significant difference in pain in these patients. More evidence is needed to rate willow bark for these uses.

(Read more about WILLOW BARK)

POSSIBLY SAFE ...when used orally and appropriately in adults. Cannabidiol doses up to 200 mg daily have been used with apparent safety for up to 13 weeks (97021,105559), while higher doses of 700 mg daily for up to 6 weeks and 1200 mg daily for up to 4 weeks have been used with apparent safety (89680,105559). A prescription cannabidiol oil (Epidiolex, GW Pharmaceuticals) has been safely used in doses of 10-25 mg/kg daily, titrated based on response and tolerability (97979,97980,99613,105495,106631). There is insufficient reliable information available about the safety of cannabidiol when used topically.

CHILDREN: POSSIBLY SAFE
when a prescription cannabidiol oil (Epidiolex, GW Pharmaceuticals) is used orally and appropriately. This cannabidiol product has been safely used in clinical research at doses of 2-50 mg/kg daily in children 1 year of age and older. However, the maximum recommended dosage of this product is 12.5 mg/kg twice daily (25 mg/kg/day); higher doses seem to carry a higher risk for adverse effects. Epidiolex is titrated based on response and tolerability (97017,97018,97019,97022,97025,97979,97980,99613,103038,105495,106631,106633). There is insufficient reliable information available about the safety of other forms of cannabidiol in children.

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally. The US Food and Drug Administration (FDA) strongly advises against the use of cannabidiol during pregnancy. Cannabidiol products might contain delta-9-tetrahydrocannabinol (THC) or other contaminants such as pesticides, heavy metals, bacteria, and fungus, which can be dangerous to the child (100891,109172). Also, animal research shows that high levels of cannabidiol can damage the reproductive system of male offspring (100891).

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LIKELY SAFE ...when peppermint oil is used orally, topically, or rectally in medicinal doses. Peppermint oil has been safely used in multiple clinical trials (3801,3804,6190,6740,6741,10075,12009,13413,14467,17681)(17682,68522,96344,96360,96361,96362,96363,96364,96365,99493).

POSSIBLY SAFE ...when peppermint leaf is used orally and appropriately, short-term. There is some clinical research showing that peppermint leaf can be used safely for up to 8 weeks (12724,13413). The long-term safety of peppermint leaf in medicinal doses is unknown. ...when peppermint oil is used by inhalation as aromatherapy (7107). There is insufficient reliable information available about the safety of using intranasal peppermint oil.

CHILDREN: POSSIBLY SAFE
when used orally for medicinal purposes. Enteric-coated peppermint oil capsules have been used with apparent safety under medical supervision in children 8 years of age and older (4469).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (96361). There is insufficient information available about the safety of using peppermint in medicinal amounts during pregnancy or lactation; avoid using.

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POSSIBLY SAFE ...when used orally and appropriately, short-term. Willow bark has been used safely for up to 12 weeks (6456,12474,12475,12804,12811,86473,91406).

CHILDREN: POSSIBLY UNSAFE
when used orally for viral infections. Salicylic acid and aspirin are contraindicated in children with viral infections (12801). Although Reye's syndrome has not been reported, the salicin constituent in willow bark is similar to aspirin and might pose the same risk.

PREGNANCY:
Insufficient reliable information available; avoid using.

LACTATION: POSSIBLY UNSAFE
when used orally. Willow bark contains salicylates which are excreted in breast milk and have been linked to adverse effects in breast-fed infants (12802,12803).

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BRIVARACETAM (Briviact) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Cannabidiol might increase brivaracetam levels.  Details Brivaracetam is a substrate of CYP2C19. Clinical research shows that cannabidiol inhibits CYP2C19 (89694,89695,97018,97022). Evidence from a case series shows that patients receiving cannabidiol experienced a 95% to 280% increase in brivaracetam levels (100881).

CAFFEINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Cannabidiol can increase caffeine levels.  Details A pharmacokinetic study in healthy adults shows that taking oral cannabidiol, starting at 250 mg once daily and titrating to 750 twice daily over a total of 24 days, increases the peak serum level of caffeine by 15% and the overall exposure to caffeine by 95% after a single dose of caffeine 200 mg taken on day 23. Caffeine is a substrate of CYP1A2, and cannabidiol has been shown to inhibit CYP1A2 metabolism (105557).

CARBAMAZEPINE (Tegretol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Cannabidiol might increase carbamazepine levels.  Details Research in murine animal models shows that giving a single oral dose of cannabidiol 50 mg/kg with carbamazepine 80 mg/kg increases carbamazepine's'area under the curve (AUC) by 53% when compared with control. A higher single dose of cannabidiol 120 mg/kg has a similar effect on carbamazepine levels. Multiple doses of cannabidiol have a slightly larger effect. Giving cannabidiol daily for 14 days increases the AUC of carbamazepine by 66% (103033).

CITALOPRAM (Celexa) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Cannabidiol can increase citalopram levels.  Details A small open-label study in young adults stabilized on citalopram or escitalopram shows that taking adjunctive cannabidiol 200-800 mg daily for 12 weeks increases plasma concentrations of citalopram from an average of 42 ng/mL at baseline to an average of 79 ng/mL at 8 weeks and 63 ng/mL at 12 weeks. Patients reported fatigue and gastrointestinal disturbances; there were no reports suggestive of serotonergic toxicity. In vitro evidence suggests that this interaction may be due to inhibition of cytochrome P450 (CYP) 2C19 and 3A4 by cannabidiol (105491). This finding is limited due to small study size and large interindividual variability.

CLOBAZAM (Onfi) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = A Cannabidiol might increase levels of clobazam and increase the occurrence of somnolence.  Details In clinical studies, concomitant administration of cannabidiol and clobazam is associated with up to a 60% increase in serum levels of N-desmethylclobazam, the primary active metabolite of clobazam. This increased concentration is likely due to inhibition of CYP2C19 by cannabidiol. However, the interaction does not appear to be dose-dependent. In children and adults, concomitant use of cannabidiol and clobazam is associated with an increased occurrence of somnolence (97018,97022,97023,97979,97980,106631).

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cannabidiol might have additive effects if used with other CNS depressants.  Details Preliminary clinical research, case reports, and animal studies suggest that high dose cannabidiol has sedative and hypnotic effects (61989,89986,89987,110248). Theoretically, concomitant use of cannabidiol with drugs with sedative and anesthetic properties may cause additive therapeutic and adverse effects.

CYTOCHROME P450 1A1 (CYP1A1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cannabidiol might increase levels of drugs metabolized by CYP1A1.  Details In vitro research shows that cannabidiol inhibits CYP1A1 (89690). However, this interaction has yet to be reported in humans. Until more is known, use with caution. Theoretically, concomitant use of cannabidiol with CYP1A1 substrates might decrease the clearance of these substrates and increase the risk for adverse effects.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Cannabidiol can increase levels of drugs metabolized by CYP1A2.  Details In vitro research shows that cannabidiol inhibits CYP1A2 (89690,107325). Furthermore, cannabidiol has been shown to inhibit the metabolism of caffeine, a CYP1A2 substrate, in humans. A pharmacokinetic study in healthy adults shows that taking cannabidiol, starting at 250 mg once daily and titrating to 750 twice daily over a total of 24 days, increases the peak serum level of caffeine by 15% and the overall exposure to caffeine by 95% after a single dose of caffeine 200 mg taken on day 23 (105557).

CYTOCHROME P450 1B1 (CYP1B1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cannabidiol might increase levels of drugs metabolized by CYP1B1.  Details In vitro research shows that cannabidiol inhibits CYP1B1 (89690). However, this interaction has yet to be reported in humans. Until more is known, use with caution. Theoretically, concomitant use of cannabidiol with CYP1B1 substrates might increase the risk for adverse effects from these substrates.

CYTOCHROME P450 2A6 (CYP2A6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cannabidiol might increase levels of drugs metabolized by CYP2A6.  Details In vitro research shows that cannabidiol inhibits CYP2A6 (89691). However, this interaction has yet to be reported in humans. Until more is known, use with caution. Theoretically, concomitant use of cannabidiol with CYP2A6 substrates might increase the risk for adverse effects from these substrates.

CYTOCHROME P450 2B6 (CYP2B6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cannabidiol might increase levels of drugs metabolized by CYP2B6.  Details In vitro research shows that cannabidiol inhibits CYP2B6 (89691,107325). However, this interaction has yet to be reported in humans. Until more is known, use with caution. Theoretically, concomitant use of cannabidiol with CYP2B6 substrates might increase the risk for adverse effects from these substrates.

CYTOCHROME P450 2C19 (CYP2C19) INDUCERS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, CYP2C19 inducers might decrease cannabidiol levels.  Details Cannabidiol is a substrate of CYP2C19 enzymes (99613). Theoretically, drugs that induce CYP2C19 enzymes might decrease the levels and effects of cannabidiol.

CYTOCHROME P450 2C19 (CYP2C19) INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, CYP2C19 inhibitors might increase cannabidiol levels.  Details Cannabidiol is a substrate of CYP2C19 enzymes (99613). Theoretically, drugs that inhibit CYP2C19 enzymes might increase levels of cannabidiol, increasing its effects and adverse effects.

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Cannabidiol might increase levels of drugs metabolized by CYP2C19.  Details Research shows that cannabidiol inhibits CYP2C19 (89694,89695,97018,97022,107325). In clinical studies and case reports, cannabidiol use resulted in significant increases in the serum levels of topiramate, methadone, citalopram, and N-desmethylclobazam, the primary active metabolite of clobazam. These chemicals are metabolized by CYP2C19 (97018,97022,97023,102958,105491). Concomitant use of cannabidiol with CYP2C19 substrates might increase the risk for adverse effects from these substrates.

CYTOCHROME P450 2C8 (CYP2C8) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cannabidiol might increase levels of drugs metabolized by CYP2C8.  Details In vitro research shows that cannabidiol inhibits CYP2C8 (99613). However, this interaction has yet to be reported in humans. Until more is known, use with caution. Theoretically, concomitant use of cannabidiol with CYP2C8 substrates might increase the risk for adverse effects from these substrates.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, cannabidiol might increase levels of drugs metabolized by CYP2C9.  Details In vitro and animal research shows that cannabidiol inhibits CYP2C9 (89694,89695,107325). In human studies, cannabidiol has been associated with an increase in plasma levels of topiramate, a CYP2C9 and CYP2C19 substrate (97018). However, this effect has not been confirmed with other CYP2C9 substrates in humans. Theoretically, concomitant use of cannabidiol with CYP2C9 substrates might increase the risk for adverse effects from these substrates.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cannabidiol might increase levels of drugs metabolized by CYP2D6.  Details In vitro research shows that cannabidiol inhibits CYP2D6 (89692,107325). Theoretically, concomitant use of cannabidiol with CYP2D6 substrates might increase the risk for adverse effects from these substrates.

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cannabidiol might increase levels of drugs metabolized by CYP2E1.  Details In vitro research shows that cannabidiol inhibits CYP2E1 (107325). So far, this interaction has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) INDUCERS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, CYP3A4 inducers might decrease cannabidiol levels.  Details Cannabidiol is a substrate of CYP3A4 enzymes (99613). Theoretically, drugs that induce CYP3A4 enzymes might reduce the levels and effects of cannabidiol.

CYTOCHROME P450 3A4 (CYP3A4) INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, CYP3A4 inhibitors might increase cannabidiol levels.  Details Cannabidiol is a substrate of CYP3A4 enzymes (99747). Theoretically, drugs that inhibit CYP3A4 enzymes might increase levels of cannabidiol, increasing its effects and adverse effects.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Cannabidiol might increase levels of drugs that are metabolized by CYP3A4.  Details In vitro and animal research shows that cannabidiol inhibits CYP3A4 (89693,89694,89695,107325). In human studies and case reports, cannabidiol has been associated with an increase in plasma levels of the CYP3A4 substrates zonisamide, tacrolimus, everolimus, citalopram, and methadone (97018,100884,100892,102958,105491).

ESLICARBAZEPINE (Aptiom) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = B Cannabidiol might increase eslicarbazepine levels.  Details In clinical research, concomitant administration of cannabidiol and eslicarbazepine is associated with a modest increase in plasma levels of eslicarbazepine. The mechanism for this interaction is unknown; eslicarbazepine is metabolized via glucuronidation. Eslicarbazepine levels stayed within the normal range and did not require dose adjustment. However, caution should be exercised when cannabidiol and eslicarbazepine are taken together (97018).

EVEROLIMUS (Zortress) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Cannabidiol might increase everolimus levels.  Details Everolimus is a substrate of CYP3A4 enzymes. Cannabidiol has been shown to inhibit CYP3A4 (89693,89694,89695,97018). A retrospective study in children taking everolimus for tuberous sclerosis has found that adding treatment with cannabidiol increases everolimus serum concentration by a median of 9.8 ng/mL (103035). In a case report, a 6-year-old girl stable on everolimus with refractory tonic seizures was started on cannabidiol titrated up to 200 mg daily for 6 weeks. This led to elevated levels of everolimus (100892).

FLUOXETINE (Prozac) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Cannabidiol might increase fluoxetine levels in certain patients.  Details In one case report, a 17-year-old male with autism previously stabilized on fluoxetine 20 mg daily developed insomnia, agitation, hyperactivity, yelling, and worsening symptoms of obsessive-compulsive disorder after taking cannabidiol 18 mg twice daily for 2 weeks. The patient was found to be a poor cytochrome P450 2D6 (CYP2D6) metabolizer (CYP2D6*4/*4). Fluoxetine is primarily metabolized by CYP2D6, and to a lesser extent, by CYP2C9. Although fluoxetine levels weren't measured, it was hypothesized that the lack of CYP2D6 activity resulted in fluoxetine being metabolized solely by CYP2C9, which was subsequently inhibited by cannabidiol. This would have increased levels of fluoxetine, resulting in adverse effects (109186). Further research is needed to confirm this complex gene-drug interaction cascade.

GLUCURONIDATED DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Cannabidiol might increase levels of certain glucuronidated drugs.  Details In vitro research shows that cannabidiol inhibits uridine diphosphoglucuronosyl transferase (UGT) 1A9 and UGT2B7, enzymes responsible for glucuronidation (99613). Theoretically, this could decrease the clearance and increase levels of glucuronidated drugs.

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Cannabidiol might precipitate lithium toxicity, but the evidence is limited to a single case report.  Details In a case report, a 13-year-old male with Lennox-Gastaut syndrome and autism, stable on lithium for one year, presented to the hospital with lithium toxicity after an increase in daily cannabidiol dose from 5 mg/kg to 10 mg/kg. Theoretically, lithium toxicity might have occurred due to cannabidiol-induced renal dysfunction (104018).

METHADONE (Dolophine) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Cannabidiol might increase levels of methadone, but the evidence is limited to a single case report.  Details In a case report, a 13-year-old female with chronic cancer pain who was previously stabilized on methadone 7.5 mg twice daily presented to the emergency room with opioid-related side effects. She had begun experiencing increased sleepiness and fatigue after being given cannabidiol oil 1.5 grams orally in six divided doses daily by her parents. Her serum levels of methadone had risen to 271 ng/mL but decreased to 124 ng/mL after discontinuation of cannabidiol. This coincided with resolution of excessive sleepiness and fatigue (102958). Theoretically, cannabidiol increases levels of methadone by inhibiting cytochrome P450 3A4 (CYP3A4) and CYP2C19 enzymes, which metabolize methadone (99613,102958).

RUFINAMIDE (Banzel) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = B Cannabidiol might increase rufinamide levels.  Details In clinical research, concomitant administration of cannabidiol and rufinamide is associated with a modest increase in plasma levels of rufinamide. The mechanism for this interaction is unknown; rufinamide is metabolized via carboxyl esterases. Rufinamide levels stayed within the normal range and did not require dose adjustment. However, caution should be exercised when cannabidiol and rufinamide are taken together (97018).

SIROLIMUS (Rapamune) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Cannabidiol might increase sirolimus levels.  Details Sirolimus is a substrate of cytochrome P450 3A4 (CYP3A4) enzymes. Cannabidiol has been shown to inhibit CYP3A4 enzymes (89693,89694,89695,97018). A retrospective study in children taking sirolimus for tuberous sclerosis has found that adding treatment with cannabidiol increases serum sirolimus concentration by a median of 5.1 ng/mL (103035).

STIRIPENTOL (Diacomit) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = A Cannabidiol can increase stiripentol levels.  Details Two clinical pharmacokinetic studies in patients stabilized on stiripentol shows that adding cannabidiol, 750 mg twice daily for 3-10 days or up to 20 mg/kg daily for 24 days, increases the average maximum concentration of stiripentol by 17% to 28% and the average area under the curve by 30% to 55% when compared with taking stiripentol alone. The mechanism for this interaction is unknown; cannabidiol might inhibit cytochrome P450 2C19 (CYP2C19) and/or UDP-glucuronosyltransferase (UGT) isoforms, which metabolize stiripentol (103030,103039). Although there were no adverse clinical outcomes, caution should be exercised when cannabidiol and stiripentol are taken together.

TACROLIMUS (Prograf) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Cannabidiol might increase tacrolimus levels.  Details Tacrolimus is a cytochrome P450 3A4 (CYP3A4) substrate. Cannabidiol has been shown to inhibit CYP3A4 enzymes (89693,89694,89695,97018). In a case report, a patient stabilized on tacrolimus experienced about a 3-fold increase in tacrolimus concentrations after starting to take cannabidiol 2000-2900 mg daily for epilepsy (100884).

TAMOXIFEN (Nolvadex) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Chronic use of cannabidiol 40 mg daily might modestly reduce levels of tamoxifen's active metabolites.  Details In one case report, a 50-year-old female who was taking tamoxifen 20 mg daily for the past 5 years and cannabidiol 40 mg daily for about four months, presented with a 9.2% increase in N-desmethyltamoxifen and an 18.8% increase in endoxifen levels after discontinuing cannabidiol for 67 days. Theoretically, cannabidiol may have modestly inhibited cytochrome P450 3A4 (CYP3A4) and CYP2D6, which metabolize tamoxifen into N-desmethyltamoxifen and endoxifen, respectively. Cannabidiol discontinuation may have resulted in a return to normal enzyme activity (104886).

TOPIRAMATE (Topamax) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = B Cannabidiol might increase topiramate levels.  Details In clinical research, concomitant administration of cannabidiol and topiramate, a CYP2C9 and CYP2C19 substrate, is associated with a modest increase in plasma levels of topiramate. Topiramate levels stayed within the normal range and did not require dose adjustment. However, caution should be exercised when cannabidiol and topiramate are taken together (97018).

VALPROATE Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = A Cannabidiol might increase the risk of hepatotoxicity and thrombocytopenia with valproic acid.  Details In clinical research, concomitant administration of valproic acid and cannabidiol is associated with elevated liver transaminases and rare cases of thrombocytopenia. Liver transaminase levels and platelet counts should be closely monitored when cannabidiol and valproic acid are taken together. Liver transaminase elevation appears to be mild in the majority of cases; however, severe elevations can occur. At least 15 cases of thrombocytopenia have been reported following concomitant administration of valproic acid and cannabidiol. While thrombocytopenia is a known adverse effect with valproic acid, the risk may be modestly higher when cannabidiol and valproic acid are administered concomitantly (97017,97018,97019,97022,97979,97980,102323,103030,103039,103041). It is unclear if and how cannabidiol contributes to the risk of these adverse events, as there does not appear to be a direct pharmacokinetic interaction. Pharmacokinetic studies in humans show that coadministration of valproate with cannabidiol does not have clinically meaningful effects on levels of valproate or its metabolite 4-ene-VPA (103030,103039).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Cannabidiol might increase warfarin levels.  Details There are at least two case reports of patients who were previously stable on warfarin presenting with a supratherapeutic International Normalized Ratio (INR) after starting cannabidiol (Epidiolex) titrated up to a dose of 20 mg/kg daily. Warfarin dose reductions of 20% to 30% were required to normalize the INR. Cannabidiol may have inhibited cytochrome P450 2C9 (CYP2C9), resulting in decreased warfarin metabolism and increased levels (104013).

ZONISAMIDE (Zonegran) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = B Cannabidiol might increase zonisamide levels.  Details In clinical research, concomitant administration of cannabidiol and zonisamide, a cytochrome P450 3A4 (CYP3A4) substrate, is associated with a modest increase in plasma levels of zonisamide. Zonisamide levels stayed within the normal range and did not require dose adjustment. However, caution should be exercised when cannabidiol and zonisamide are taken together (97018).

(Read more about CANNABIDIOL (CBD))

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, peppermint oil might increase the levels and adverse effects of cyclosporine.  Details In animal research, peppermint oil inhibits cyclosporine metabolism and increases cyclosporine levels. Inhibition of cytochrome P450 3A4 (CYP3A4) may be partially responsible for this interaction (11784). An interaction between peppermint oil and cyclosporine has not been reported in humans.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, peppermint might increase the levels of CYP1A2 substrates.  Details In vitro and animal research shows that peppermint oil and peppermint leaf inhibit CYP1A2 (12479,12734). However, in clinical research, peppermint tea did not significantly affect the metabolism of caffeine, a CYP1A2 substrate. It is possible that the 6-day duration of treatment may have been too short to identify a difference (96359).

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, peppermint might increase the levels of CYP2C19 substrates.  Details In vitro research shows that peppermint oil inhibits CYP2C19 (12479). So far, this interaction has not been reported in humans.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, peppermint might increase the levels of CYP2C9 substrates.  Details In vitro research shows that peppermint oil inhibits CYP2C9 (12479). So far, this interaction has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, peppermint might increase the levels of CYP3A4 substrates.  Details Clinical research in healthy volunteers shows that a single dose of peppermint oil 600 mg inhibits CYP3A4 enzymes and increases the AUC of felodipine, a CYP3A4 substrate (11783). However, in vitro research suggests that peppermint oil only inhibits CYP3A4 at very high concentrations (12479).

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ACETAZOLAMIDE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, willow bark might result in additive adverse effects associated with acetazolamide.  Details Willow bark contains salicin, a plant salicylate. Human case reports suggests that a combination of acetazolamide and salicylate increases unbound plasma levels of acetazolamide, as well as adverse effects related to acetazolamide (86481).

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, willow bark might increase the risk of bleeding when taken with anticoagulant/antiplatelet drugs.  Details Willow bark has antiplatelet effects, but less so than aspirin (12810).

ASPIRIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, willow bark might increase the effects and adverse effects of aspirin.  Details Willow bark contains salicin, a plant salicylate. It might have an additive effect when taken with other salicylate-containing drugs such as aspirin (12808).

CHOLINE MAGNESIUM TRISALICYLATE (Trilisate) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, willow bark might increase the effects and adverse effects of choline magnesium trisalicylate.  Details Willow bark contains salicin, a plant salicylate. It might have an additive effect when taken with other salicylate-containing drugs such as choline magnesium trisalicylate (12808).

SALSALATE (Disalcid) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, willow bark might increase the effects and adverse effects of salsalate.  Details Willow bark contains salicin, a plant salicylate. It might have an additive effect when taken with other salicylate-containing drugs such as salsalate (12808).

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General ...Orally, cannabidiol seems to be well tolerated.
Most Common Adverse Effects:
Orally: For prescription cannabidiol (Epidiolex), somnolence in up to 30% of patients and diarrhea in up to 24% of patients. Also, decreased appetite, drowsiness, dry mouth, fatigue, pyrexia, vomiting, and weight loss. Higher doses over 15-20 mg/kg daily are more likely to cause somnolence, decreased appetite, diarrhea, liver enzyme elevations, and weight loss. Pharmacogenetic variation may also affect susceptibility to certain adverse effects, particularly diarrhea, sedation, and abnormal liver enzyme levels.
Serious Adverse Effects (Rare):
Orally: There have been rare case reports of hepatitis, respiratory depression, and pneumonia.

Cardiovascular ...Orally, cannabidiol has been associated with cardiovascular effects in some reports. In one clinical study, some patients experienced hypotension, orthostatic hypotension, and lightheadedness (89700). Also, cannabidiol has also been linked to tachycardia and hypertension. In Poison Control Center reports of up to 5248 oral single-substance exposures to cannabidiol in adults and children, up to 7% of cases involved tachycardia (105493,110248). However, the doses of cannabidiol that precipitated these reports are unclear. Other research suggests that taking cannabidiol orally does not significantly change blood pressure or heart rate when compared with placebo (61832,89675,89909).

Dermatologic ...Orally, cannabidiol might cause rare skin reactions (105696,109178). In a clinical study in healthy adults, two cases of skin reactions, one severe and one mild, were reported (105696). These and two additional cases were reported in a follow-up publication specific to cannabidiol-induced skin rash (109178). The rash occurred in four female patients after taking oral cannabidiol 300 mg daily for up to 9 days. The earliest case started 6 hours after initial use; all rashes resolved within 5-11 days of treatment discontinuation (105696,109178). The cannabidiol was 99.6% pure (PurMed Global; United States) and dissolved in medium chain triglyceride oil (109178). Taking the medium chain triglyceride oil alone did not reproduce symptoms. In one case, the patient required treatment with oral prednisone 0.5 mg/kg daily (109178). A systematic review of randomized controlled trials shows that rash makes up approximately 6% of all adverse effects related to oral cannabidiol use (110244).
Topically, cannabidiol has resulted in pain on application, as well as dryness, rash, and itching (110243).

Gastrointestinal ...Orally, cannabidiol has caused dry mouth in some patients in clinical research (89700,105559,109177,110245,110249). In children and adults, cannabidiol oil has caused mild to moderate diarrhea, decreased appetite, weight loss, nausea, and vomiting. Diarrhea, decreased appetite, and weight loss or weight gain have been reported at a higher frequency with doses greater than 15-20 mg/kg daily (97017,97019,97021,97022,97025,97979,97980,102323,103031,103042)(104884,105493,105495,106631,106633,107327,109176,109177,110248). Weight loss also seems to be more prevalent with long-term cannabidiol use. Other adverse effects like diarrhea and vomiting also seem to be more prevalent during long-term (42-96 weeks) cannabidiol treatment when compared with short-term (about 12-14 weeks) (103034). Pharmacogenetic variation has also been shown to affect susceptibility to cannabidiol-associated diarrhea (107324). In a 75-year-old female, chronic cannabidiol use for one year was associated with microscopic colitis. Colitis resolved when cannabidiol was discontinued, and recurred after a re-challenge (104885). A systematic review of randomized controlled trials shows that gastrointestinal symptoms, including diarrhea, nausea, vomiting, abdominal pain, abdominal distention, and constipation, make up approximately 60% of all adverse effects related to oral cannabidiol use. About 17% of patients report loss of appetite (110244).

Hepatic ...Orally, cannabidiol oil has been associated with an elevation in liver transaminases, consistent with drug-induced liver injury, in some people. A systematic review has found that elevated liver transaminases make up about 13% of adverse effects related to cannabidiol use (110244). In a study of 16 healthy patients, taking cannabidiol 1500 mg (~20 mg/kg) daily resulted in elevations in alanine aminotransferase (ALT) over 5 times the upper limit of normal in 31% of participants after 2-4 weeks. Three of these patients developed eosinophilia, nausea, and vomiting, which are symptoms of hepatitis. There was no correlation found between serum cannabidiol levels and peak ALT levels (104890). In a clinical study in 59 healthy adults, four cases of elevated liver transaminases occurred after taking cannabidiol 300 mg daily for up to 28 days. In one patient, liver enzymes increased to more than 3 times the upper limit of normal, but normalized when cannabidiol was discontinued (105696). In another study, abnormal liver transaminases occurred in 4 of 25 patients after taking cannabidiol up to 20 mg/kg daily for 4 weeks; levels normalized within 4 weeks of study completion (109176). Pharmacogenetic variation has also been shown to affect susceptibility to liver transaminase elevations with cannabidiol use (107324).
Conversely, a large industry-funded observational study suggests that the prevalence of elevated liver transaminases in those taking cannabidiol for at least 30 days is similar when compared with the general adult population. The mean daily dose of cannabidiol used in this study was 50 mg, which is much lower than the doses reported in cases of elevated liver transaminases (107336).
The elevation in liver transaminases appears to occur more frequently at higher doses (20-25 mg/kg), in patients with elevated levels at baseline, and in patients already taking valproic acid or clobazam. While most reported elevations have been mild, some patients taking cannabidiol oil alone or with valproic acid have experienced significant elevations which required discontinuation of either valproic acid or cannabidiol (97017,97018,97019,97022,97025,97979,97980,102323,103031,104884)(104890,106631,106633,107327,110244).

Neurologic/CNS ...Orally, cannabidiol has been most commonly reported to cause somnolence, sedation, dizziness, agitation, and fatigue (61989,100883,102323,103031,104884,105493,105495,105559,109177,110245)(110248,110249), with a significantly higher incidence when used in conjunction with clobazam (97017,97019,97022,97025,97979,106631). Hallucinations, delusions, confusion, and slurred speech have been reported in a Poison Control Center report (110248). Other symptoms reported in clinical research include low mood, temperature dysregulation, and insomnia, although the prevalence and clinical significance is unclear (109177). Cannabidiol has been reported to cause sedation and psychomotor slowing in some patients (89700,103029). Pharmacogenetic variation has also been shown to affect susceptibility to cannabidiol-associated sedation (107324). There is concern that cannabidiol can cause cognitive impairments when used for a long duration. However, cannabidiol does not seem to negatively impact cognition in adults with treatment-resistant epilepsy used for up to one-year (100885). In children, cannabidiol oil has caused drowsiness, fatigue, sedation, and gait disturbance (97017,97019,97022,97025).
Cannabidiol does not seem to be associated with withdrawal symptoms. Clinical research in healthy volunteers taking cannabidiol daily for 4 weeks shows that stopping cannabidiol abruptly does not cause withdrawal symptoms (103042).
Limited research suggests that cannabidiol does not cause driving impairment. A small study has found that inhaling vaporized cannabis containing cannabidiol 13.75 mg does not increase lane weaving when compared with placebo. The lane weaving seen in those inhaling this product was equivalent to having a blood alcohol concentration (BAC) of 0.02%, which is below the lower limit of clinically relevant impairment that is considered to occur with a BAC of 0.05% (104482). Other research shows that taking a single oral dose of cannabidiol (GD Cann-C; GD Pharma Pty Ltd) 15 mg, 300 mg, or 1500 mg, confirmed to be devoid of delta-9-tetrahydrocannabinol (THC) and other cannabinoids, does not affect cognitive function or driving performance after 15-240 minutes when compared with placebo (109179). The validity of these findings is limited because these studies only tested a single dose of cannabidiol, which does not mimic real-world use (104484,109179).

Ocular/Otic ...Ocular pain and irritation and mydriasis related to oral cannabidiol exposures have been reported in a Poison Control Center report (110248).

Pulmonary/Respiratory ...Orally, cannabidiol oil has been associated with rare respiratory depression and increased odds of pneumonia (103029,103031,106631,106633). In a case report, a 56-year-old obese male presented to the emergency room with severe respiratory depression 3 hours after consuming two packages of gummies labeled to contain cannabidiol 370 mg. Symptoms included respiratory acidosis, slurred speech, bradycardia, and vomiting. The patient was treated with supportive care (103029). It is uncertain whether these effects were caused by cannabidiol or other adulterant substances in the gummies.
A small preliminary clinical trial in patients with cancer found that taking cannabidiol (GD-Cann C, Norwood, South Australia) in median doses of 400 mg daily for up to 2 weeks results in an increased number of patients with dyspnea when compared with placebo (110247).

Other ...There is some concern that cannabidiol could be used as a substance of abuse. Cannabidiol derived from marijuana is classified as a Schedule I controlled substance by the United States Drug Enforcement Administration (DEA). Epidiolex, an approved prescription formulation of cannabidiol, is classified as a schedule V controlled substance (99606). In a clinical study of healthy recreational polydrug abusers, a single dose of cannabidiol 750 mg was rated no differently than placebo for drug-liking, likelihood of repeat use, or the occurrence of positive effects, such as feeling high or feeling stoned. However, a single dose of cannabidiol 1500 mg or 4500 mg scored higher for likelihood of repeat use and occurrence of positive effects when compared with placebo, although these ratings were lower than those for dronabinol and alprazolam (99605).

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General ...Orally, topically, or rectally, peppermint oil is generally well tolerated. Inhaled, peppermint oil seems to be well tolerated. Intranasally, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted. Orally, peppermint leaf seems to be well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, anal burning, belching, diarrhea, dry mouth, heartburn, nausea, and vomiting.
Topically: Burning, dermatitis, irritation, and redness.

Dermatologic ...Topically, peppermint oil can cause skin irritation, burning, erythema, and contact dermatitis (3802,11781,31528,43338,68473,68457,68509,96361,96362). Also, a case of severe mucosal injury has been reported for a patient who misused an undiluted over the counter mouthwash that contained peppermint and arnica oil in 70% alcohol (19106).
In large amounts, peppermint oil may cause chemical burns when used topically or orally. A case of multiple burns in the oral cavity and pharynx, along with edema of the lips, tongue, uvula, and soft palate, has been reported for a 49-year-old female who ingested 40 drops of pure peppermint oil. Following treatment with intravenous steroids and antibiotics, the patient's symptoms resolved over the course of 2 weeks (68432). Also, a case of chemical burns on the skin and skin necrosis has been reported for a 35-year-old male who spilled undiluted peppermint oil on a previous skin graft (68572). Oral peppermint oil has also been associated with burning mouth syndrome and chronic mouth ulceration in people with contact sensitivity to peppermint (6743). Also, excessive consumption of mint candies containing peppermint oil has been linked to cases of stomatitis (13114).

Gastrointestinal ...Orally, peppermint oil can cause heartburn, nausea and vomiting, anal or perianal burning, abdominal pain, belching, dry mouth, diarrhea, and increased appetite (3803,6740,6741,6742,10075,11779,11789,17682,68497,68514)(68532,68544,96344,96360,102602,104219,107955). Enteric-coated capsules might help to reduce the incidence of heartburn (3802,4469,6740,11777). However, in one clinical study, a specific enteric-coated formulation of peppermint oil (Pepogest; Nature's Way) taken as 180 mg three times daily was associated with a higher rate of adverse effects when compared with placebo (48% versus 31%, respectively). Specifically, of the patients consuming this product, 11% experienced belching and 26% experienced heartburn, compared to 2% and 12%, respectively, in the placebo group (107955). A meta-analysis of eight small clinical studies in patients with irritable bowel syndrome shows that taking enteric-coated formulations of peppermint oil increases the risk of gastroesophageal reflux symptoms by 67% when compared with a control group (109980). Enteric-coated capsules can also cause anal burning in people with reduced bowel transit time (11782,11789).

Genitourinary ...Orally, a sensitive urethra has been reported rarely (102602).

Hepatic ...One case of hepatocellular liver injury has been reported following the oral use of peppermint. Symptoms included elevated liver enzymes, fatigue, jaundice, dark urine, and signs of hypersensitivity. Details on the dosage and type of peppermint consumed were unavailable (96358).

Immunologic ...One case of IgE-mediated anaphylaxis, characterized by sudden onset of lip and tongue swelling, tightness of throat, and shortness of breath, has been reported in a 69-year-old male who consumed peppermint candy (89479). An allergic reaction after use of peppermint oil in combination with caraway oil has been reported in a patient with a history of bronchial asthma (96344). It is not clear if this reaction occurred in response to the peppermint or caraway components.

Neurologic/CNS ...Orally, headache has been reported rarely (102602).

Ocular/Otic ...Orally, peppermint has been reported to cause blurry vision (3803).

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General ...Orally, willow bark seems to be well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea, dyspepsia, heartburn, and vomiting. May cause itching and rash in sensitive individuals.
Serious Adverse Effects (Rare):
Orally: Gastrointestinal bleeding and renal impairment. May cause serious allergic reactions, including anaphylaxis, in people who are allergic to aspirin.

Cardiovascular ...In one clinical trial, a single patient withdrew from the study investigating oral willow bark due to blood pressure instability that the authors determined was 'possibly' related to treatment (12804).

Dermatologic ...Orally, willow bark may cause itching and rash in some people due to allergy (6456,12474,12475,12804,86459).

Gastrointestinal ...Orally, willow bark extract can cause gastrointestinal adverse effects, but these appear to be less frequent than those caused by NSAIDs. Examples include diarrhea, heartburn, vomiting, and dyspepsia (12474,12475,12804,86459). In a case report of a child, severe gastrointestinal bleeding occurred following use of a specific syrup (FreddoBaby), which contained ribwort plantain, licorice, willow bark, black elder, meadowsweet, and propolis. The adverse effect was attributed to salicylate content of the syrup. This product has since been withdrawn from the market (86477).

Immunologic ...Orally, willow bark may cause serious allergic reactions, including anaphylaxis, in people who are allergic to aspirin (10392)

Neurologic/CNS ...Orally, willow bark may cause headache and dizziness (12804). In a clinical trial evaluating a combination product containing willow bark, black cohosh, sarsaparilla, poplar bark, and guaiac wood (Reumalex), severe headaches occurred (35946).

Ocular/Otic ...Orally, symptoms of allergy to willow bark have included swollen eyes (6456).

Renal ...Salicylates can inhibit prostaglandins, which can reduce renal blood flow (12805). Salicin can cause renal papillary necrosis (12806). The risk for toxicity is greater with high acute doses or chronic use (12805).

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