Full Spectrum Gold CBD Oil 100 mg/mL by Green Roads

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 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 (109177). The validity of these findings is limited by the lack of a control group. 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. Similarly, a moderate-sized clinical study in patients with elevated trait worry shows that taking cannabidiol 300 mg daily for 2 weeks improves self-reported scores related to anxiety symptoms when compared with placebo but does not improve scores assessing the severity of worry (113035). However, other preliminary clinical research in college students who self-report 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. Sublingual cannabidiol has also been investigated. A small 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 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 4 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 (108676,111095). 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.
• Canker sores. It is unclear if topical cannabidiol is beneficial for recurrent canker sores. Details: A moderate-sized clinical study in adults with recurrent canker sores shows that applying a cannabidiol 0.1% patch three times daily for 7 days reduces ulcer size and accelerates ulcer healing at day 7 when compared with placebo (113052). The interpretation of these results is limited by the lack of a statistical comparison to the active control group that received topical triamcinolone cream.
• 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.
• Chemotherapy-related taste changes. It is unclear if oral cannabidiol is beneficial for improving taste- related changes from chemotherapy. Details: A small clinical trial in patients receiving paclitaxel- or oxaliplatin-based chemotherapy shows that taking cannabidiol 300 mg daily for 8 days during each cycle of chemotherapy improves the ability to differentiate between weak or strong degrees of saltiness and sweetness at the third cycle of chemotherapy when compared to baseline (113029). However, the interpretation of these results is limited by the lack of a statistical comparison to the control group.
• 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. It is unclear if oral cannabidiol is beneficial for behavioral and mood symptoms in dementia. 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). In contrast, a very small clinical study in patients with dementia shows that taking full spectrum hemp extract cannabidiol (Care Drops, Kannabio) 3% titrated to 10 drops per day for 6 months does not improve scores regarding behavior and mood symptoms when compared with usual care and adjusting for baseline differences in neuropsychiatric symptoms between groups (113023).
• Diabetes. It is unclear if oral cannabidiol is beneficial for glucose and lipid management in patients with type 2 diabetes. Details: A small clinical study in adults with type 2 diabetes conducted in Iran shows that taking a specific product containing cannabidiol 100 mcg and delta-9-tetrahydracannabinol 10 mcg (CBDEX10, Yas Daru) 2 puffs twice daily for 8 weeks modestly improves fasting blood glucose, glycated hemoglobin, total and low-density lipoprotein cholesterol, and triglycerides when compared with placebo, but does not increase high-density lipoprotein cholesterol (113056). Conversely, 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).
• Exercise-induced muscle soreness. Cannabidiol has only been studied in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in exercise-trained adults shows that taking cannabidiol 70 mg combined with cannabigerol 50 mg, beta caryophyllene 25 mg, branched-chain amino acids 3.8 grams, and magnesium citrate 420 mg twice daily for 3.5 days does not improve self-reported muscle soreness or functional aspects of recovery when compared with placebo (113050).
• 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).
• Gastroparesis. It is unclear if cannabidiol is beneficial for gastroparesis. Details: A small clinical study in patients with gastroparesis shows that taking cannabidiol 10 mg/kg twice daily for 4 weeks improves scores for global gastroparesis symptoms, ability to finish a full-sized meal, and number of vomiting episodes when compared with placebo, but does not improve measured gastric volumes (113054). However, the interpretation of these results is limited by the subjectivity of self-reported outcomes.
• 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. It is unclear if oral cannabidiol is beneficial for hypertension. Details: A moderate-size crossover study in adults with mild to moderate untreated or treated hypertension shows that taking a specific cannabidiol product (DehydraTECH 2.0, Lexaria Bioscience), starting at 225-300 mg and titrating to 375-450 mg over 2.5 weeks, typically split in 2-3 doses daily for a total of 5 weeks, reduces systolic blood pressure by approximately 5 mmHg and 24-hour mean arterial pressure by approximately 3 mmHg when compared to baseline (113031). However, interpretation of these findings is limited by the lack of a statistical comparison to the placebo group. Similarly, another small crossover study in adults with untreated hypertension shows that taking cannabidiol 150 mg every 8 hours for 1 day reduces systolic blood pressure by approximately 5 mmHg and arterial blood pressure by approximately 3 mmHg when compared with placebo (113030). However, the interpretation of these findings is limited by the short study duration and circadian fluctuations in blood pressure. 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. Oral cannabidiol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical trial in adults with self-reported poor or very poor sleep shows that taking gummies containing cannabidiol 10 mg, 20 mg, or 100 mg combined with 20 mg of cannabinol daily for 7 days does not improve sleep quality, sleep onset, unintended waking after sleeping, or daytime fatigue when compared with placebo (113055). Additionally, a crossover 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 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 interpretation of the findings in both studies is limited by the short duration of treatment. Another very large clinical trial in adults with sleep disturbance shows that taking cannabidiol 15 mg alone or in varied combinations with cannabinol, cannabichromene, or melatonin daily over 4 weeks improves sleep quality when compared to baseline. However, the odds of achieving a clinically important difference in sleep quality is not improved when cannabidiol alone is compared with combination therapy or with melatonin 5 mg alone (113051). It is unclear if these effects are from cannabidiol, other ingredients, or the combination.
• 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.
• Kidney stones (nephrolithiasis). It is unclear if cannabidiol is beneficial for post-ureteroscopy pain. Details: A moderate-sized clinical study in adults undergoing ureteroscopy with stent placement for kidney and ureteral stones receiving standard treatment with tamsulosin, oxybutynin, and phenazopyridine shows that taking cannabidiol 20 mg daily for 3 days does not reduce pain or opioid usage when compared with placebo (113048).
• Multiple sclerosis (MS). A specific cannabis oromucosal spray and oral cannabis extract, providing standard doses of cannabidiol in combination with delta-9-tetrahydrocannabinol (THC), seems to modestly reduce spasticity in patients with MS. The effect of cannabidiol alone on symptoms of MS is unclear. Details: Meta-analysis of several clinical studies in patients with MS shows that using a specific oromucosal spray containing cannabis extract (Sativex, GW Pharmaceuticals), standardized to deliver cannabidiol 2.5 mg and THC 2.7 mg per actuation, for at least 3 weeks modestly reduces subjective spasticity, but does not seem to reduce neuropathic pain or bladder dysfunction, when compared with placebo (104895). Another meta-analysis of 5 clinical studies, that includes many of the same studies as the prior meta-analysis, shows that using Sativex as add-on therapy improves the likelihood of reduced spasticity by 2.4 times when compared with placebo (113020). Limited research suggests that the benefit of Sativex might last for over 11 months and withdrawal of Sativex may cause a rebound of MS symptoms (89923,89924). Sativex has been approved in the United Kingdom as a prescription medicine to treat MS-related spasticity (89913) and in Canada to treat neuropathic pain associated with MS (61775). This product has not been approved in the United States. The American Academy of Neurology states that Sativex does not improve objective measures of spasticity, reduce the number of urinary incontinence episodes, or reduce MS-related tremors (89460). Notably, much of the research was funded by the manufacturer. Other oral cannabis extracts containing cannabidiol have also been studied. A meta-analysis of clinical research in patients with MS shows that taking a cannabis extract containing cannabidiol 8-18 mg and THC 25-30 mg daily for up to 15 weeks modestly reduces subjective spasticity, neuropathic pain, and bladder dysfunction when compared with placebo. However, objective spasticity measures (Ashworth scale) were not improved when compared with placebo (104895). 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 as adjunct treatment for improvement of pain, muscle spasm, and sleep in patients with MS and inadequate response to other treatments. These recommendations are based on low or moderate quality evidence of smoked cannabis, cannabis extract, and oromucosal cannabidiol/THC, suggesting that benefits exceed the risks of non-serious adverse effects. The strongest evidence of benefit has been shown with oils and capsules, as opposed to smoking or oromucosal formulations. The evidence related to cannabidiol-predominant formulations for this purpose is unclear (110321).
• 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 or topical cannabidiol is beneficial for chronic pain. Details: A small observational cohort study suggests that taking cannabidiol for 8 weeks is associated with reduced opioid use, as well as improved chronic pain and sleep quality (104498). Additionally, a small observational study in former professional athletes with chronic pain suggests that applying cannabidiol 10 mg in combination with lemongrass, ylang ylang, wintergreen, and camphor to affected extremities twice daily for 6 weeks is associated with improved self-reported pain scores and pain-related disability compared to baseline (113037). However, the interpretation of these findings is limited by the lack of a comparator group and a 30% dropout rate. It is also unclear if these effects are from cannabidiol, other ingredients, or the combination. 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 to baseline (104884). The lack of comparator groups limits the validity of these findings. Conversely, a small clinical study in adults with Parkinson disease conducted in Thailand shows that taking sublingual cannabidiol-enriched cannabis extract, approximately 16 mg, daily for 6 weeks after a 2-week titration does not improve validated Parkinson disease rating scores, anxiety, or depression when compared with placebo (113039). However, the interpretation of these findings is limited by the use of lower dosages of cannabidiol and subjective outcomes.
• 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 delta-9-tetrahydrocannabinol (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 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 reduces cravings for cigarettes or limits nicotine withdrawal symptoms. 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 interpretation of this finding is limited by the short study duration and a lack of statistical comparison to the placebo group. A small crossover study in e-cigarette users with nicotine withdrawal shows that taking cannabidiol 320 mg once before an abstinence session reduces self-reported nicotine withdrawal severity and anxiety at 4 hours after administration when compared with not taking cannabidiol before the session (113036). The interpretation of these findings is also limited by the short study duration, as well as lack of blinding.
• 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 cannabidiol 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.

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LIKELY EFFECTIVE

• Cystic fibrosis. Long-term nebulized hypertonic sodium chloride improves lung function and reduces pulmonary exacerbations in patients with cystic fibrosis. Details: Meta-analyses of clinical research in adults with cystic fibrosis show that, when taken along with a bronchodilator and other standard therapies, nebulized hypertonic sodium chloride in concentrations of 3% to 7%, up to 10 mL twice daily for 4 weeks, increases forced expiratory volume at one second (FEV1) when compared with isotonic saline (sodium chloride 0.9%) (26230,26230). This benefit was not seen at 48 weeks. Other clinical research in adults with cystic fibrosis shows that inhaling sodium chloride 7%, 4 mL twice daily for 48 weeks, does not improve FEV1 when compared with isotonic saline. However, chronic treatment with hypertonic saline does reduce the number of pulmonary exacerbations and increase the number of patients without pulmonary exacerbations when compared with isotonic saline (29402). It is not clear if this benefit occurs in children with cystic fibrosis. The Pulmonary Clinical Practice Guidelines Committee of the Cystic Fibrosis Foundation recommends that individuals with cystic fibrosis aged 6 years or older use nebulized hypertonic saline long-term to improve lung function, reduce the number of exacerbations, and improve quality of life (29403).

POSSIBLY EFFECTIVE

• Amphotericin B nephrotoxicity. Oral sodium chloride seems to prevent nephrotoxicity associated with use of amphotericin B. Details: Clinical research shows that administering oral or intravenous sodium chloride 150 mEq daily during treatment with amphotericin B can attenuate the rise in serum creatinine levels and preserve renal function when compared to treatment with amphotericin B alone (26226).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Bipolar disorder. It is unclear if oral sodium is beneficial in preventing lithium level fluctuations in patients with bipolar disorder. Details: A moderate-sized open-label clinical study in adults with type I bipolar disorder receiving lithium carbonate shows that taking sodium chloride 1 gram daily for 12 weeks along with dietary salt restriction of 1 gram daily reduces the percentage of patients with lithium level fluctuations above 0.8 mEq/L, but does not significantly affect serum sodium, potassium, aldosterone, or creatinine levels when compared with controls who were not salt restricted, but were advised not to consume additional salt at the table (112909). However, the interpretation of these findings is limited by missing data in both groups.
• Canker sores. Although there is interest in using topical sodium chloride for canker sores, there is insufficient reliable information about the clinical effects of sodium chloride for this condition.
• Congestive heart failure. It is unclear if oral sodium is beneficial in patients with acute decompensated heart failure requiring decongestive therapy with diuretics. Details: A moderate-sized clinical study in adults hospitalized with acute decompensated heart failure requiring high-dose intravenous furosemide shows that taking sodium chloride 2 grams three times daily for up to 96 hours does not affect patient weight or serum creatinine levels when compared with placebo (112911). However, the clinical relevance of this study is unclear and it may have been inadequately powered to detect a difference between groups.
• Conjunctivitis. Although there is interest in using ophthalmic sodium chloride for conjunctivitis, there is insufficient reliable information about the clinical effects of sodium chloride for this condition.
• Hyponatremia. Although there is interest in using oral sodium chloride for hyponatremia, there is insufficient reliable information about the clinical effects of oral sodium chloride for this condition.
• Pharyngitis. Although there is interest in using topical sodium chloride for pharyngitis, there is insufficient reliable information about the clinical effects of sodium chloride for this condition.
• Prematurity. It is unclear if oral sodium is beneficial for premature infants. Details: Preliminary clinical research in infants born at less than 32 weeks' gestation shows that adding sodium 4 mEq/kg daily to enteral feedings, starting from the 7th day after birth and continuing through the 35th day, reduces the risk of developing hyponatremia and improves weight gain when compared with adding water (98180). A small, open-label clinical study in newborns less than 35 weeks gestation shows that high sodium intake, defined as an average of 0.25% sodium in maintenance fluids, for 48 hours on day 2 and 3 after birth results in less weight loss within the first 72 hours of life when compared with control, but does not improve mortality, length of hospital stay, or complications from prematurity (112908). However, interpretation of these findings is limited by varied concentrations of sodium as an intervention. More evidence is needed to rate sodium for these uses.

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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 510-25 mg/kg daily, titrated based on response and tolerability for up to 20 months (97979,97980,99613,105495,106631,113034). ...when a specific cannabis extract spray that contains cannabidiol 2.5 mg and delta-9-tetrahydrocannabinol (THC) 2.7 mg per actuation (Sativex, GW Pharmaceuticals) is applied topically into the oral mucosa for up to 2 years. This product is available as a prescription drug in the UK and Canada; it is an investigational new drug in the US (61775,61820,89460,89913,111095). There is insufficient reliable information available about the safety of cannabidiol when used topically on the skin.

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 used orally and appropriately. Sodium is safe in amounts that do not exceed the Chronic Disease Risk Reduction (CDRR) intake level of 2.3 grams daily (100310). Higher doses can be safely used therapeutically with appropriate medical monitoring (26226,26227).

POSSIBLY UNSAFE ...when used orally in high doses. Tell patients to avoid exceeding the CDRR intake level of 2.3 grams daily (100310). Higher intake can cause hypertension and increase the risk of cardiovascular disease (26229,98176,98177,98178,98181,98183,98184,100310,109395,109396,109398,109399). There is insufficient reliable information available about the safety of sodium when used topically.

CHILDREN: LIKELY SAFE
when used orally and appropriately (26229,100310). Sodium is safe in amounts that do not exceed the CDRR intake level of 1.2 grams daily for children 1 to 3 years, 1.5 grams daily for children 4 to 8 years, 1.8 grams daily for children 9 to 13 years, and 2.3 grams daily for adolescents (100310).

CHILDREN: POSSIBLY UNSAFE
when used orally in high doses. Tell patients to avoid prolonged use of doses exceeding the CDRR intake level of 1.2 grams daily for children 1 to 3 years, 1.5 grams daily for children 4 to 8 years, 1.8 grams daily for children 9 to 13 years, and 2.3 grams daily for adolescents (100310). Higher intake can cause hypertension (26229).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Sodium is safe in amounts that do not exceed the CDRR intake level of 2.3 grams daily (100310).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in higher doses. Higher intake can cause hypertension (100310). Also, both the highest and the lowest pre-pregnancy sodium quintile intakes are associated with an increased risk of hypertensive disorders of pregnancy, including gestational hypertension and pre-eclampsia, and the delivery of small for gestational age (SGA) infants when compared to the middle intake quintile (106264).

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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 = A Cannabidiol can increase caffeine levels.  Details Caffeine is a substrate of CYP1A2, and cannabidiol has been shown to inhibit CYP1A2 metabolism. 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 (105557). Other clinical research also shows that cannabidiol modestly increases the area under the curve of caffeine but does not increase peak serum levels of caffeine (113025).

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 = A Cannabidiol may increase levels of drugs metabolized by CYP1A2.  Details In vitro research shows that cannabidiol inhibits CYP1A2 (89690,107325). Furthermore, clinical studies show that cannabidiol may inhibit the metabolism of caffeine, a CYP1A2 substrate. Two pharmacokinetic studies in healthy adults show that taking cannabidiol dosed 640 mg once up to 750 twice daily increases the area under the curve of caffeine. However, results are mixed over whether cannabidiol impacts peak serum levels of caffeine (105557,113025).

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 = A Cannabidiol may increase levels of drugs metabolized by CYP2C19.  Details Research shows that cannabidiol inhibits CYP2C19 (89694,89695,97018,97022,107325,113025). In clinical studies and case reports, cannabidiol use resulted in significant increases in the serum levels of topiramate, methadone, citalopram, omeprazole, and N-desmethylclobazam, the primary active metabolite of clobazam. These chemicals are metabolized by CYP2C19 (97018,97022,97023,102958,105491,113025). Concomitant use of cannabidiol with CYP2C19 substrates may 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 = Probable •  Level of Evidence = A Cannabidiol may increase levels of drugs metabolized by CYP2C9.  Details In vitro and animal research shows that cannabidiol inhibits CYP2C9 (89694,89695,107325,111098). In human studies, cannabidiol has been associated with an increase in plasma levels of topiramate and losartan, CYP2C9 substrates (97018,113025). Concomitant use of cannabidiol with CYP2C9 substrates may 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. However, a clinical crossover trial in healthy adults shows that cannabidiol does not inhibit dextromethorphan, a substrate of CYP2D6 (113025).

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 = Probable •  Level of Evidence = A Cannabidiol may increase levels of drugs that are metabolized by CYP3A4.  Details In vitro and animal research shows that cannabidiol inhibits CYP3A4 (89693,89694,89695,107325,111098). In human studies and case reports, cannabidiol has been associated with an increase in plasma levels of the CYP3A4 substrates zonisamide, tacrolimus, everolimus, citalopram, midazolam, and methadone (97018,100884,100892,102958,105491,113025).

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 may increase everolimus levels.  Details Everolimus is a substrate of CYP3A4 enzymes. Cannabidiol has been shown to inhibit CYP3A4 (89693,89694,89695,97018). A very small open-label clinical study shows that cannabidiol 12.5 mg/kg twice daily increases the area under the curve of a single dose of everolimus by about 2.5-fold (113053). 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).

LOSARTAN (Cozaar) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = A Cannabidiol may increase levels of losartan.  Details A crossover clinical study shows that taking cannabidiol 640 mg once increases area under the curve of losartan, a CYP2C9 substrate, by 77% (113025).

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).

MIDAZOLAM (Versed) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = A Cannabidiol may increase levels of midazolam.  Details A crossover clinical study shows that taking cannabidiol 640 mg once increases area under the curve of midazolam by 56%, likely by inhibiting CYP3A (113025).

OMEPRAZOLE (Prilosec) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = A Cannabidiol may increase levels of omeprazole.  Details A crossover clinical study shows that taking cannabidiol 640 mg once increases area under the curve of omeprazole by 207%, likely by inhibiting CYP2C19 (113025).

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).

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ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = A Theoretically, a high intake of dietary sodium might reduce the effectiveness of antihypertensive drugs.  Details High intake of dietary sodium can increase systolic and diastolic blood pressure (26222). Also, high intake of sodium may necessitate increased use of antihypertensive medications to achieve blood pressure control in some patients, such as those with chronic kidney disease (26223).

CORTICOSTEROIDS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Concomitant use of mineralocorticoids and some glucocorticoids with sodium supplements might increase the risk of hypernatremia.  Details Mineralocorticoids and some glucocorticoids (corticosteroids) cause sodium retention. This effect is dose-related and depends on mineralocorticoid potency. It is most common with hydrocortisone, cortisone, and fludrocortisone, followed by prednisone and prednisolone (4425).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Altering dietary intake of sodium might alter the levels and clinical effects of lithium.  Details High sodium intake can reduce plasma concentrations of lithium by increasing lithium excretion (26225). Reducing sodium intake can significantly increase plasma concentrations of lithium and cause lithium toxicity in patients being treated with lithium carbonate (26224,26225). Stabilizing sodium intake is shown to reduce the percentage of patients with lithium level fluctuations above 0.8 mEq/L (112909). Patients taking lithium should avoid significant alterations in their dietary intake of sodium.

SODIUM-CONTAINING DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Concomitant use of sodium-containing drugs with additional sodium from dietary or supplemental sources may increase the risk of hypernatremia and long-term sodium-related complications.  Details The Chronic Disease Risk Reduction (CDRR) intake level of 2.3 grams of sodium daily indicates the intake at which it is believed that chronic disease risk increases for the apparently healthy population (100310). Some medications contain high quantities of sodium. When used in conjunction with sodium supplements or high-sodium diets, the CDRR may be exceeded. Additionally, concomitant use may increase the risk for hypernatremia; this risk is highest in the elderly and people with other risk factors for electrolyte disturbances.

TOLVAPTAN (Samsca) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Theoretically, concomitant use of tolvaptan with sodium might increase the risk of hypernatremia.  Details Tolvaptan is a vasopressin receptor 2 antagonist that is used to increase sodium levels in patients with hyponatremia (29406). Patients taking tolvaptan should use caution with the use of sodium salts such as sodium chloride.

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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). A case of ventricular bigeminy and a case of circulatory collapse have been considered to be related to treatment with a specific oromucosal spray that contains cannabidiol 2.5 mg and delta-9-tetrahydrocannabinol (THC) 2.7 mg per actuation (Sativex, GW Pharmaceuticals) (61759,61820).

Dermatologic ...Orally, cannabidiol might cause rare skin reactions (105696,109178). In a clinical study in healthy adults, 2 cases of skin reactions, one severe and one mild, were reported (105696). These and 2 additional cases were reported in a follow-up publication specific to cannabidiol-induced skin rash (109178). The rash occurred in 4 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 suggests that rash makes up approximately 6% of all adverse effects related to oral cannabidiol use, and one meta-analysis of 3 clinical trials in patients with epilepsy shows that taking cannabidiol is associated with about a 3-fold relative risk of rash compared with placebo (110244,113032).
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). In one case, persistent diarrhea and eosinophilic esophagitis due to cannabidiol oil were resolved with dose reduction from 20 mg/kg/day to 15 mg/kg/day in a 13-year-old female with epilepsy (113049). 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). However, other rare gastrointestinal events are reported. One case reports cannabinoid hyperemesis syndrome that resolved completely 2 months after cessation in a teenaged male taking cannabidiol 15 mg/kg/day chronically (113040).
Cannabis oromucosal spray that contains cannabidiol 2.5 mg and delta-9-tetrahydrocannabinol (THC) 2.7 mg per actuation (Sativex, GW Pharmaceuticals) can cause dizziness, dry mouth, nausea, and bad taste (61759,61764,61820,61896,61909,108698). Less commonly, this product may cause red and white buccal mucosal patches to develop inside the mouth (61820).

Hepatic ...Orally, cannabidiol oil has been associated with an elevation in liver transaminases and drug-induced liver injury (DILI). A meta-analysis of 12 clinical trials shows that taking cannabidiol daily is associated with approximately 5 times greater odds of DILI and 6 times greater odds of liver enzyme elevations when compared with placebo (113045). However, many patients were on concomitant medications that can also cause liver injury. A systematic review has also found that elevated liver transaminases make up about 13% of adverse effects related to cannabidiol use (110244). 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). In an observational study, elevated liver function tests occurred in 2.7% of patients who took prescription cannabidiol oil (Epidiolex) and were the reason for discontinuation in 1 of 25 patients (113034). Pharmacogenetic variation has also been shown to affect susceptibility to liver transaminase elevations with cannabidiol use (107324).
Conversely, 2 large observational studies suggest 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 these studies was about 50-55 mg, which is much lower than the doses reported in cases of elevated liver transaminases (107336,113041).
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)(104890,106631,106633,107327,110244,113024).

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)(110248,110249,113024,113034), 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). In an observational study, sedation occurred in approximately 17% of patients who took prescription cannabidiol oil (Epidiolex) and was the reason for discontinuation in about 1 in 5 patients (113034). Pharmacogenetic variation has 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). Cannabis extract oromucosal spray that contains cannabidiol 2.5 mg and delta-9-tetrahydrocannabinol (THC) 2.7 mg per actuation (Sativex, GW Pharmaceuticals) can cause dizziness, lightheadedness, sleepiness, and fatigue (61759,61764,61820,61896,61909,96814). Additionally, a small study in healthy adults shows that consumption of brownies containing cannabidiol 640 mg plus THC 20 mg increases feelings of sedation and memory impairment when compared with brownies containing only THC 20 mg (111092). 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).

Psychiatric ...Limited research suggests that consuming large amounts of cannabidiol might increase the adverse effects of delta-9-tetrahydrocannabinol (THC). A small study in healthy adults shows that consumption of brownies containing cannabidiol 640 mg plus THC 20 mg increases feelings of anxiety, paranoia, and irritability when compared with brownies containing only THC 20 mg (111092).

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 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).
Using a specific oromucosal spray that contains cannabidiol 2.5 mg and delta-9-tetrahydrocannabinol 2.7 mg (THC) per actuation (Sativex, GW Pharmaceuticals) may cause pharyngitis, hoarseness, and throat irritation (61759).

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, sodium is well tolerated when used in moderation at intakes up to the Chronic Disease Risk Reduction (CDRR) intake level. Topically, a thorough evaluation of safety outcomes has not been conducted.
Serious Adverse Effects (Rare):
Orally: Worsened cardiovascular disease, hypertension, kidney disease.

Cardiovascular ...Orally, intake of sodium above the CDRR intake level can exacerbate hypertension and hypertension-related cardiovascular disease (CVD) (26229,98176,100310,106263). A meta-analysis of observational research has found a linear association between increased sodium intake and increased hypertension risk (109398). Observational research has also found an association between increased sodium salt intake and increased risk of CVD, mortality, and cardiovascular mortality (98177,98178,98181,98183,98184,109395,109396,109399). However, the existing research is unable to confirm a causal relationship between sodium intake and increased cardiovascular morbidity and mortality; high-quality, prospective research is needed to clarify this relationship (100312). As there is no known benefit with increased salt intake that would outweigh the potential increased risk of CVD, advise patients to limit salt intake to no more than the CDRR intake level (100310).
A reduction in sodium intake can lower systolic blood pressure by a small amount in most individuals, and diastolic blood pressure in patients with hypertension (100310,100311,106261). However, post hoc analysis of a small crossover clinical study in White patients suggests that 24-hour blood pressure variability is not affected by high-salt intake compared with low-salt intake (112910). Additionally, the available research is insufficient to confirm that a further reduction in sodium intake below the CDRR intake level will lower the risk for chronic disease (100310,100311). A meta-analysis of clinical research shows that reducing sodium intake increases levels of total cholesterol and triglycerides, but not low-density lipoprotein (LDL) cholesterol, by a small amount (106261).
It is unclear whether there are safety concerns when sodium is consumed in amounts lower than the adequate intake (AI) levels. Some observational research has found that the lowest levels of sodium intake might be associated with increased risk of death and cardiovascular events (98181,98183). However, this finding has been criticized because some of the studies used inaccurate measures of sodium intake, such as the Kawasaki formula (98177,98178,101259). Some observational research has found that sodium intake based on a single 24-hour urinary measurement is inversely correlated with all-cause mortality (106260). The National Academies Consensus Study Report states that there is insufficient evidence from observational studies to conclude that there are harmful effects from low sodium intake (100310).

Endocrine ...Orally, a meta-analysis of observational research has found that higher sodium intake is associated with an average increase in body mass index (BMI) of 1. 24 kg/m2 and an approximate 5 cm increase in waist circumference (98182). It has been hypothesized that the increase in BMI is related to an increased thirst, resulting in an increased intake of sugary beverages and/or consumption of foods that are high in salt and also high in fat and energy (98182). One large observational study has found that the highest sodium intake is not associated with overweight or obesity when compared to the lowest intake in adolescents aged 12-19 years when intake of energy and sugar-sweetened beverages are considered (106265). However, in children aged 6-11 years, usual sodium intake is positively associated with increased weight and central obesity independently of the intake of energy and/or sugar-sweetened beverages (106265).

Gastrointestinal ...In one case report, severe gastritis and a deep antral ulcer occurred in a patient who consumed 16 grams of sodium chloride in one sitting (25759). Chronic use of high to moderately high amounts of sodium chloride has been associated with an increased risk of gastric cancer (29405).

Musculoskeletal ...Observational research has found that low sodium levels can increase the risk for osteoporosis. One study has found that low plasma sodium levels are associated with an increased risk for osteoporosis. Low levels, which are typically caused by certain disease states or chronic medications, are associated with a more than 2-fold increased odds for osteoporosis and bone fractures (101260).
Conversely, in healthy males on forced bed rest, a high intake of sodium chloride (7.7 mEq/kg daily) seems to exacerbate disuse-induced bone and muscle loss (25760,25761).

Oncologic ...Population research has found that high or moderately high intake of sodium chloride is associated with an increased risk of gastric cancer when compared with low sodium chloride intake (29405). Other population research in patients with gastric cancer has found that a high intake of sodium is associated with an approximate 65% increased risk of gastric cancer mortality when compared with a low intake. When zinc intake is taken into consideration, the increased risk of mortality only occurred in those with low zinc intake, but the risk was increased to approximately 2-fold in this sub-population (109400).

Pulmonary/Respiratory ...In patients with hypertension, population research has found that sodium excretion is modestly and positively associated with having moderate or severe obstructive sleep apnea. This association was not found in normotensive patients (106262).

Renal ...Increased sodium intake has been associated with impaired kidney function in healthy adults. This effect seems to be independent of blood pressure. Observational research has found that a high salt intake over approximately 5 years is associated with a 29% increased risk of developing impaired kidney function when compared with a lower salt intake. In this study, high salt intake was about 2-fold higher than low salt intake (101261).

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