Omega CBD by NS Natural Stacks

LIKELY EFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about CANNABIDIOL (CBD))

POSSIBLY EFFECTIVE

• Hyperlipidemia. Most research shows that taking oral DHA alone or with eicosapentaenoic acid (EPA) seems to modestly reduce triglyceride levels. However, DHA does not decrease total cholesterol and may increase levels of low-density lipoprotein (LDL) cholesterol. Details: Clinical research shows that taking DHA 1.25-4 grams daily for up to 7 weeks can reduce triglyceride levels by 17% to 24% in adult patients with mild hyperlipidemia, dyslipidemia, or hypertriglyceridemia (6143,48013,48338). Also, taking DHA-enriched fish oil providing DHA 810 mg plus EPA 210 mg daily for 8 weeks reduces triglyceride levels by 23% in premenopausal adults with mild hypertriglyceridemia (99131). Most clinical research suggests that DHA does not decrease total cholesterol (6143,48013,99131). Although some conflicting research exists, most research suggests that DHA modestly increases HDL cholesterol (6143,48013,48338,99131,109216). Most clinical research shows that DHA increases LDL cholesterol by about 8% to 13.6% (6143,48174,48338,109216). However, it may actually decrease levels of small, dense LDL particles (48174). There are conflicting results regarding the effects of DHA on cholesterol levels in children. One preliminary clinical study in children with primary hyperlipidemia shows that taking DHA 500 mg alone or along with EPA does not improve cholesterol levels when compared with control. However, this study was probably too small to detect statistically significant changes (90712). Other research in children aged 9 years and up with familial hypercholesterolemia or familial combined hyperlipidemia shows that taking DHA (DHASCO oil, Martek Biosciences Corp.) 1.2 grams daily for 6 weeks along with the National Cholesterol Education Program Step II (NCEP-II) diet actually increases total cholesterol and LDL cholesterol when compared to following the diet alone (48078,48083). However, some clinical research shows that DHA increases the large buoyant type of LDL particles, but actually decreases the small, dense type (48083).
• Preterm labor. Most research shows that oral DHA seems to prevent preterm labor in those with low DHA status at baseline. Details: A large clinical trial shows that taking DHA 1000 mg daily during pregnancy, starting at 12-20 weeks' gestation and continuing until delivery, results in an early preterm birth rate of 1.7%, compared with 2.4% in those taking DHA 200 mg daily. Benefits were strongest in those with low DHA status at baseline, with no benefit in those with high DHA status at baseline and in those with high adherence to DHA 1000 mg daily (109204,110360). A secondary analysis of two studies shows that taking DHA 800 mg from algal oil or 1000 mg from fish oil modestly reduces the early preterm and preterm birth rates in those with a low DHA status at baseline compared with taking DHA 200 mg (110361). However, conflicting evidence exists. Some clinical research shows that taking DHA during pregnancy does not reduce the risk of preterm delivery. One study has used a specific fish oil supplement (Incromega DHA 500TG) 900 mg containing DHA 800 mg and eicosapentaenoic acid (EPA)100 mg daily, starting at 20 weeks' gestation and continuing to delivery or 34 weeks' gestation (101505). In another clinical trial, use of a high-DHA fish oil, providing EPA 100 mg and DHA 800 mg daily, from before 20 weeks' until 34 weeks' gestation, increases the risk of preterm birth prior to 34 weeks' gestation when compared with placebo in patients with baseline omega-3 status of greater than 4.9%. However, the risk is reduced from 3.2% to 0.7% in patients with baseline omega-3 status below 4.1%. In addition, taking this high-DHA fish oil had no effect on the risk of preterm birth prior to 37 weeks' gestation (103496). The reasons for any discrepancies may be due to the baseline omega-3 status, the use of algal or fish oil as the source of DHA, and/or the specific timing of preterm labor.

POSSIBLY INEFFECTIVE

• Age-related cognitive decline. Most research shows that taking oral DHA alone or with other ingredients does not slow or improve cognitive decline associated with age. Details: Most clinical research, from individual studies and a meta-analysis, shows that taking DHA orally, alone or with additional eicosapentaenoic acid (EPA) for up to 36 months, does not slow or improve age-related cognitive decline (97175,103313). In contrast, results from one large clinical study show that taking DHA 900 mg daily in the absence of EPA for 24 weeks improves episodic memory and visuospatial learning when compared with placebo in patients with age-related cognitive decline. However, DHA did not affect working memory or executive function (90717).
• Alzheimer disease. Taking oral DHA does not seem to slow Alzheimer disease progression. Details: Population research has found that a 0.1 gram per day increment of dietary DHA intake is associated with a 37% reduced risk of Alzheimer disease when taken for 2-21 years (15041,96527). However, a dose-response relationship was not seen, and a correlation between DHA blood concentration and dementia was not seen (96527). Furthermore, clinical research shows that taking DHA 2 grams daily for 18 months does not slow cognitive or functional decline in patients with mild to moderate Alzheimer disease (48290). DHA has also been examined in combination with other ingredients. Preliminary clinical research in patients with mild to moderate Alzheimer disease shows that taking DHA 500 mg, as part of fish 1 gram with eicosapentaenoic acid (EPA) 150 mg, and along with lutein 10 mg, zeaxanthin 2 mg, meso-zeaxanthin 10 mg, and vitamin E 15 mg (Memory Health) daily for 12 months does not affect disease severity when compared with placebo. However, there were modest increases the number of patients experiencing either an improvement or an attenuated decline in memory and mood (109764). The effect of DHA alone is unclear from this study.
• Attention deficit-hyperactivity disorder (ADHD). Most research shows that taking oral DHA does not improve ADHD symptoms. Details: Low plasma levels of DHA are associated with ADHD in children (7599,15496). Although some preliminary clinical research shows that DHA might improve aggression, emotional problems, and social relationships in children with ADHD (15494,100940), taking DHA 345-500 mg daily or 3.6 grams weekly does not seem to improve objective or subjective measures of ADHD symptoms when compared with placebo (7599,15495,100940).
• Bronchopulmonary dysplasia. Most research shows that oral DHA does not prevent bronchopulmonary dysplasia (BPD) in preterm infants. Some research suggests that it might increase the risk of BPD in infants born before 29 weeks gestation. Details: One meta-analysis of clinical research in over 3,500 preterm infants shows that administration of EPA and DHA as part of formula or as a direct oral dose, starting within one month of birth, does not increase or decrease the risk for BPD, regardless of the dose of DHA administered (102390). A more recent meta-analysis of four clinical trials limited to infants born less than 29 weeks gestation also shows that administration of DHA at levels of at least 40 mg/kg, or at levels of at least 0.4% total fatty acids in breast milk or formula, does not increase or decrease the risk of bronchopulmonary dysplasia (110359). However, in this latter meta-analysis, when only clinical trials using a more stringent definition of bronchopulmonary dysplasia were included, there was a modest INCREASED risk (110359). Similar findings occurred in a study that was terminated early. This research shows that maternal supplementation with DHA 1.2 grams daily, starting within 72 hours of delivery of infants born before 29 weeks gestation, has no effect on mortality of breastfed infants or survival without BPD at 36 weeks postmenstrual age. However, the occurrence of BPD and severe BPD in surviving infants of mothers taking DHA were increased when compared to those whose mothers took placebo (104559). The conclusions of this study are limited by the early termination, the provision of intravenous DHA-rich lipids to some infants per standard of clinical care, and the increased number of infants born via cesarean delivery to the mothers randomized to DHA. A more recent clinical trial has investigated the inclusion of arachidonic acid in an enteral emulsion providing DHA. One clinical trial in preterm infants born before 29 weeks gestation shows that supplementation with an enteral emulsion containing DHA 50 mg/kg and arachidonic acid 100 mg/kg (Formulaid, DSM Nutritional Products Inc.) until 36 weeks postmenstrual age does not increase the risk of bronchopulmonary dysplasia or other major morbidities compared to control (MCToil, Nutricia) emulsion. Also, infants given the arachidonic acid and DHA required 17 fewer days of respiratory support (110356).
• Cognitive function. Most research shows that oral DHA does not improve cognitive function in healthy adults. Details: Most clinical research shows that taking DHA 250-1000 mg daily for up to 6 months does not improve cognitive function in healthy children, healthy adults, or older females (48194,48216,48266,90668,90708,104560). Also, cognitive function does not seem to be improved when compared with placebo in trials in which omega-3 products containing higher ratios of DHA to eicosapentaenoic acid (EPA) were used. These trials have used a specific product (Efamol Ltd) containing DHA 1.16 grams and EPA 0.17 grams daily (90707), DHA 900 mg plus EPA 270 mg (Accelon DHA EE, BASF) daily (109215), or fish oil (Dasbrain, Max Biocare) providing DHA 520 mg or 270 mg daily (109310), for 3 or 6 months in children and adults. However, some clinical research shows that taking algal oil containing DHA 600 mg daily for 16 weeks improves reading scores when compared with placebo in a subgroup of children ages 6-10 years who are below the 20th percentile for reading (90699). However, these results could not be replicated in a later study that included only children below the 20th percentile for reading (98542). The reason for this discrepancy is not clear. Taking DHA does not appear to improve reading scores in children at or above the 20th percentile for reading, and there does not appear to be any benefit of DHA on working memory in any children (90699).
• Cystic fibrosis. Most research shows that oral DHA does not improve symptoms of cystic fibrosis. Details: Clinical research in infants, children, and young adults with cystic fibrosis shows that taking DHA (DHA-basic, CASEN Fleet SLU) 50 mg/kg daily for 48 weeks does not improve spirometry measures, reduce Pseudomonas aeruginosa primary infections, or reduce the number of, or time to, total or severe pulmonary exacerbations when compared with placebo (109217). Also, small clinical studies show that taking DHA 70 mg/kg daily for 6 weeks, or 100 mg/kg daily for one month and then 1 gram daily for 11 months, does not improve lung function or overall health in patients with cystic fibrosis (48119,90665).
• Depression. Most research shows that oral DHA does not improve depression, regardless of the type. Details: Taking DHA orally does not seem to relieve symptoms of major depression, peripartum depression, or postpartum depression in most patients (10869,48030,48238,90680,90691,90692,89353,102391). Also, taking DHA for two weeks prior to the start of interferon-alpha therapy does not appear to prevent depression during interferon-alpha treatment in patients with hepatitis C, although it may delay depression onset by about 6 weeks (90710).
• Macrosomia. Taking oral DHA during pregnancy does not seem to prevent fetal macrosomia. Details: Clinical research in overweight or obese individuals shows that taking DHA (S-oil, DSM Nutritional Products) 800 mg daily, starting before 15 weeks' gestation and continuing until delivery, with or without dietary counselling, does not reduce the incidence of macrosomia when compared with taking DHA 200 mg daily (109218).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Increased dietary consumption of DHA is associated with a decreased risk of AMD (10324). Preliminary clinical research shows that taking a combination of DHA 280 mg, lutein 12 mg, and zeaxanthin 0.6 mg daily for one year increases macular pigment optical density by 31% when compared with placebo in patients with AMD. Increased macular pigment optical density is associated with improve vision performance and a reduced risk of AMD (90678). However, other clinical research suggests that adding DHA plus EPA to an AREDS formula, with or without lutein and zeaxanthin, does not reduce the time to development of AMD or vision loss in patients at high risk of progression to advanced AMD when compared with the AREDS formula alone (60281).
• Allergic rhinitis (hay fever). Although there has been interest in using oral DHA for allergic rhinitis, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Atopic dermatitis (eczema). It is unclear if adding DHA to infant formula prevents atopic dermatitis. Details: Evidence from an observational, open-label study shows that giving full-term infants formula with added DHA 17 mg/100 kcal and arachidonic acid 34 mg/100 kcal (Enfamil Premium 1 and Enfamil Premium 2, Mead Johnson Nutrition) as needed for 12 months does not prevent the development of eczema when compared to control formulas without DHA and arachidonic acid (92505).
• Atopic disease. It is unclear if oral DHA during pregnancy prevents atopic disease in the infant. Details: Clinical research shows that supplementation with DHA during pregnancy may modestly protect against some respiratory symptoms in the infants of atopic mothers. Prenatal supplementation with DHA 400 mg, taken daily from 18-22 weeks gestation until delivery, reduces the incidence of phlegm with nasal discharge or nasal congestion in the infant by the age of 18 months by approximately 22% and the incidence of fever with phlegm and nasal discharge or nasal congestion in the infant by approximately 47% when compared with placebo (90676). However, it is unclear if these symptoms are due to atopy or infections.
• Atrial fibrillation. Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Population research suggests that adipose tissue levels of DHA are not associated with a decreased risk of atrial fibrillation (90700). However, clinical research suggests that taking 2 grams per day of a combination of DHA plus EPA (2:1 ratio), starting 7 days before cardiac surgery and continuing until hospital discharge, reduces the relative risk of post-cardiac surgery atrial fibrillation by 72% when compared with placebo. These patients also received vitamin C 1 gram daily plus vitamin E 400 IU daily, starting 2 days prior to surgery and continuing until discharge (90701).
• Autism spectrum disorder. It is unclear if oral DHA is beneficial for autism. Details: One preliminary clinical study shows that taking DHA 200 mg daily for 6 months does not improve autism symptoms in children and may even worsen some behaviors (90713). Another preliminary clinical study in children and adults with autism shows that taking a specific product (SUNTGA40S, Aravita, Suntory Ltd) containing DHA, arachidonic acid, and astaxanthin daily for 16 weeks does not improve overall symptoms when compared with placebo, although the combination product may improve certain symptoms such as social withdrawal or social communication (90716).
• Behcet disease. Although there has been interest in using oral DHA for Behcet disease, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Bipolar disorder. It is unclear if oral DHA is beneficial for bipolar disorder in adults. Details: A small clinical trial shows that taking DHA 1250 mg daily for 12 weeks does not improve cognitive function when compared with placebo in patients with bipolar disorder (103312).
• Breast cancer. It is unclear if oral DHA is beneficial for breast cancer treatment or prevention. Details: Population research has found no association between dietary fatty acid intake, including DHA, and the risk of breast cancer (96528). The effect of DHA supplementation on breast cancer risk is unknown. Some early research has investigated the effects of DHA in patients with breast cancer. Preliminary clinical research shows that taking DHA (DHASCO, Martek Biosciences Corp.) 600 mg three times daily for 7-10 days prior to chemotherapy initiation, and then for 5 months during chemotherapy, induces complete or partial response in 44% of breast cancer patients. Patients with a greater increase in DHA levels (at least 2.5%) show a longer time to progression and longer survival when compared to those with a smaller increase in DHA levels (90671).
• Cancer. Taking oral DHA with oral eicosapentaenoic acid (EPA) does not seem to decrease the risk of cancer in patients with cardiovascular disease and may actually INCREASE the risk of cancer in females. The effect of DHA alone is unclear. Details: Clinical research suggests that taking a combination of EPA 400 mg plus DHA 200 mg, with or without B vitamins, for a median of 4.7 years does not reduce the risk of cancer in middle-aged and elderly patients with cardiovascular disease. Furthermore, this combination appears to increase the risk of cancer in females (90666).
• Child development. It is unclear if oral DHA is beneficial for child development. However, due to the lack of significant safety concerns and the possibility of some cognitive benefit, many experts recommend DHA 200 mg daily during pregnancy. Details: Clinical research shows that giving infants DHA-supplemented formula during infancy does not appear to improve language and school readiness by the age of 2-3.5 years, or improve neurodevelopment by the age of 6 years (90674,92503). In addition, most research suggests that DHA supplementation during pregnancy, occasionally continuing postpartum for 6 months, does not affect visual acuity, attention, working memory, behavior and most other measures of neurodevelopment by 1-7 years of age (48095,48285,48293,90679,90690,94600,96522,109219). There is some evidence to suggest that maternal supplementation with DHA 400 mg daily from 16 weeks gestation until delivery may reduce the risk of poor language development in the infant at age 14 and 18 months and the risk of lower visual acuity at 2 months when compared with placebo (90694); however, this benefit did not have lasting effects at 5-6 years of age (99133).
• Cognitive impairment. It is unclear if oral DHA is beneficial for cognitive impairment in the elderly. Details: Clinical research shows that taking DHA 800 mg daily, alone or with folic acid 800 mcg daily for 6 months, modestly improves some measures of cognitive function when compared with placebo in elderly patients with mild cognitive impairment (103978). Also, taking a specific product (Vayacog, Enzymotec Ltd.) providing phosphatidylserine 300 mg, DHA about 59 mg, and eicosapentaenoic acid (EPA) about 20 mg daily for 15 weeks improves verbal immediate recall when compared with placebo (94665). However, other research in elderly patients with mild cognitive impairment disagrees. One clinical trial shows that taking DHA 1491 mg plus EPA 351 mg daily for 12 months does not improve cognitive measures when compared with placebo (109220). In addition, taking DHA along with EPA and other ingredients for up to 24 weeks does not significantly improve memory, forgetfulness, or other measures of cognition in elderly patients with mild cognitive impairment (90704,94665). Also, a small clinical study shows that taking DHA 720 mg daily along with EPA and other ingredients for 12 weeks does not significantly improve memory, forgetfulness, or other measures of cognition (62847).
• Coronary heart disease (CHD). It is unclear if oral DHA is beneficial for CHD. Details: Increased dietary consumption of DHA may reduce the risk of death in patients with CHD (10322). However, the effect of DHA supplements is unclear.
• Crohn disease. It is unclear if oral DHA is beneficial for Crohn disease prevention. Details: Population research suggests that increased dietary intake of DHA is associated with a reduced risk of Crohn disease (90673).
• Dementia. It is unclear if oral DHA is beneficial for dementia prevention. Details: Population research has found that a 0.1 gram per day increment of dietary DHA intake is associated with a 14% reduced risk of dementia when taken for 2-21 years. However, a dose-response relationship was not seen, and a correlation between DHA blood concentration and dementia was not seen (96527).
• Developmental coordination disorder (DCD). Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in children with DCD shows that taking a tuna fish oil product providing DHA 480 mg daily for 4 months, in combination with evening primrose oil providing arachidonic acid 35 mg and gamma-linolenic acid 96 mg, thyme oil 24 mg, and vitamin E 80 mg (Efalex, Efamol Ltd.), modestly decreases movement disorders as determined by objective measures when compared with baseline (5708). It is unclear if these benefits are due to DHA, other ingredients, or the combination. Also, the validity of this finding is limited by the lack of a comparator group.
• Diabetes. It is unclear if oral DHA is beneficial for glycemic control or the prevention of type 1 or gestational diabetes. Details: A small clinical study in adults with type 2 diabetes shows that taking DHA orally does not improve levels of low-density lipoprotein (LDL) cholesterol or decrease blood sugar or glycated hemoglobin. However, triglyceride levels are reduced (10321). DHA has also been evaluated for the prevention of gestational or type 1 diabetes. Clinical research in overweight or obese individuals shows that taking DHA (S-oil, DSM Nutritional Products) 800 mg daily, starting before 15 weeks' gestation and continuing until delivery, with or without dietary counselling, does not reduce the incidence of gestational diabetes when compared with taking DHA 200 mg daily (109218). Additionally, population research suggests that maternal serum levels of DHA are not associated with the risk of childhood onset of type 1 diabetes (90705).
• Diabetic retinopathy. Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with diabetic macular edema related to diabetic retinopathy receiving ranibizumab shows that taking a combination supplement containing DHA 1050 mg daily along with other free fatty acids, minerals, and vitamins (Brudyretina, Brudy Lab S.L.) for 2 years reduces macular thickness, but not visual acuity, when compared with ranibizumab alone. The effect of DHA alone is unknown (96526).
• Diarrhea. It is unclear if infant formula containing DHA is beneficial for diarrhea prevention. Details: Preliminary clinical research suggests that giving full-term infants formula with added DHA 17 mg/100 kcal and arachidonic acid 34 mg/100 kcal (Enfamil Premium 1 and Enfamil Premium 2, Mead Johnson Nutrition) as needed for 12 months reduces the incidence of diarrhea requiring medical attention when compared to control formulas (92505).
• Dyslexia. It is unclear if oral DHA is beneficial for improving night vision in children with this condition. Details: One small clinical study in children with dyslexia shows that taking fish oils rich in DHA, providing 480 mg daily for one month, seem to develop significantly better dark adaptation when compared with controls (5708).
• Dysmenorrhea. Although there has been interest in using oral DHA for dysmenorrhea, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Fractures. Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical study shows that taking omega-3 fatty acids 1 gram daily, providing DHA 660 mg and eicosapentaenoic acid (EPA) 330 mg, for 3 years does not prevent fractures in adults over 70 years of age when compared with placebo. These findings were consistent in adults taking omega-3 fatty acids alone or combined with vitamin D 2000 IU daily and/or strength training three times weekly (104619).
• Hypertension. It is unclear if oral DHA is beneficial for reducing blood pressure in adults or if prenatal supplementation reduces blood pressure in children. Details: Clinical research shows that taking DHA-enriched canola oil containing 63% oleic acid and 6% DHA for 4 weeks reduces systolic blood pressure by 3% and diastolic blood pressure by 4% when compared to baseline in adults with at least one cardiovascular risk factor (26466). A meta-analysis of clinical research in adults with dyslipidemia shows that supplemental DHA reduces diastolic, but not systolic, blood pressure when compared with control (102389). A large clinical study shows that taking omega-3 fatty acids 1 gram daily, providing DHA 660 mg and eicosapentaenoic acid (EPA) 330 mg, for 3 years does not reduce blood pressure levels in adults over 70 years of age when compared with placebo. These findings were consistent in adults taking omega-3 fatty acids alone or combined with vitamin D 2000 IU daily and/or strength training three times weekly. About 39% of the individuals included in this study were diagnosed with hypertension and about 50% were using antihypertensives (104619). The effect of DHA alone on blood pressure levels in a population of adults with diagnosed hypertension is unclear. Prenatal supplementation with DHA has also been evaluated for the prevention of hypertension in children. A secondary analysis of a large clinical trial shows that overweight children or children with obesity whose mothers took DHA 600 mg daily, starting at about 14.5 weeks' gestation and continuing until birth, have lower diastolic and systolic blood pressure at 5 years of age when compared with those whose mothers took placebo. Systolic and diastolic blood pressure were reduced by about 4 mm Hg and 5 mm Hg, respectively, in the children exposed to DHA during pregnancy when compared with those exposed to placebo. The blood pressure of the children exposed to DHA during pregnancy was similar to that of children with normal weight (98891). Results of this study are limited by the fact that confounding factors, such as shorter duration of breast-feeding and increased sodium intake for children with obesity in the placebo group, may have also contributed to differences in blood pressure. It is unclear if this reduction in elevated blood pressure during childhood reduces the risk of hypertension in adulthood.
• IgA nephropathy. Although there has been interest in using oral DHA for IgA nephropathy, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Infant development. Infant supplementation with DHA does not seem to improve development. Also, most evidence shows that maternal supplementation with DHA is not beneficial for infant cognitive development. However, due to the lack of significant safety concerns and the possibility of some cognitive benefit, many experts recommend DHA 200 mg daily during pregnancy. Details: Most clinical research shows that giving healthy, full-term infants formula supplemented with DHA 0.32% to 0.96% modestly improves measures of visual acuity at 2, 4, and 12 months of age when compared with standard infant formula (14403,15003,47980,48355,90670). However, formula supplemented with DHA 0.15% does not appear to improve visual acuity by about 12 months when given to preterm infants (48008). There is some evidence that giving healthy, full-term infants DHA-supplemented formula during infancy might improve language comprehension and development, as well as fine motor skills, by the age of 12-14 months when compared with standard formula (48247,48356). However, most clinical research, including meta-analyses of high-quality clinical trials, shows that giving infants formula supplemented with DHA during infancy does not improve overall cognition or motor skills at 12-14 months of age, regardless of DHA dosing or prematurity status (48247,48356,89363). Experts generally recommend breast-feeding as the preferred feeding method over DHA-supplemented formula; however, if formula is used, some experts suggest a formula providing at least 0.2% of lipids from DHA (14403). Some population research suggests that higher maternal DHA levels are associated with improved use of gestures and problem solving in infants (90709,99132). However, population research suggests that higher maternal DHA levels also appear to be associated with worsening mental development (90709), and most clinical research shows that maternal ingestion of DHA has little effect on fetal or infant development. Maternal ingestion of DHA 33-133 mg daily from an egg source or 400 mg daily from an algal-based source does not seem to significantly increase weight, length, or head circumference at birth (14395,48286). Also, maternal ingestion of DHA 200-400 mg daily from week 15-22 of pregnancy until term does not significantly improve visual or auditory development in term infants (14393,90706). A small clinical trial shows that taking DHA 1440 mg daily from fish oil also providing eicosapentaenoic acid (EPA) 260 mg, from 22-24 weeks gestation until delivery, does not improve most measures of developmental or behavioral milestones in the infant at 6 months, when compared with olive oil placebo (110354). In addition, most research suggests that DHA supplementation during pregnancy, occasionally continuing postpartum for 6 months, does not affect growth to age 18 months or visual acuity, attention, working memory, behavior and most other measures of neurodevelopment by 1-7 years of age (48095,48285,48293,90679,90690,94600,96522,109219). However, there is some evidence to suggest that maternal supplementation with DHA 214 mg daily may improve infant sleep patterning on the first day of life (90687). Also, maternal supplementation with DHA 400 mg daily from 16 weeks gestation until delivery may reduce the risk of poor language development in the infant at age 14 and 18 months and the risk of lower visual acuity at 2 months when compared with placebo (90694). However, this benefit did not have lasting effects at 5-6 years of age (99133).
• Intraventricular hemorrhage. It is unclear if oral DHA is beneficial for preventing intraventricular hemorrhage in premature infants. Details: Preliminary clinical research in infants born before 29 weeks gestation shows that supplementation with an enteral emulsion containing DHA 50 mg/kg and arachidonic acid 100 mg/kg (Formulaid, DSM Nutritional Products Inc.) until 36 weeks postmenstrual age has no effect on the incidence of intraventricular hemorrhage when compared with a control emulsion (110356).
• Keratoconus. It is unclear if oral DHA is beneficial for improving vision in people with keratoconus. Details: A small clinical trial in patients with early to advanced keratoconus shows that taking DHA 1000 mg daily for 3 months does not improve corneal thickness, measurements of corneal curve, or most other ophthalmological measures when compared with taking no DHA (110358).
• Lower respiratory tract infections. It is unclear if formula containing DHA is beneficial for preventing lower respiratory tract infections in infants. Details: Clinical research shows that giving preterm infants formula or breast milk containing high-dose DHA (1% of fatty acids) does not prevent hospitalizations due to bronchiolitis and other lower respiratory tract conditions when compared with giving breast milk or formula containing 0.35% DHA (90667). However, preliminary clinical research shows that giving full-term infants formula with added DHA 17 mg/100 kcal and arachidonic acid 34 mg/100 kcal (Enfamil Premium 1 and Enfamil Premium 2, Mead Johnson Nutrition) as needed for 12 months reduces the risk of bronchiolitis and croup when compared with control formulas (92505).
• Male infertility. It is unclear if oral DHA is beneficial for improving fertility. Details: Clinical research shows that taking DHA (NuaDHA, Nua Biological Innovations SL) 0.5, 1, or 2 grams daily for 3 months increases progressive sperm motility by 24% to 30% when compared with placebo in men with a history of infertility. The greatest effects were seen in men with asthenozoospermia, with an overall effect of 35 (99134). It is unclear if the effects of DHA on sperm function correlate with increased fertility rates.
• Metabolic syndrome. Although there has been interest in using oral DHA for metabolic syndrome, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Migraine headache. Although there has been interest in using oral DHA for migraine headache, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Muscle strength. It is unclear if oral DHA is beneficial for increasing muscle strength. Details: A large clinical study shows that taking omega-3 fatty acids 1 gram daily, providing DHA 660 mg and eicosapentaenoic acid (EPA) 330 mg, for 3 years does not increase muscle strength in adults over 70 years of age when compared with placebo. These findings were consistent in adults taking omega-3 fatty acids alone or combined with vitamin D 2000 IU daily and/or strength training three times weekly (104619).
• Necrotizing enterocolitis (NEC). It is unclear if oral DHA is beneficial for preventing NEC in preterm infants. Details: Clinical research in preterm infants shows that providing DHA (Neuromins for Kids life's DHA; DSM Nutritional Products Inc.) 75 mg/kg for 14 days from the first enteral feed reduces the risk of confirmed NEC by 7% when compared with a control oil. Treatment of 15 infants with DHA would be needed to prevent one case of NEC (109213). However, preliminary clinical research shows that maternal supplementation with DHA 1.2 grams daily, starting within 72 hours of delivery of infants born before 29 weeks' gestation, has no effect on the incidence of NEC in breastfed infants at 36 weeks postmenstrual age when compared with placebo (104559). Other preliminary clinical research in infants born before 29 weeks gestation shows that supplementation with an enteral emulsion containing DHA 50 mg/kg and arachidonic acid 100 mg/kg (Formulaid, DSM Nutritional Products Inc.) until 36 weeks postmenstrual age has no effect on the incidence of NEC when compared with a control emulsion (110356).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral DHA is beneficial for NAFLD. Details: Preliminary clinical research shows that taking DHA (Martek Biosciences Corporation) 250-500 mg daily for 6-24 months reduces the risk of severe liver steatosis when compared with placebo in children with NAFLD (48295,90695,90696).
• Obesity. It is unclear if oral DHA is beneficial for improving weight loss in overweight or obese adults. Details: Preliminary clinical research shows that taking 2.8 grams daily of an oil emulsion containing approximately 46% DHA for 12 weeks decreases carbohydrate and fat intake, but does not reduce body weight or improve body composition, when compared with placebo in overweight or obese adults (90681).
• Otitis media. It is unclear if DHA in infant formula is beneficial for preventing otitis media in infants. Details: Preliminary clinical research shows that giving full-term infants formula with added DHA 17 mg/100 kcal and arachidonic acid 34 mg/100 kcal (Enfamil Premium 1 and Enfamil Premium 2, Mead Johnson Nutrition) for 12 months does not prevent the development of ear infection when compared with control formulas (92505).
• Phenylketonuria (PKU). It is unclear if oral DHA is beneficial for PKU. Details: Children with PKU consume very low amounts of DHA. Clinical research shows that taking DHA up to approximately 7 mg/kg daily for 6 months improves DHA status, but not neurological function, in children aged 5-13 years with PKU (99631). The effect of higher doses of DHA, or the effect of DHA supplementation on neurological function in younger children with PKU, have not been determined.
• Physical performance. It is unclear if oral DHA is beneficial for increasing physical performance in older adults. Details: A large clinical study shows that taking omega-3 fatty acids 1 gram daily, providing DHA 660 mg and eicosapentaenoic acid (EPA) 330 mg, for 3 years does not improve physical performance in adults over 70 years of age when compared with placebo. These findings were consistent in adults taking omega-3 fatty acids alone or combined with vitamin D 2000 IU daily and/or strength training three times weekly (104619).
• Postoperative pain. It is unclear if oral DHA is beneficial for reducing postoperative analgesic use. Details: A post-hoc analysis shows that enteral DHA 75 mg/kg administered perioperatively to infants born at greater than 34 weeks gestation who are undergoing cardiac surgery reduces the cumulative analgesic dose and shortens the duration of buprenorphine during the postoperative period when compared with placebo. However, the use of fentanyl or ketorolac were not reduced (96524).
• Prematurity. It is unclear if oral DHA during lactation or early in infancy is beneficial for increasing growth or neurodevelopment of the premature infant. Details: Clinical research in lactating individuals who delivered prior to 29 weeks' gestation shows that taking DHA 1.2 grams daily, starting within 72 hours of delivery and continuing until the infant reached 36 weeks postmenstrual age, might have beneficial effects on the growth of female infants, but not male infants, when compared with placebo. Weight velocity and weight gain were significantly increased in the female infants, with a weight gain of 52.6 grams. However, weight gain and weight velocity were not improved in the male infants, and weight at 36 weeks postmenstrual age was 89 grams less than those whose mothers took placebo (109221). In addition, there was no improvement in neurodevelopmental outcomes at 18 to 22 months corrected age (110364). Other clinical research in infants born before 29 weeks' gestation shows that giving enteral DHA 60 mg/kg daily until 36 weeks corrected gestational age does not improve most measures of intelligence at 5 years when compared with placebo (110363).
• Prostate cancer. It is unclear if oral DHA is beneficial for prostate cancer prevention. Details: Observational research has found that higher consumption of DHA is associated with a reduced risk of total, advanced, and aggressive prostate cancer when compared to lower consumption of DHA (12961,25937). However, a meta-analysis of multiple population studies has found that higher DHA blood levels are associated with a 2.5-fold higher risk of aggressive prostate cancer, but not low-grade prostate cancer, when compared with lower blood percentages of DHA (25936). Another meta-analysis of population research has found that a higher blood level of DHA is associated with a slight increased risk of non-aggressive prostate cancer (90677).
• Psoriasis. Although there has been interest in using oral DHA for psoriasis, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Raynaud syndrome. Although there has been interest in using oral DHA for Raynaud syndrome, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Restenosis. It is unclear if oral DHA is beneficial for preventing restenosis in people with stents. Details: Observational research has found that initiation of statin therapy in patients receiving stent placement after an acute coronary event is associated with a reduction in DHA levels. These reductions in DHA are associated with a greater prevalence of in-stent restenosis. From these results, researchers postulate that patients newly started on a statin after stent placement for acute coronary syndrome might benefit from DHA supplementation (100939). However, the effect of DHA supplementation is unknown.
• Retinitis pigmentosa. Evidence for the use of oral DHA for retinitis pigmentosa is inconsistent and contradictory. Details: Some clinical research shows that taking DHA 1200 mg daily for 4 years does not improve eye function in patients with retinitis pigmentosa who are also taking vitamin A when compared with placebo (48070). Also, taking DHA 600-3600 mg daily for 4 years does not maintain rod or cone function in boys or men with retinitis pigmentosa when compared with placebo (90683). However, a report of ancillary outcomes from this study shows that taking DHA might slow the rate of decline in final dark-adapted thresholds and visual field sensitivity in these patients (95738). Also, some research shows that taking DHA 400 mg daily for 4 years does maintain rod and cone function in some patients, although visual function is not improved when compared with placebo (48057,48115).
• Retinopathy of prematurity. It is unclear if maternal or infant supplementation with oral DHA is beneficial for preventing retinopathy of prematurity. Details: Preliminary clinical research shows that maternal supplementation with DHA 1.2 grams daily, starting within 72 hours of delivery of infants born before 29 weeks gestation, has no effect on the incidence of retinopathy of prematurity in breastfed infants at 36 weeks postmenstrual age when compared with placebo (104559). Other preliminary clinical research in infants born before 29 weeks gestation shows that supplementation with an enteral emulsion containing DHA 50 mg/kg and arachidonic acid 100 mg/kg (Formulaid, DSM Nutritional Products Inc.) until 36 weeks postmenstrual age has no effect on the incidence of retinopathy of prematurity when compared with a control emulsion (110356).
• Rheumatoid arthritis (RA). Although there has been interest in using oral DHA for RA, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Schizophrenia. Oral DHA has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking EPA 1000 mg, DHA 500 mg, and alpha-lipoic acid 150 mg twice daily for up to 2 years after discontinuing antipsychotic treatment does not prevent relapse in patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder (90675).
• Sepsis. It is unclear if oral DHA is beneficial for preventing sepsis in premature infants. Details: Preliminary clinical research shows that maternal supplementation with DHA 1.2 grams daily, starting within 72 hours of delivery of infants born before 29 weeks gestation, has no effect on the incidence of sepsis in breastfed infants at 36 weeks postmenstrual age when compared with placebo (104559). Other preliminary clinical research in infants born before 29 weeks gestation shows that supplementation with an enteral emulsion containing DHA 50 mg/kg and arachidonic acid 100 mg/kg (Formulaid, DSM Nutritional Products Inc.) until 36 weeks postmenstrual age has no effect on the incidence of sepsis when compared with a control emulsion (110356).
• Spinocerebellar ataxia (SCA). It is unclear if oral DHA is beneficial for SCA. Details: Preliminary clinical research in patients with SCA shows that taking DHA 600 mg daily for 16 weeks reduces ataxia and improves cerebellar hypometabolism upon brain imaging when compared with placebo. These beneficial effects are sustained when DHA is taken for an additional 40 weeks (96525).
• Stroke. It is unclear if oral DHA is beneficial for stroke prevention. Details: Population research has found that serum DHA levels may be associated with a reduced risk of ischemic stroke, as well as any specific type of ischemic stroke, including cardioembolic stroke, atherothrombotic stroke, and lacunar stroke (90715).
• Systemic lupus erythematosus (SLE). Although there has been interest in using oral DHA for SLE, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Systemic lupus erythematosus (SLE) nephritis. Although there has been interest in using oral DHA for SLE nephritis, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Ulcerative colitis. Although there has been interest in using oral DHA for ulcerative colitis, there is insufficient reliable information about the clinical effects of DHA for this condition.
• Vascular dementia. It is unclear if DHA is beneficial for improving dementia severity. Details: Preliminary clinical research in patients with vascular dementia shows that taking DHA 0.72 grams daily for one year improves dementia severity based on the Hasegawa's Dementia Rating Scale and Mini-Mental State Examination Scale scores when compared to baseline (47940). More evidence is needed to rate DHA for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Atopic dermatitis (eczema). It is unclear if oral hemp seed oil is beneficial in patients with eczema. Details: A small preliminary clinical trial in patients with eczema shows that taking hemp seed oil 30 mL daily for 8 weeks improves skin dryness, itchiness, and use of dermal medication when compared with baseline, but not when compared with an olive oil control (101125).
• Constipation. Oral hemp seed has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with functional constipation shows that taking a proprietary Chinese herbal medicine (Hemp Seed Pill) containing hemp seed, rhubarb root, peony root, apricot kernel, bitter orange fruit, and magnolia bark twice daily for 8 weeks results in a response rate to 43%, compared with 8% in those taking placebo. The response rate was defined as an increase of at least 1 complete spontaneous bowel movement per week. This combination product also improved the responder rate in the 2 weeks after treatment, as well as the overall use of rescue therapy, when compared with placebo (101127). Data from this study pooled with data from another larger study in adults with functional constipation shows that this same product increases the likelihood of complete response, defined as at least 3 complete spontaneous bowel movements per week or an increase over baseline of at least 1 weekly, by 1.43 times when compared with placebo. Complete spontaneous bowel movements per week also increased by 1 when compared with placebo (107319). It is unclear if these effects are due to hemp seed, other ingredients, or the combination.
• Dysmenorrhea. Although there is interest in using oral hemp for dysmenorrhea, there is insufficient reliable information about the clinical effects of oral hemp for this condition.
• Familial hypercholesterolemia. It is unclear if oral hemp seed oil is beneficial in children with this condition. Details: A small preliminary clinical trial shows that taking hemp seed oil (AlfaLife, Freia Farmaceutici Srl) 3 grams daily for 8 weeks does not improve levels of total or low-density lipoprotein (LDL) cholesterol when compared with no treatment in hyperlipidemic children aged 6-16 years who are also following a low-fat diet with high fruit and vegetable intake (101144).
• Joint pain. Although there is interest in using oral hemp for joint pain, there is insufficient reliable information about the clinical effects of oral hemp for this condition.
• Multiple sclerosis (MS). Oral hemp seed has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with relapsing-remitting MS shows that taking a combination of hemp seed oil 5.4-6.3 grams and evening primrose oil three times daily for 6 months seems to improve disability scores and relapse rate when compared to baseline. However, the control group in this study ingested olive oil and also experienced notable improvements in disability and relapse rates (88183). This study is limited due to high dropout rate and because there was no statistical comparison between treatment and control groups.
• 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, CV Sciences) as 60 mg, providing 15 mg cannabidiol, daily for 6 weeks, does not reduce weight or body mass index when compared with placebo (103805). The validity of this study is limited due to its exploratory nature and lack of control for voluntary dietary changes.
• Osteoarthritis. It is unclear if oral hemp seed is beneficial in patients with osteoarthritis. Details: A clinical study in 18 older adults with osteoarthritis undergoing in-hospital rehabilitation following knee or hip arthroplasty shows that consuming pasta enriched with hemp seed flour for 6 weeks improves pain scores by about 3 points, compared with only 1 point in those consuming a regular pasta control (107320).
• Psychological well-being. Although there is interest in using oral hemp for psychological well-being, there is insufficient reliable information about the clinical effects of oral hemp for this condition. More evidence is needed to rate hemp 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 10-25 mg/kg daily, titrated based on response and tolerability (97979,97980,99613,105495,106631). There is insufficient reliable information available about the safety of cannabidiol when used topically.

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

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

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LIKELY SAFE ...when used orally and appropriately. DHA has been used safely in studies lasting up to 4 years (1016,1043,6413,10321,10869,11333,90684). Fish oil supplements containing DHA have also been safely used in studies lasting up to 7 years (1016). While doses of DHA up to 4 grams orally daily have been used safely in some clinical research (6143), there is some concern that high intake of omega-3 fatty acids such as DHA might increase the risk of bleeding. For this reason, the US Food and Drug Administration (FDA) recommends that consumers limit intake of DHA plus eicosapentaenoic acid (EPA), another omega-3 fatty acid also found in fish oil, to 3 grams daily, with no more than 2 grams daily from a dietary supplement (95739).

POSSIBLY SAFE ...when used intravenously and appropriately, in combination with eicosapentaenoic acid (EPA), short-term. Daily infusions with an omega-3 fatty acid-based lipid emulsion (Omegavenous 10%, Fresenius Aktiengesellschaft) providing 4.2 grams/day of DHA and EPA has been used safely for 14 days (1004).

POSSIBLY UNSAFE ...when used orally in high doses. Doses greater than 3 grams daily might decrease platelet aggregation and increase the risk of bleeding (1313). The US Food and Drug Administration (FDA) recommends that consumers limit intake of DHA plus eicosapentaenoic acid (EPA), another omega-3 fatty acid, to 3 grams daily, with no more than 2 grams daily from a dietary supplement (95739).

CHILDREN: LIKELY SAFE
when used orally and appropriately. DHA is a component of some infant formula (424,1045,5708,5941,7599,14403,15003,15495,17735,48088)(48194,48266,48343,90665,90713,90716,110357). In children 7 years and older, DHA 30 mg/kg daily has been used safely for up to 4 years (90684). Also, DHA 0.4-1 grams daily has been safely used in children ages 4 years and older for up to 1 year (11333,90665,100940,104560).

CHILDREN: POSSIBLY UNSAFE
when used orally in preterm infants born less than 29 weeks gestation. Although not all findings agree (110356,110359), supplementation with an enteral emulsion containing DHA 40 mg/kg to 60 mg/kg daily might increase the risk of developing or worsening bronchopulmonary dysplasia compared to control emulsion (96523,110359).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. An intake of DHA 650 mg daily from food and/or supplements during pregnancy seems to be required to prevent a reduction in DHA status before delivery (110329). DHA is commonly used during pregnancy and lactation and is a component of some prenatal supplements. DHA is a normal component of breast milk, with higher levels in breast milk following term vs. preterm pregnancies (14393,14394,14396,14400,14403,14397,20000,47977,47994,48095)(90672,90718,110355). When taken as a prenatal supplement, DHA increases DHA levels in breast milk (90685). Doses of DHA ranging from 300-600 mg daily beginning during the first trimester of pregnancy have been used safely in clinical research (90672,90676,90687,90694). When taken during lactation, DHA increases DHA levels in breast milk (109214,110362). When initiated within 72 hours of delivery of a very preterm infant, taking DHA 1.2 grams daily increases DHA levels in breast milk within 14 days (109214). One study found that DHA supplementation during lactation increased the risk of bronchopulmonary dysplasia in breast-feeding infants born less than 29 weeks gestational age (104559); however, it is unclear if this was due to DHA or various confounding factors. The tolerable upper intake level of DHA during pregnancy or lactation has not been established; most experts recommend DHA 200-300 mg daily. While it is typically advised that this need is met by consuming 8-12 ounces of seafood weekly during pregnancy and 4-8 ounces weekly during lactation, those with nutrient deficiency or those following a vegan diet may meet this need with supplementation (95740,95741).

(Read more about DOCOSAHEXAENOIC ACID (DHA))

LIKELY SAFE ...when hemp seed, hemp protein, and hemp seed oil are used orally in food amounts. Hulled hemp seed, hemp seed protein powder, and hemp seed oil are generally recognized as safe (GRAS) in the US (100531).

POSSIBLY SAFE ...when hemp seed oil is used orally and appropriately as medicine, short-term. Hemp seed oil in doses of 2-6.3 grams daily has been safely used for 3-6 months (88183,16791,101145). Hemp seed oil in doses of 30 mL (27.6 grams) daily has been used safely for 2 months (101125). There is insufficient reliable evidence available about the safety of hemp oil, flowers, or leaves.

CHILDREN:
There is insufficient reliable information available about the safety of hemp in children. Adverse effects have been noted in case reports, but details related to specific hemp products are limited (101153,110287).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

(Read more about HEMP)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(Read more about CANNABIDIOL (CBD))

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, DHA may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Although some clinical evidence suggests that DHA might reduce collagen-stimulated platelet aggregation and thromboxane release, most clinical evidence suggests that DHA alone does not affect blood clotting (11112,11113,48020). However, theoretically, when given in combination with EPA as fish oil, concomitant use with anticoagulant or antiplatelet drugs (including aspirin) might increase risk of bleeding.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking DHA with antidiabetes drugs might reduce the effects of these medications.  Details In people with type 2 diabetes, including those taking oral hypoglycemic medications, DHA seems to increase fasting blood glucose levels (10321).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking DHA with antihypertensive drugs might increase the risk of hypotension.  Details Fish oils containing DHA can lower blood pressure and might have additive effects in patients treated with antihypertensives (1001,1020,1030,1033,47944,48013,48020,48163); use with caution.

(Read more about DOCOSAHEXAENOIC ACID (DHA))

ACE INHIBITORS (ACEIs) Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, consuming hemp seed protein isolate with ACE inhibitors might have additive effects and increase the risk of hypotension.  Details Hemp seed protein hydrolysate has shown ACE inhibitor-like effects in a hypertensive animal model (101136). However, hempseed oil consumption does not seem to reduce blood pressure in humans (101144). Until more is known, monitor blood pressure and potassium levels.

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, hemp seed might increase the risk of bleeding when used concomitantly with anticoagulant/antiplatelet drugs.  Details In animal research, hemp seed at 5% of the diet inhibits platelet aggregation in vitro (101137). However, in human research, taking hemp seed oil 2 grams daily for 12 weeks does not inhibit the aggregation of platelets in vitro (16791).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, hemp seed protein may have additive effects with antihypertensive drugs.  Details In a hypertensive animal model, hemp seed protein hydrolysate reduced systolic blood pressure by a mechanism possibly involving the inhibition of renin and angiotensin converting enzyme (ACE) activities. However, there was no effect of hemp seed protein on blood pressure in normotensive animals (101136). Furthermore, hempseed oil consumption does not seem to reduce blood pressure in humans (101144).

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, hemp might interfere with hormone therapy due to its estrogenic effects.  Details In an ovariectomized animal model, a diet containing hemp seed 1%, 2%, or 10% resulted in normalized plasma levels of 17-beta-estradiol (101132). The mechanism of action for this effect is unclear.

(Read more about HEMP)

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

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

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

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

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

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

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

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

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

(Read more about CANNABIDIOL (CBD))

General ...Orally, DHA is generally well-tolerated when used in doses up to 3 grams daily. Intravenously, DHA seems to be well tolerated.
Most Common Adverse Effects:
Orally: Belching, fishy aftertaste, loose stools, and nausea.
Serious Adverse Effects (Rare):
Orally: Some case reports raise concerns about increased risk of bleeding with high doses of fish oil containing DHA.

Cardiovascular ...Orally, DHA might increase low-density lipoprotein (LDL) cholesterol levels. However, this appears to be primarily due to increases in the large buoyant type of LDL particles. The small, dense type of LDL particles are reduced (6143,48013,48078,48083,48174,48338).

Dermatologic ...Orally, DHA has been associated with one report of rash and one report of warmth on hands in one clinical study (48217). In another clinical study, two patients taking DHA 400 mg daily reported acne (11333). In another clinical study, one parent of a pediatric patient treated with DHA 600 mg daily reported increased hair loss beginning 6 weeks after completion of supplementation (90699). It is unclear if this adverse effect is specifically related to DHA intake.

Gastrointestinal ...Orally, DHA may cause gastrointestinal upset, fishy aftertaste, belching, flatulence, heartburn, loose stools, anorexia, and dry mouth (10869,11333,48217,109218). There is also some evidence that increased serum levels of DHA might be associated with an increased risk for atrophic gastritis associated with Helicobacter pylori infection, but further research is needed to clarify this finding (8709).
For fish oils containing EPA and DHA, side effects can include fishy taste, belching, nausea, and loose stools (1009,1313,8699,10007). Three people with pre-existing familial adenomatous polyposis were diagnosed with malignant lesions during the course of long-term fish oil use (999).

Genitourinary ...Orally, one patient in one clinical study who was taking DHA 1, 2, or 4 grams daily (specific dose unclear) reported decreased libido (48217).

Hematologic ...Orally, DHA might cause nose bleeds, but this is uncommon. Onset of severe nose bleeds has been reported in one clinical study in one child who took DHA 600 mg daily (98542). Although most clinical research shows that DHA does not affect blood clotting when taken alone (11112,11113,48020), there is some concern that taking high doses of oils providing DHA along with eicosapentaenoic acid (EPA) might decrease blood coagulation and increase the risk of bleeding (1313). The US Food and Drug Administration (FDA) recommends that consumers limit intake of EPA plus DHA to 3 grams daily, with no more than 2 grams daily from a dietary supplement (95739).

Neurologic/CNS ...Orally, DHA may cause dizziness, headache, insomnia, fatigue, and anxiety (10869,11333,48217). In one clinical study, one parent of a pediatric patient treated with DHA 600 mg daily reported increased disruptive behavior in the child (90699).

Ocular/Otic ...Orally, DHA may cause watery eyes but results are inconsistent. In one clinical study, five of 167 infants fed formula containing 0.32% or 0.64% DHA experienced watery eyes. However, none of the infants fed formula containing 0.96% DHA experienced watery eyes (90670). In one clinical study, one patient taking DHA 400 mg daily experienced an ear infection. It is unclear if this event was related to DHA supplementation.

Oncologic ...Orally, DHA may increase the risk of prostate cancer, but additional research is needed to clarify this finding. A meta-analysis of data from observational studies found that higher dietary intake of DHA is associated with a non-linear increased risk of prostate cancer (90677). It is unclear if supplemental DHA intake is associated with increased risk of prostate cancer.

Pulmonary/Respiratory ...Orally, worsened asthma symptoms were reported by one parent of one patient with asthma taking DHA 600 mg daily (90699).

(Read more about DOCOSAHEXAENOIC ACID (DHA))

General ...Orally, hemp products are generally well tolerated in food amounts. In larger amounts, hemp seed oil seems to be well tolerated.
Serious Adverse Effects (Rare):
Orally: Rare cases of anaphylaxis have been reported. Long QT syndrome, torsades de pointes, and syncope have also been reported rarely.

Cardiovascular ...Acquired long QT syndrome, torsades de pointes, and syncope have been reported in a 56-year-old woman following the intake of supplements containing hemp oil. The hemp supplements provided cannabidiol (CBD), and possibly cannabigerol (CBG). Although the exact dose is unknown, up to six times the recommended dose had been used for approximately 6 weeks, in combination with a supplement containing berberine. While hospitalized, intravenous magnesium and saline were used to stabilize heart rhythm. It is unknown whether this adverse effect was related to the hemp oil, berberine, or their interaction (110104).

Hepatic ...Orally, there is a case report of elevated liver enzymes and hepatitis in a two-year-old boy given hemp extract 2. 5 mL, providing 125 mg phytocannabinoid, five to eight times daily for infantile spasms and refractory seizures. The total dose of phytocannabinoids was approximately 60-100 mg/kg daily (110287).

Immunologic ...Orally, there are case reports of allergy to hemp seed, although this is uncommon (101140,101154). A 44-year-old male developed hives during a meal of hemp seed-crusted seafoods. Later, he developed facial swelling, shortness of breath, and problems speaking. Evaluation revealed allergy to a specific protein in hemp seed. He did not react to smoked cannabis (101140). In other cases, anaphylaxis, facial swelling, and worsening asthma have been reported in association with a first exposure to hemp seed, although some had smoked cannabis previously (101154).
Topically, a case of patch-test confirmed allergic contact dermatitis to hemp seed oil has been reported in a 22-year-old woman. The initial rash started at the application point on her back and spread to her arms, hands, and neck (110288).
Airborne exposure to hemp pollen is a relatively common cause of allergic respiratory symptoms in some locations (101155).

Neurologic/CNS ...Orally, cases of acute cannabinoid toxicity with neurological symptoms in children and adults have been associated with intake of hemp seed oil. There is a case report of decreased alertness, stupor, bloodshot eyes, and fixed gaze in a 2-year-old male probably related to the intake of one teaspoon hemp seed oil (CANAH) containing 0.06% delta-9-tetrahydrocannabinol (THC) twice daily for 3 weeks. After stopping the oil, irritability was reported over the next few days (101153).

(Read more about HEMP)