Delta-9 THC 10 mg Gummies Mango by OXZGEN

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alcohol use disorder. Although there has been interest in using THC for alcohol use disorder, there is insufficient reliable information about the clinical effects of THC for this purpose.
• Blepharospasm. Oral THC has only been evaluated as a component of a cannabis extract; its effect when used alone is unclear. Details: A very small clinical trial in adults with blepharospasm unsuccessfully treated with botulism toxin A injections shows that using a cannabis extract containing delta-9-tetrahydrocannabinol (THC) 3.2% (1 drop estimated to contain 1.2 mg), titrated to a maximum of 10 drops, nightly for 12 weeks improves the frequency, duration, and severity of eyelid spasm attacks when compared with placebo (108691). The validity of this study is limited by poor study design and lack of follow-up.
• Cachexia. Oral THC has only been evaluated as a component of a cannabis extract; its effect when used alone is unclear. Details: One clinical study shows that using a cannabis extract standardized to contain THC 2.5 mg and cannabidiol (CBD) 1 mg twice daily for 6 weeks does not increase appetite when compared with placebo in patients with cancer-related anorexia-cachexia syndrome (61785). However, the substantial placebo effect and dropout rate limits the reliability of these findings.
• Cancer-related pain. Non-inhaled THC may be 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 (CBD) titrated to effect, followed by the gradual addition of THC, with a maximum daily dose of CBD 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 CBD 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 THC 2.7 mg and CBD 2.5 mg per spray, for 2-5 weeks does not improve prescribed opioid consumption, sleep, or pain, and actually increases nausea and vomiting by 43% and 50%, respectively, when compared with opioids alone (108676,111095). All studies instructed patients not to alter the prescribed opioid dose, which may have increased the risk for adverse effects such as nausea and vomiting. The effect of pure THC is unclear.
• Chemotherapy-induced nausea and vomiting (CINV). It is unclear if a cannabis oromucosal spray or oral cannabis extract, providing standard doses of THC in combination with other ingredients, is beneficial for the prevention of CINV. Details: A small clinical study in patients receiving moderate-to-highly emetogenic chemotherapy and still experiencing CINV despite conventional antiemetic prophylaxis shows that taking a cannabis extract (TN-TC11M) containing THC 2.5 mg and cannabidiol (CBD) 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 THC 2.7 mg and CBD 2.5 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 THC is unclear.
• Crohn disease. Oral THC has only been evaluated as a component of cannabis products; its effect when used alone is unclear. Details: A small clinical study in patients with mild to moderate Crohn disease shows that using a cannabis oil containing THC 4% and cannabidiol (CBD) 16%, titrated gradually to satisfactory response to a maximum of 20 drops (THC 40 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). Another very small clinical study shows that smoking cigarettes containing cannabis flowers 0.5 grams standardized to THC 115 mg twice daily for 8 weeks does not improve Crohn disease remission rates when compared with placebo cigarettes. However, the response rate, defined as a reduction in Crohn Disease Activity Index score of at least 100 points, was 90% in the cannabis group, compared with 40% in the placebo group. Quality of life was also improved (96387). The effect of pure THC is unclear.
• Dementia. It is unclear if oral THC might reduce neuropsychiatric symptoms of dementia in hospitalized patients. Details: A meta-analysis of small clinical studies in mostly hospitalized patients with neuropsychiatric symptoms of dementia shows that using cannabinoids such as THC, dronabinol, and nabilone modestly improves neuropsychiatric symptoms such as agitation and aggression when compared with control (103015). The validity of these findings is limited by the small size and heterogeneity of the included studies.
• Diabetes. Sublingual THC has only been evaluated as a component of a cannabis extract; its effect when used alone is unclear. Details: A small clinical study in adults with type 2 diabetes conducted in Iran shows that taking a specific product containing THC 10 mcg and cannabidiol 100 mcg (CBDEX10, Yas Daru) 2 puffs sublingually twice daily for 8 weeks modestly improves fasting blood glucose, glycated hemoglobin, total and low-density lipoprotein cholesterol, and triglycerides when compared with placebo, but does not increase high-density lipoprotein cholesterol (113056).
• Fibromyalgia. It is unclear if inhaled THC in cannabis vapor might reduce fibromyalgia pain. Details: A small clinical study in female adults with fibromyalgia and chronic pain shows that a single vapor inhalation of cannabis containing THC 22.4 mg and less than 1 mg of CBD reduces pain scores by 30% when compared with placebo. However, inhaling cannabis containing THC 13.4 mg and CBD 17.8 mg does not improve pain when compared with placebo. Additionally, no cannabis products affected electrical pain thresholds or spontaneous pain scores (101420). Also, the effect of pure THC is unclear. Recent clinical practice guidelines for the use of cannabis and cannabinoid-based medicines for the management of chronic pain strongly recommend the use of cannabinoid-based medicines as adjunct treatment for improvement of chronic back, fibromyalgia, or other pain in patients with fibromyalgia and inadequate response to other treatments. These recommendations are based on low quality evidence suggesting that benefits exceed the risks of non-serious adverse effects. Initiating treatment with a low dose of THC reduces the risk of adverse effects (110321).
• Glaucoma. It is unclear if oromucosal THC reduces glaucoma risk. Details: Using an oromucosal spray containing THC 5 mg seems to reduce intraocular pressure in patients with glaucoma. However, the effect appears to last for only three to four hours (61790). The effect of pure THC is unclear.
• HIV/AIDS-related wasting. It is unclear if oral THC attenuates wasting in patients with HIV. Details: While a prescription drug called dronabinol (Marinol), a synthetic form of THC, is approved for treating loss of appetite in patients with HIV who have lost weight (6606,11166), the effect of non-prescription THC is unclear.
• Hypertension. Oral THC 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 1% to 10% delta-9-tetrahydrocannabinol (THC) and 2% to 20% cannabidiol (CBD), 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. Also, the effects of THC alone are unclear.
• Insomnia. Sublingual THC 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 THC 20 mg/mL, cannabinol (CBN) 2 mg/mL, and cannabidiol (CBD) 1 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.
• Multiple sclerosis (MS). A specific cannabis oromucosal spray and oral cannabis extract, providing standard doses of THC in combination with other ingredients, seems to modestly reduce spasticity in patients with MS. The effect of THC alone on symptoms of MS is unclear. Details: Meta-analysis of several clinical studies in patients with MS shows that using a specific oromucosal spray containing cannabis extract (Sativex, GW Pharmaceuticals), standardized to deliver THC 2.7 mg and cannabidiol (CBD) 2.5 mg per actuation, for at least 3 weeks modestly reduces subjective spasticity, but does not seem to reduce neuropathic pain or bladder dysfunction, when compared with placebo (104895). Another meta-analysis of 5 clinical studies, that includes many of the same studies as the prior meta-analysis, shows that using Sativex as add-on therapy improves the likelihood of reduced spasticity by 2.4 times when compared with placebo (113020). Limited research suggests that the benefit of Sativex might last for over 11 months and withdrawal of Sativex may cause a rebound of MS symptoms (89923,89924). Sativex has been approved in the United Kingdom as a prescription medicine to treat MS-related spasticity (89913) and in Canada to treat neuropathic pain associated with MS (61775). This product has not been approved in the United States. The American Academy of Neurology states that Sativex does not improve objective measures of spasticity, reduce the number of urinary incontinence episodes, or reduce MS-related tremors (89460). Notably, much of the research was funded by the manufacturer. Other oral cannabis extracts containing THC have also been studied. A meta-analysis of clinical research in patients with MS shows that taking a cannabis extract containing THC 25-30 mg and CBD 8-18 mg daily for up to 15 weeks modestly reduces subjective spasticity, neuropathic pain, and bladder dysfunction when compared with placebo. However, objective spasticity measures (Ashworth scale) were not improved when compared with placebo (104895). Two of the largest studies included in the meta-analysis used a specific cannabis extract (Cannador, Society for Clinical Research) (11168,91919). A third study used cannabis extract standardized to THC 2.5 mg and CBD 0.9 mg per capsule, for an escalating daily dose of 6-12 capsules in three divided doses (61746). One small clinical study in patients with MS with upper limb tremors shows that taking a specific cannabis extract (Cannador) titrated to a maximum of THC 0.125 mg/kg twice daily for 2 weeks does not appear to improve tremor when compared with placebo (61739). Recent clinical practice guidelines for the use of cannabis and cannabinoid-based medicines for the management of chronic pain strongly recommend the use of cannabinoid-based medicines as adjunct treatment for improvement of pain, muscle spasm, and sleep in patients with MS and inadequate response to other treatments. These recommendations are based on low or moderate quality evidence of smoked cannabis, cannabis extract, and oromucosal THC, suggesting that benefits exceed the risks of non-serious adverse effects. The strongest evidence of benefit has been shown with oils and capsules, as opposed to smoking or oromucosal formulations. A total daily dose of THC 10-15 mg was most commonly used in clinical research. Initiating treatment with a low dose reduces the risk of adverse effects (110321).
• Neuropathic pain. It is unclear if oral THC is beneficial for neuropathic pain. Details: Clinical research shows that taking THC up to 25 mg alone or with cannabidiol 50 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).
• Pain (chronic). Non-inhaled THC seems to reduce pain in patients with chronic pain due to various causes. The effect of inhaled THC on chronic pain is unclear. 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 (CBD) titrated to effect, followed by the gradual addition of THC, with a maximum daily dose of CBD 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 CBD 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). 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, especially THC-predominant formulations, alone and/or as adjunct treatment for improvement of anxiety, pain, and sleep, in individuals with chronic pain not responsive to, or intolerant of, non-pharmacologic treatment. This recommendation includes slowly introducing cannabinoid-based medicines for individuals experiencing unsatisfactory response from, using high doses of, or experiencing adverse effects related to, opioids. These guidelines also weakly recommend the adjunct use of cannabinoid-based medicines for improvement of depression, mobility, and nausea, and post-traumatic stress disorder (PTSD) in patients with chronic pain. The risk of non-serious adverse events outweighs the risk of adverse events associated with standard analgesics. These recommendations are based on studies investigating a variety of cannabinoid-based medicines, including oral or inhaled whole plant, extracts, and isolated cannabinoids. The use of non-inhaled products, and/or initiating treatment with a low dose and titrating as needed, reduces the risk of adverse effects (110321). A small clinical study in patients with chronic pain shows that a single inhalation of a cannabis extract containing THC 0.5 mg or 1 mg reduces pain for 150 minutes when compared with baseline. However, only the THC 1 mg dose reduces pain when compared with placebo (104481). Due to the single-dose nature of this study, the effects of continued administration of inhaled THC on chronic pain are unclear. The placebo response in the available research is moderate to large and any additional benefit of cannabis-based products is small and possibly insignificant (110230).
• Parkinson disease. Oral THC has only been evaluated as a component of a cannabis extract; its effect when used alone is unclear. Details: A small clinical trial in patients with Parkinson disease, shows that using a specific cannabis extract standardized to THC 2.5 mg and cannabinol (CBD) 0.8-1.8 mg per capsule (Cannador, Society for Clinical Research) twice daily for 4 weeks does not improve the severity of disease when compared with placebo. Dosing was escalated over the 4-week period reaching THC levels of 0.034 to 0.25 mg/kg daily (108342). The effects of THC alone are unclear.
• Rheumatoid arthritis (RA). It is unclear whether an oromucosal cannabis spray containing 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 THC 2.7 mg and cannabidiol (CBD) 2.5 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 THC alone are unclear.
• Ulcerative colitis. It is unclear if inhaled THC as part of smoked cannabis flower improves symptoms of ulcerative colitis. Details: A small clinical trial in patients with mild to moderately active ulcerative colitis shows that smoking a cannabis flower cigarette containing delta-9-tetrahydrocannabinol (THC) 80 mg twice daily for 8 weeks, in conjunction with standard therapy, improves Lichtiger disease activity index scores, abdominal pain, and number of bowel movements, but does not improve endoscopic disease activity or markers of inflammation, when compared with placebo. At a 1-year follow-up, all patients who received cannabis and achieved remission during the study retained long-term remission (108680). The effects of THC alone are unclear. More evidence is needed to rate THC 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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LIKELY EFFECTIVE

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

POSSIBLY EFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

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POSSIBLY SAFE ...when a specific cannabis extract spray that contains THC 2. 7 mg and cannabidiol 2.5 mg per actuation (Sativex, GW Pharmaceuticals) is applied topically into the oral mucosa for up to 2 years. This product is available as a prescription drug in the UK and Canada; it is an investigational new drug in the US (61775,61820,89460,89913,111095).

POSSIBLY UNSAFE ...when THC is used orally or inhaled in large amounts or for an extended duration. Edible cannabis products containing at least 50 mg of THC have been associated with cases of anxiety, psychosis, myocardial infarction, and ventricular arrhythmia (103796). In addition, e-cigarette, or vaping, product-use associated lung injury (EVALI) is thought to be associated with THC. EVALI has occurred among adults and children who use these products. The majority of patients with EVALI reported using THC-containing products in the 3 months prior to the development of symptoms (101421). Although it is possible that other ingredients, such as vitamin E acetate, may be involved in these cases of lung injury, the US Food and Drug Administration (FDA) has warned the public to stop using all THC-containing vaping products due to the risk for EVALI (101429). Use of cannabis containing THC has also been associated with seizures, cognitive impairment, and mood disturbances. Cessation of cannabis containing THC may precipitate cannabis withdrawal syndrome, the severity of which depends on the frequency and quantity of use prior to cessation (61896,91909,96378,96381,99588,99576,99580,102801). Excessive and prolonged use of cannabis containing THC, either by smoking and/or oral use, can lead to cannabinoid hyperemesis syndrome (CHS). This condition is characterized by severe, repeat bouts of nausea and vomiting that cannot be alleviated by conventional antiemetics (99585,99577). In several cases, CHS has been linked to severe complications resulting in death (99585). THC likely plays a role in these adverse effects; however, it is also possible that other constituents are involved. A meta-analysis of clinical research involving adults with a mean age of at least 50 years shows that increasing the dose of natural or synthetic THC in cannabinoid-based medicines is associated with a modest increase in overall adverse effects, but not with serious adverse effects or death (105559). A meta-analysis of lower quality clinical and observational research suggests that the incidence rate of adverse effects related to use of natural or synthetic THC in cannabinoid-based medicines is low, and serious adverse events are lacking (110257).

PREGNANCY: UNSAFE
when used orally or inhaled. Cannabinoid constituents in cannabis, such as THC, pass through the placenta and can reduce fetal growth and increase the risk for preterm birth (101425,101481,103792,104490). Cannabis use during pregnancy is also associated with placental abruption, stillbirth, preterm delivery, fetal abnormalities, low birth weight, small for gestational age, increased need for neonatal intensive care, and childhood leukemia (4260,25162,61855,96380,101425,101481,101483,108699). Prenatal cannabis use has also been associated with long-term adverse developmental effects in the offspring, such as worsened cognition, increased risk for neurodevelopmental disorders such as autism spectrum disorder, and increased risk for psychological issues during adolescence (103792,104485). Due to the observational nature of these studies, it is unclear if cannabis causes these adverse effects. Umbilical artery Doppler scans also show that cannabis use can increase placental vascular resistance (101483). Cannabis use during pregnancy has been associated with increased risk of anemia and hypertension in the mother (96380,101481). Although the safety of pure THC has not been investigated during pregnancy, it is likely that THC is at least partially responsible for these safety concerns. The rate of negative fetal outcomes due to cannabis use during pregnancy may have been previously underestimated due to reliance on maternal self-reporting of use. Recent programs requiring maternal urine toxicology testing have increased awareness of maternal cannabis use and suggest that negative fetal outcomes occur more frequently than previously recorded (101481,101482).

LACTATION: LIKELY UNSAFE
when used orally or inhaled. THC is concentrated and excreted in breast milk for longer than 6 weeks after cessation of use (2619,2620,104894); prolonged use of cannabis containing THC during lactation has been associated with delayed motor development (25163). Observational research in mothers who successfully abstained from cannabis use for 6 weeks (confirmed by a negative THC urine screen) after smoking cannabis prenatally at least twice weekly, found that THC levels in breastmilk increased during the first 2 weeks of abstinence and then decreased but remained detectable at 6 weeks (104894). For patients planning to breastfeed, recommend abstaining from THC use prenatally and during lactation. Recommendations to discard breastmilk until THC levels are undetectable are not practical, as this may take more than 6 weeks.

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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.

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

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

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

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

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

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

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ALCOHOL (Ethanol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, THC might have additive effects when used with alcohol.  Details THC can have CNS depressant effects. Theoretically, concomitant use of alcohol with THC can have additive effects including psychomotor impairment, sedation, and changes in mood and behavior (2619).

ANESTHESIA Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B THC use might alter the safety and clinical effects of various forms of anesthesia.  Details Cannabis contains THC. A small clinical study shows that higher doses of propofol may be needed to achieve relaxation and loss of consciousness in chronic cannabis users compared with nonusers (96378). Another small clinical study shows that use of cannabis within 72 hours prior to undergoing surgery requiring atropine anesthesia may increase the risk of sustained postoperative tachycardia (95727). The exact mechanisms of these interactions are unclear. Obtain a patient's history of cannabis use preoperatively and advise patients to discontinue use for at least 2 weeks prior to undergoing surgery.

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, THC might increase the risk of bleeding when used concomitantly with anticoagulant/antiplatelet drugs.  Details In vitro research shows that THC inhibits platelet aggregation (61689,61917).

BARBITURATES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, THC might increase the levels and adverse effects of barbiturates.  Details Some research shows that synthetic THC (dronabinol) increases the elimination half-life of pentobarbital by 4 hours when dosed concomitantly (16815). Also, in animal research, THC potentiated pentobarbital-induced sleep by more than three-fold (108343).

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, THC might have additive effects if used with other CNS depressants.  Details Cannabis containing THC can have CNS depressant effects. Combining THC with other CNS depressants might result in additive or synergistic effects (16815,61934,111096).

CYTOCHROME P450 2C9 (CYP2C9) INDUCERS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, drugs that are CYP2C9 inducers might decrease the levels and clinical effects of THC.  Details THC is a substrate of CYP2C9 enzymes (99747).

CYTOCHROME P450 2C9 (CYP2C9) INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, drugs that are CYP2C9 inhibitors might increase the levels and adverse effects of THC.  Details THC is a substrate of CYP2C9 enzymes (99747).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, THC might increase the levels and adverse effects of CYP2C9 substrates.  Details In vitro research shows that THC moderately inhibits the CYP2C9-mediated 7-hydroxylation of S-warfarin in a concentration-dependent manner (99578,111098). In vitro research also shows that cannabis extracts containing THC modestly inhibit the CYP2C9 metabolism of tolbutamide; extracts providing the specific cannabinoids cannabidiol (CBD) or cannabigerol (CBG) alone had stronger inhibitory effects than extracts containing both THC and CBD (111098). Theoretically, THC may inhibit the metabolism of other CYP2C9 substrates. Conversely, a crossover clinical study in healthy adults shows that oral THC does not inhibit CYP2C9 (113025).

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, THC might decrease the levels and clinical effects of CYP2E1 substrates.  Details In vitro research shows that cannabis containing THC can induce the activity of CYP2E1, which might increase the metabolism of CYP2E1 substrates (61726). It is unclear if this effect is due to THC, other constituents, or the combination.

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 reduce the levels and clinical effects of THC.  Details THC is a substrate of CYP3A4 enzymes (99747).

CYTOCHROME P450 3A4 (CYP3A4) INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, CYP3A4 inhibitors might increase the levels and clinical effects of THC.  Details THC is a substrate of CYP3A4 enzymes (99747).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, THC may increase the levels and clinical effects of CYP3A4 substrates.  Details In vitro research shows that cannabis containing THC might modestly inhibit the activity of CYP3A4 enzymes, which might decrease the metabolism of CYP3A4 substrates (25160,111098). It is unclear if this effect is due to THC, other constituents, or the combination. In vitro research also shows that cannabis extracts containing THC modestly inhibit the CYP3A4 metabolism of testosterone; extracts providing the specific cannabinoids cannabidiol (CBD) or cannabigerol (CBG) alone had stronger inhibitory effects than extracts containing both THC and CBD (111098). Conversely, a crossover clinical study in healthy adults shows that oral THC does not inhibit CYP3A4 (113025).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, THC might alter levels of drugs that are substrates of P-glycoprotein (P-gp).  Details Most in vitro research suggests that THC can inhibit P-gp and increase the accumulation of probe compounds by reducing P-gp mediated drug efflux. In vitro studies in kidney cell lines show that a 1-hour exposure to CBD and THC inhibits P-gp (61769,104889). THC may also alter the expression of P-gp, although this effect appears to vary based on duration of exposure. Some in vitro research in lymphoblastoid leukemia cell lines indicates that a 1-hour exposure to cannabinoids does not affect P-gp expression, while a prolonged 72-hour exposure decreases P-gp expression (61771). Other in vitro research in these cell lines shows that a 4-hour exposure to THC and CBD induces P-gp gene expression, while exposure for longer than 4 hours and up to 48 hours does not induce P-gp gene expression (104893).

THEOPHYLLINE Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, THC might reduce the levels and clinical effects of theophylline.  Details Smoking cannabis containing THC seems to increase the metabolism of theophylline (16815). It is unclear if this effect is due to THC, other constituents, or the combination.

THROMBOLYTIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D THC might augment the effects of thrombolytic drugs and increase the risk of severe bleeding.  Details Cannabis contains THC. A case of cerebral hemorrhage has been reported for a 51-year-old female and chronic cannabis user who had consumed a large amount of cannabis prior to receiving recombinant tissue plasminogen activator (rtPA) for ischemic stroke. Hemorrhage had been ruled out prior to providing the rtPA. The exact mechanism of this interaction is unclear (96799). It is also unclear if this effect is due to THC, other constituents, or the combination.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Concomitant use with THC seems to increase the levels and clinical effects of warfarin.  Details In vitro research shows that the cannabinoids THC, cannabidiol (CBD), and cannabinol inhibit the cytochrome P450 2C9 (CYP2C9)-mediated 7-hydroxylation of S-warfarin in a concentration-dependent manner. There are also three case reports of patients chronically taking warfarin that developed a spike in international normalized ratio (INR) after smoking cannabis or taking medical cannabis orally. Although the dose of THC consumed in all cases is unknown, one of the patients doubled the amount of THC consumed from 7.5 mg to 14.7 mg daily for one week (16832,99578,104483).

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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.

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

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

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

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

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

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General ...There is limited reliable information available about the adverse effects associated with pure THC. When inhaled or used orally, cannabis can cause various adverse effects, many of which are thought to be related to THC. For more information on cannabis-related adverse effects, see the Cannabis monograph.
Most Common Adverse Effects:
All ROAs: When cannabis containing THC is used, dizziness, dry mouth, fatigue, headache, increased appetite, nausea, paranoid and dissociative thinking, and sedation have occurred. Intoxicating doses can impair declarative memory, motor coordination, reaction time, and visual perception for up to 8 hours. It is unclear if these adverse effects are due to THC, other constituents, or a combination.
Serious Adverse Effects (Rare):
All ROAs: When higher doses of cannabis containing THC are used, acute coronary syndrome, arrhythmias, blood pressure changes, cannabinoid hyperemesis syndrome (CHS), hallucinations, pancreatitis, panic, psychosis, and seizures have occurred. It is unclear if these adverse effects are due to THC, other constituents, or a combination.

Cardiovascular ...Orally, edible cannabis products containing 50 mg or more of THC have been associated with myocardial infarction and ventricular arrhythmia (103796). In a case report, a 2-year-old boy developed bradycardia with first-degree atrioventricular block which lasted 12 hours, after accidentally consuming an unknown number of cannabis gummies containing THC (110237). Additionally, taking a prescription drug called dronabinol (Marinol) or nabilone (Cesamet), a synthetic form of THC, has been associated with hypotension, hypertension, syncope and/or tachycardia (110258,110259).
There is case report of pericardial effusion suspected to be related to vaping cannabis 1.5 mg daily, providing 95% THC, for two months. However, the presence of contaminants in the product could not be ruled out. Treatment included aspirin 325 mg every 8 hours, colchicine 0.5 mg every 12 hours, and pantoprazole 40 mg every 12 hours (110231).
A case of ventricular bigeminy and a case of circulatory collapse have been considered to be related to treatment with a specific oromucosal spray that contains THC 2.7 mg and cannabidiol 2.5 mg per actuation (Sativex, GW Pharmaceuticals) (61759,61820).
Cannabis containing THC has also been associated with other cardiovascular adverse effects, including increased blood pressure, increased heart rate, arrhythmia, acute coronary syndrome, myocardial infarction, and stroke. However, it is unclear if these adverse effects are due to the THC constituent of cannabis, other constituents, or a combination. For more information on cannabis-related adverse effects, see the Cannabis monograph.

Dermatologic ...Cannabis containing THC has been associated with dermatologic adverse effects, including erythema multiforme-like recurrent drug eruption. However, it is unclear if these adverse effects are due to the THC constituent of cannabis, other constituents, or a combination. For more information on cannabis-related adverse effects, see the Cannabis monograph.
Taking a prescription drug called dronabinol (Marinol), a synthetic form of THC, has been associated with hypersensitivity reactions, including skin hives, rash, or flushing (110258).

Endocrine ...Cannabis containing THC has been associated with endocrine adverse effects, including weight gain, worsened glycemic control, and acute pancreatitis. However, it is unclear if these adverse effects are due to the THC constituent of cannabis, other constituents, or a combination. For more information on cannabis-related adverse effects, see the Cannabis monograph.

Gastrointestinal ...Meta-analyses of clinical and observational research involving adults with a mean age of at least 50 years shows that increasing the dose of natural or synthetic THC in cannabinoid-based medicines is associated with a modest increase in the rate of dry mouth, nausea, and vomiting (105559,110257). Dry mouth has also been reported in clinical research (110249). In addition, taking a prescription drug called dronabinol (Marinol) or nabilone (Cesamet), synthetic forms of THC, has been associated with abdominal pain (110258,110259).
Cannabis oromucosal spray that contains THC 2.7 mg and cannabidiol 2.5 mg per actuation (Sativex, GW Pharmaceuticals) can cause dizziness, dry mouth, nausea, and bad taste (61759,61764,61820,61896,61909,108698). Less commonly, this product may cause red and white buccal mucosal patches to develop inside the mouth (61820).
Cannabis containing THC has been associated with other gastrointestinal adverse effects, including cannabinoid hyperemesis syndrome (CHS). However, it is unclear if these adverse effects are due to the THC constituent of cannabis, other constituents, or a combination. For more information on cannabis-related adverse effects, see the Cannabis monograph. Taking a prescription drug called nabilone (Cesamet) 2 mg, a synthetic compound similar to THC, for 7 weeks exacerbated nausea and vomiting in a patient with cancer. CHS was suspected. Symptoms did not recur after the nabilone was stopped. The patient had been using nabilone 0.5 mg for 5 years to control neuralgia; however, the dose had been increased to 2 mg to help with cancer pain (110239).

Genitourinary ...A meta-analysis of clinical research involving adults with a mean age of at least 50 years shows that increasing the dose of natural or synthetic THC in cannabinoid-based medicines is associated with a modest increase in the rate of male impotence (105559).
Cannabis containing THC has been associated with other genitourinary adverse effects, including priapism and abnormal menstruation. However, it is unclear if these adverse effects are due to the THC constituent of cannabis, other constituents, or a combination. For more information on cannabis-related adverse effects, see the Cannabis monograph.

Hematologic ...Cannabis containing THC has been associated with hematologic adverse effects, including hemorrhage. However, it is unclear if these adverse effects are due to the THC constituent of cannabis, other constituents, or a combination. For more information on cannabis-related adverse effects, see the Cannabis monograph.

Immunologic ...Taking a prescription drug called dronabinol (Marinol), a synthetic form of THC, has been associated with hypersensitivity reactions, including lip swelling and oral lesions, skin hives, rash, or flushing, or throat tightness (110258). A meta-analysis of lower quality clinical and observational research suggests that the use of natural or synthetic THC in cannabinoid-based medicines is associated with a slight increase in respiratory and urinary tract infections (110257).

Musculoskeletal ...Cannabis containing THC has been associated with musculoskeletal adverse effects, including hypotonia. However, it is unclear if these adverse effects are due to the THC constituent of cannabis, other constituents, or a combination. For more information on cannabis-related adverse effects, see the Cannabis monograph.

Neurologic/CNS ...Meta-analyses of clinical and observational research involving adults with a mean age of at least 50 years show that increasing the dose of natural or synthetic THC in cannabinoid-based medicines is associated with a modest increase in overall adverse effects, including dizziness/light-headedness, mobility/balance/coordination difficulties, somnolence, disorientation, memory impairment, fatigue, and euphoria (105559,110257). Euphoria is also reported in clinical research (110249). Cannabis extract oromucosal spray that contains THC 2.7 mg and cannabidiol 2.5 mg per actuation (Sativex, GW Pharmaceuticals) can cause dizziness, lightheadedness, sleepiness, and fatigue (61759,61764,61820,61896,61909,96814).
Intoxicating doses of THC-containing cannabis impair reaction time, motor coordination, declarative memory, and visual perceptions, and can also produce panic reactions and other emotional disturbances. An individual's driving ability can be impaired for up to 8 hours (18,61896,103023). A small prospective study has found that inhaling vaporized cannabis containing THC 13.75 mg or THC/cannabidiol 13.75 mg increases lane weaving for the first 100 minutes when compared with placebo. This impairment was comparable to that of a blood alcohol concentration of 0.05%, which is considered to indicate clinically relevant impairment (104482). The validity of this finding is limited because the study only tested a single dose of cannabis, which does not mimic typical real-world use (104484). Acute use of cannabis has also been associated with increased motor collision risk (61911,61904), especially if the driver is using alcohol or other drugs concomitantly (103024). Two retrospective studies have found that state-based legalization and commercialization of cannabis is associated with increased traffic fatalities (103022,103024,103027). These studies are limited due to their retrospective nature and a lack of control over other confounding factors such as out-of-state cannabis tourism that could have affected driving fatalities. It is unclear if these adverse effects are due to THC, other constituents, or a combination.
A case of cannabis-induced acute encephalopathy and severe dehydration is reported in a 94-year-old woman given cannabis by a family member. The product had been marketed as pure cannabidiol (CBD); however, a urinary analysis resulted positive for THC. The patient was hospitalized, received supportive care, and was discharged after 6 days with complete resolution of cognitive symptoms (111071). Additionally, 2 cases of recurrent reversible cerebral vasoconstriction requiring hospitalization and escalated care are reported in adults. Both cases involved the use of THC, history of hypertension, and presentations that included thunderclap headaches and stroke, one ischemic and the other hemorrhagic, adding further complexity to their cases that only resulted in partial recovery (112113). However, the role of THC in these cases is not well understood.
Some evidence shows that the adverse effects of THC may be increased when consumed with large amounts of CBD. A small study in healthy adults shows that consumption of brownies containing CBD 640 mg plus THC 20 mg increases feelings of sedation and memory impairment when compared with brownies containing only THC 20 mg (111092).
Cannabis containing THC has also been associated with other neurologic adverse effects, including headache, disorientation, cognitive impairment, and fatigue. However, it is unclear if these adverse effects are due to the THC constituent of cannabis, other constituents, or a combination. For more information on cannabis-related adverse effects, see the Cannabis monograph.

Ocular/Otic ...A meta-analysis of clinical research involving adults with a mean age of at least 50 years shows that increasing the dose of natural or synthetic THC in cannabinoid-based medicines is associated with a modest increase in overall adverse effects, including visual symptoms (105559).
Cannabis containing THC has been associated with other ocular or otic adverse effects, including dry eye, reddening of the eyes, and tinnitus. However, it is unclear if these adverse effects are due to the THC constituent of cannabis, other constituents, or a combination. For more information on cannabis-related adverse effects, see the Cannabis monograph.

Oncologic ...There is some concern that use of cannabis containing THC increases the risk for cancer. A meta-analysis of observational case-control studies found that cannabis is not associated with an increased risk for head and neck squamous cell carcinoma or oral cancer. However, more than 10 years of cannabis use is associated with an increased risk for testicular germ cell tumor (101430). It is unclear if this is due to THC, other constituents, or a combination.

Psychiatric ...Cannabinoids such as THC can increase anxiety, confusion, depressed mood, and hallucinations, and reduce motivation (96384,110252,110257). Cannabis dabbing, the making of a waxy product with extremely high concentrations of THC, is thought to increase the risk of anxiety, agitation, paranoia, and psychosis (108341). When consumed in large amounts, edible cannabis products containing at least 50 mg of THC have been associated with anxiety, abnormal behavior, psychosis, and suicidal tendencies (91914,103796).
A case of erratic speech and hostile behaviors, followed by suicidal actions resulting in death, has been reported in a 19-year-old male who consumed an edible cannabis cookie. According to the product label, the serving size should have been one-sixth of the cookie, or 10 mg of THC. However, the patient ate the entire cookie after not experiencing effects within 30-60 minutes of the initial dose (91914). Due to this case and other cases of overconsumption of edible cannabis products, in February 2015 the state of Colorado began requiring that edible cannabis products contain no more than 10 mg of THC per serving or that the products have clear demarcation of each 10 mg serving if they contain more than 10 mg of THC (91914).
One small clinical trial shows that inhaling vaporized cannabis containing THC 10 mg, alone or with cannabidiol (CBD) 10-30 mg, modestly induces psychotic symptoms (110242). Also, a single dose of inhaled cannabis providing THC 13.75 mg and < 1% CBD increases feelings of anxiety when compared to cannabis providing CBD 13.75 mg and <1% THC (110254). Some evidence shows that the adverse effects of THC may be increased when consumed with large amounts of CBD. A small study in healthy adults shows that consumption of brownies containing CBD 640 mg plus THC 20 mg increases feelings of anxiety, paranoia, and irritability when compared with brownies containing only THC 20 mg (111092).
Use of cannabis containing THC can be habit-forming. Meta-analyses of the available research suggest that as many as 47% of regular cannabis users develop some form of dependence, and up to 9% of all users develop cannabis use disorder (101701,102801). In patients with cannabis dependence, cessation of use can precipitate cannabis withdrawal within 1-2 days. The risk for cannabis withdrawal syndrome seems to be greater in males, those with higher cannabis use, and those with concomitant drug or tobacco use (102801). Symptoms of cannabis use withdrawal typically last for 7-14 days and include irritability, nervousness, difficulty sleeping, decreased appetite, and depressed mood. Physical symptoms such as stomach pain, tremors, sweating, fever, or headache might also occur. Severity of withdrawal varies, and largely depends on the cumulative amount of cannabis used prior to cessation (99576,101702). Withdrawal symptoms may be particularly problematic in individuals with pre-existing depression or anxiety, resulting in failed cessation attempts (102801).
Cannabis containing THC has also been associated with other psychiatric adverse effects, including anxiety, dissociation, depression, confusion, hallucinations, paranoia, and psychosis. However, it is unclear if these adverse effects are due to the THC constituent of cannabis, other constituents, or a combination. For more information on cannabis-related adverse effects, see the Cannabis monograph.

Pulmonary/Respiratory ...Using a specific oromucosal spray that contains THC 2. 7 mg and cannabidiol 2.5 mg per actuation (Sativex, GW Pharmaceuticals) may cause pharyngitis, hoarseness, and throat irritation (61759).

Renal ...A case of acute kidney injury has been reported in a 94-year-old adult after consumption of cannabis containing THC; it was likely caused by pre-existing mild dehydration related to a lack of fluid intake, followed by cannabis-induced diarrhea (111071).

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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).

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

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

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

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

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

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

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

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

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