| Ingredients | Amount Per Serving |
|---|---|
| 944 mg | |
|
(whole plant)
(in organic MCT Oil)
(Hemp extract (Form: in organic MCT Oil (Form: from Coconut)) PlantPart: whole plant )
|
|
|
(CBD)
|
15 mg |
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(Cucumis melo L.)
(fruit)
|
140 IU |
|
Entourage Effect Blend
|
3.83 mg |
|
(peel)
|
|
|
Essence of organic Lavandin (flower & stem) oil
(flower & stem)
|
|
|
Essence of organic Chamomile (leaf) oil
(leaf)
|
|
|
(flower & stem)
|
|
|
(resin)
|
organic Mint spice flavor, organic Stevia extract PlantPart: leaf Genus: Stevia
Below is general information about the effectiveness of the known ingredients contained in the product CBD+ Stress Relief. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
Below is general information about the safety of the known ingredients contained in the product CBD+ Stress Relief. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
LIKELY SAFE ...when used orally and appropriately. Boswellia serrata extract in doses up to 1000 mg daily has been safely used in several clinical trials lasting up to 6 months (1708,1709,12432,12434,12438,17948,17949,17950,91379)(100699,100713,102089,109568). Boswellia serrata extract has been used with apparent safety at a dose of 2400 mg for up to 1 month (102092).
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (4912).
There is insufficient reliable information available about the safety of using Boswellia serrata in medicinal amounts; avoid using.
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).
LIKELY SAFE ...when used orally in amounts commonly found in foods. Clove, clove oil, and eugenol have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912).
POSSIBLY SAFE ...when clove oil is applied topically (272). A clove oil 1% cream has been applied to the anus with apparent safety for up to 6 weeks (43487). A liposome-based product containing clove oil 45% has been applied to the palms with apparent safety for up to 2 weeks (100596).
LIKELY UNSAFE ...when clove smoke is inhaled. Smoking clove cigarettes can cause respiratory injury (17,43599). ...when clove oil is injected intravenously. This can cause pulmonary edema, hypoxemia, and acute dyspnea (16384). There is insufficient reliable information available about the safety of using clove orally in medicinal amounts.
CHILDREN: LIKELY UNSAFE
when clove oil is taken orally.
Ingesting 5-10 mL of undiluted clove oil has been linked to reports of coagulopathy, liver damage, and other serious side effects in infants and children up to 3 years of age (6,17,43385,43395,43419,43457,43652).
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts found in foods (4912).
Clove, clove oil, and eugenol have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912). There is insufficient reliable information available about the safety of using clove in medicinal amounts during pregnancy and lactation; avoid using.
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.
POSSIBLY SAFE ...when used orally and appropriately. A gliadin-protected formulation of superoxide dismutase (Glisodin, Isocell Laboratory) has been used with apparent safety at doses up to 1 gram daily for up to 12 weeks or 500 mg daily for up to 24 weeks (106849). In combination with other ingredients, superoxide dismutase 140 IU and 10 mg have been used with apparent safety for up to 4 months and 12 months, respectively (20488,105502). ...when used parenterally, short term. Intravenous, intramuscular, and local injections of superoxide dismutase have been used with apparent safety, short-term (2230,2231,2232,2233,2241,2243). However, since some preparations are derived from animals, there is concern about contamination with diseased animal parts (1825). So far, there are no reports of disease transmission to humans due to use of contaminated preparations. Lecithinized recombinant superoxide dismutase 20-160 mg as a single intravenous dose has been used with apparent safety (105503). There is insufficient reliable information available about the safety of superoxide dismutase when used topically or in the eye.
CHILDREN: POSSIBLY SAFE
when administered via subcutaneous injection.
Superoxide dismutase 0.25 mg/kg twice daily until ventilator support is no longer required has been used with apparent safety in pre-term infants (2242).
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
LIKELY SAFE ...when sweet orange juice or fruit is used orally in amounts commonly found in foods (1310,3340,15171,92309).
POSSIBLY SAFE ...when the essential oil of sweet orange is inhaled as aromatherapy, short-term (35735,58060,90505,105455). There is insufficient reliable information available about the safety of sweet orange peel when used orally.
CHILDREN: LIKELY SAFE
when sweet orange juice or fruit is used orally in amounts commonly found in foods.
CHILDREN: POSSIBLY UNSAFE
when the sweet orange peel is used orally in excessive amounts.
There have been reports of intestinal colic, convulsions, and death in children given large amounts of sweet orange peel (11).
PREGNANCY AND LACTATION: LIKELY SAFE
when sweet orange juice or fruit is used orally in amounts commonly found in foods (1310,3340).
Below is general information about the interactions of the known ingredients contained in the product CBD+ Stress Relief. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
Theoretically, Boswellia serrata might increase the levels of CYP1A2 substrates.
 Details
In vitro research shows that Boswellia serrata gum resin inhibits CYP1A2 enzymes (21178).
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Theoretically, Boswellia serrata might increase the levels of CYP2C19 substrates.
Details
In vitro research shows that Boswellia serrata gum resin inhibits CYP2C19 enzymes (21178).
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Theoretically, Boswellia serrata might increase the levels of CYP2C9 substrates.
Details
In vitro research shows that Boswellia serrata gum resin inhibits CYP2C9 enzymes (21178).
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Theoretically, Boswellia serrata might increase the levels of CYP2D6 substrates.
Details
In vitro research shows that Boswellia serrata gum resin inhibits CYP2D6 enzymes (21178).
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Theoretically, Boswellia serrata might increase the levels of CYP3A4 substrates.
Details
In vitro research shows that Boswellia serrata gum resin inhibits CYP3A4 enzymes (21178).
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Theoretically, Boswellia serrata might alter the effects of immunosuppressive drugs.
Details
Some in vitro research suggests that Boswellia serrata extracts might inhibit mediators of autoimmune disorders such as leukotrienes and reduce production of antibodies and cell-mediated immunity (12432,12435,12437,12438). However, other in vitro research suggests that, when coupled with calcium ions, boswellic acids containing the keto group have immunostimulant properties within specific cell signaling pathways (21180).
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Cannabidiol might increase brivaracetam levels.
Details
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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).
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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).
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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.
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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).
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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.
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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.
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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).
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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Theoretically, cannabidiol might increase levels of drugs metabolized by CYP2D6.
Details
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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.
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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.
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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.
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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).
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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).
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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).
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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.
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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.
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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).
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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).
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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).
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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).
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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.
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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).
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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).
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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).
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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).
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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).
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Cannabidiol might increase zonisamide levels.
Details
In clinical research, concomitant administration of cannabidiol and zonisamide, a cytochrome P450 3A4 (CYP3A4) substrate, is associated with a modest increase in plasma levels of zonisamide. Zonisamide levels stayed within the normal range and did not require dose adjustment. However, caution should be exercised when cannabidiol and zonisamide are taken together (97018).
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Theoretically, clove oil may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.
Details
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Theoretically, concomitant use of clove extracts with antidiabetes drugs might increase the risk of hypoglycemia.
Details
Clinical and laboratory research suggest that polyphenol extracts from clove flower buds might lower blood glucose levels (100595). Dosing adjustments for insulin or oral hypoglycemic agents may be necessary when taken with clove. Monitor blood glucose levels closely.
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Theoretically, topical application of clove oil with ibuprofen might increase the absorption and side effects of topical ibuprofen.
Details
Laboratory research shows that topical application of clove oil increases the absorption of topical ibuprofen (98854). This interaction has not been reported in humans.
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Theoretically, consuming hemp seed protein isolate with ACE inhibitors might have additive effects and increase the risk of hypotension.
Details
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Theoretically, hemp seed might increase the risk of bleeding when used concomitantly with anticoagulant/antiplatelet drugs.
Details
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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).
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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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Consuming sweet orange with celiprolol can decrease oral absorption of celiprolol.
Details
A pharmacokinetic study in healthy volunteers shows that celiprolol levels, after a single dose of 100 mg, are decreased by up to 90% in people who drink sweet orange juice 200 mL three times daily. It's not known if lower consumption of sweet orange juice will have the same effect. Theoretically, this occurs due to short-term inhibition of organic anion transporting polypeptide (OATP) (12115,17603,17604). Recommend separating drug administration and consumption of sweet orange by at least 4 hours (17603,17604).
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Consuming sweet orange juice with fexofenadine can decrease oral absorption of fexofenadine.
Details
Clinical research shows that coadministration of sweet orange juice 1200 mL decreases bioavailability of fexofenadine by about 72% (7046,17604). In an animal model, sweet orange juice decreased bioavailability of fexofenadine by 31% (17605). Fexofenadine manufacturer data indicates that concomitant administration of sweet orange juice and fexofenadine results in larger wheal and flare sizes in research models. This suggests that sweet orange reduces the clinical response to fexofenadine (17603). Theoretically, this occurs due to short-term inhibition of organic anion transporting polypeptide (OATP) (7046). Recommend separating drug administration and consumption of sweet orange by at least 4 hours (17603,17604).
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Consuming sweet orange juice with ivermectin can decrease the oral absorption of ivermectin.
Details
A pharmacokinetic study in healthy volunteers shows that taking ivermectin orally with sweet orange juice 750 mL over 4 hours reduces the bioavailability of ivermectin. This effect does not seem to be related to effects on P-glycoprotein. The effect on ivermectin is more pronounced in males compared to females (12154).
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Consuming sweet orange juice can decrease oral absorption of OATP substrates. Separate administration by at least 4 hours.
Details
Clinical research shows that consuming sweet orange juice inhibits OATP, which reduces bioavailability of oral drugs that are substrates of OATP (17603,17604). For example, sweet orange juice decreases bioavailability of fexofenadine, a substrate of OATP, by about 72% and of celiprolol, another OATP substrate, by up to 90% (7046,12115). Since sweet orange juice seems to affect OATP for a short time, recommend separating drug administration and consumption of sweet orange juice by at least 4 hours (17603,17604).
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Sweet orange juice seems to modulate P-glycoprotein (P-gp), which might affect the blood levels of P-gp substrates.
Details
Animal and in vitro research suggest that orange juice extract inhibits drug efflux by P-gp, increasing absorption and levels of P-gp substrates (12116,15327). In contrast, pharmacokinetic research in humans shows that drinking large amounts of sweet orange juice decreases absorption and levels of the P-gp substrate celiprolol. This suggests that orange juice actually induces drug efflux by P-gp or affects drug levels by another mechanism such as inhibiting the gut drug transporter called organic anion transporting polypeptide (OATP) (7046,12115). Until more is known, sweet orange juice should be used cautiously in people taking P-gp substrates.
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Consuming sweet orange juice with pravastatin can increase the absorption of pravastatin.
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A small pharmacokinetic study in healthy volunteers shows that consuming sweet orange juice 800 mL over 3 hours, including before, during, and after taking pravastatin 10 mg, increases pravastatin levels by about 149%, without affecting pravastatin elimination. Theoretically this effect might be due to modulation of organic anion transporting polypeptides (OATPs) by sweet orange juice (14348). Sweet orange juice does not seem to affect simvastatin levels, but it is not known if sweet orange affects any of the other statins.
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Calcium-fortified sweet orange juice might reduce quinolone absorption.
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Below is general information about the adverse effects of the known ingredients contained in the product CBD+ Stress Relief. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
General
...Orally, Boswellia serrata extract is generally well-tolerated.
For information on the safety of Boswellia serrata when applied topically or used as aromatherapy, see the Frankincense monograph.
Most Common Adverse Effects:
Orally: Abdominal pain, diarrhea, headache, heartburn, itching, nausea.
Serious Adverse Effects (Rare):
Orally: Large amounts of Boswellia serrata gum resin can cause bezoar formation.
Dermatologic ...Orally, Boswellia serrata extract (5-Loxin) has been associated with itching at doses of 100-250 mg daily (17948).
Gastrointestinal ...Orally, Boswellia serrata extract may cause diarrhea, nausea, abdominal pain, and heartburn (1708,12432,12438,17948,17949,17950,21149,109567). A case of a large gastrointestinal bezoar has been reported in a 17-year-old female who chewed and swallowed large quantities of boswellia gum resin (Boswellia species not specified) for celiac disease (36914).
Musculoskeletal ...Orally, Boswellia serrata extract (5-Loxin) has been associated with one case of foot edema and four cases of generalized weakness in one clinical study (17948).
Neurologic/CNS ...Orally, Boswellia serrata extract may cause dizziness, headache, and vertigo. In one clinical study, nearly 11% of patients taking a specific Boswellia serrata extract (K-Vie) reported headache. Dizziness and vertigo were also reported, but at lower rates (109567). In another study, headache was reported in one patient taking a specific Boswellia serrata extract (5-Loxin) (17948).
Psychiatric ...Orally, one case of mania is reported in a 73-year-old male who took Boswellia powder mixed with honey for 3 days. The patient recovered after hospitalization and treatment with olanzapine (110526).
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).
General
...Orally, clove is well tolerated when consumed as a spice; however, clove oil in doses of only 5-10 mL can be toxic in children.
Topically, clove is generally well tolerated. When inhaled or used intravenously, clove may be unsafe.
Most Common Adverse Effects:
Topically: Burning, contact dermatitis, dental decay, itching, mucous membrane irritation, tingling, ulcers.
Inhaled: Dental decay, hypertension, itching, tachycardia.
Serious Adverse Effects (Rare):
Orally: Liver failure, respiratory distress.
Inhaled: Pneumonitis, pulmonary edema, respiratory distress.
Cardiovascular ...Smoking clove cigarettes increases heart rate and systolic blood pressure (12892).
Dental ...Population research has found that the risk of dental decay is increased in clove cigarette smokers (43332). Repeated topical application of clove in the mouth can cause gingival damage and skin and mucous membrane irritation (4,272,512). Eugenol, a constituent of clove and a material commonly found in dentistry, has been associated with side effects including gum inflammation and irritation (43365,43373,43522).
Dermatologic ...The American Dental Association has accepted clove for professional use, but not nonprescription use, due to potential damage to soft tissue that may be induced by clove application. In clinical research, small aphthous-like ulcers appeared in the area of the mouth where clove gel was applied in four participants (43448). Skin irritation and stinging have been reported with clove oil application (43338,43626). In a 24-year-old, exposure to a clove oil spill resulted in permanent local anesthesia and anhidrosis, or lack of sweating, at the affected area (43626).
Endocrine ...A case of hypoglycemia and metabolic acidosis have been reported after administration of one teaspoon of clove oil to a seven-month-old infant (43457). A case of electrolyte imbalance following accidental ingestion by a seven-month-old has also been reported (6).
Hematologic ...A case of disseminated intravascular coagulation has been reported in a 2-year-old patient after consuming between 5-10 mL of clove oil. The patient was treated with heparin, fresh frozen plasma, protein C, factor VII, and antithrombin III. On the fifth day, the patient started to improve and made a full recovery (43652).
Hepatic ...There are three cases of hepatic failure occurring in children after ingestion of 5-10 mL of clove oil (43395,43419,43652). Liver injury also occurred in a 3-year-old male (96949). These patients were successfully treated with N-acetylcysteine. The course of liver injury seems to be milder and shorter with early N-acetylcysteine treatment (43395,43419,96949). Another patient, who also presented with disseminated intravascular coagulation, was successfully treated with heparin, fresh frozen plasma, protein C, factor VII, and antithrombin III (43652).
Immunologic ...Contact dermatitis and urticaria has been reported following topical exposure to clove oil or eugenol, a constituent of clove oil (12635,43339,43606,43346).
Neurologic/CNS ...CNS depression has been reported in a 7-month-old who was given one teaspoon of clove oil accidentally in place of mineral oil for diarrhea. The patient was successfully treated with supportive care and gastric lavage (43457). A case of confusion and inability to speak has been reported secondary to oral exposure to clove oil and alcohol. The patient required intubation and was successfully treated with thiamine and normal saline (43580). Seizure and coma have been reported in a two-year-old male after ingesting 5-10 mL of clove oil (43652).
Pulmonary/Respiratory
...Clove cigarettes have been associated with throat and chest tightness (43337), pulmonary edema (43618), and fatal aspiration pneumonitis (43599).
The causative factor may be clove alone or clove along with other substances found in cigarettes. Clove cigarettes contain significant amounts of nicotine, tar, and carbon monoxide and increase plasma levels of nicotine and exhaled carbon monoxide, which might cause long-term health effects similar to tobacco smoking (12892). According to the American Medical Association, inhaling clove cigarette smoke has been associated with severe lung injury in a few susceptible individuals with prodromal respiratory infection. Also, some individuals with normal respiratory tracts have apparently suffered aspiration pneumonitis as the result of a diminished gag reflex induced by a local anesthetic action of eugenol, which is volatilized into the smoke (43602).
Intravenous injection of clove oil in a 32-year-old female resulted in hypoxia, acute dyspnea, interstitial and alveolar infiltrates, and non-cardiogenic pulmonary edema. The patient was managed with supplemental oxygen and recovered over the next seven days (16384).
Occupational exposure to eugenol, a constituent of clove, has also been reported to cause asthma and rhinitis (43492).
Renal ...Proteinuria and other urinary abnormalities were observed in a seven-month-old infant given one teaspoon of clove oil accidentally in place of mineral oil for diarrhea. The patient was successfully treated with supportive care and gastric lavage (43457).
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).
General
...Orally and parenterally, superoxide dismutase seems to be well tolerated.
Most Common Adverse Effects:
Parenterally: Pain and injection site reactions.
Serious Adverse Effects (Rare):
Parenterally: Anaphylaxis, possibly related to impurities in parenteral formulations.
Hematologic ...As an injection, superoxide dismutase may cause elevations in triglyceride and direct bilirubin levels. Cases of transient elevations in triglycerides and direct bilirubin have been reported after a single injection of lecithinized recombinant superoxide dismutase (105503).
Immunologic ...As an injection, superoxide dismutase can cause allergic reactions at the injection site in some patients (2235). It can also cause anaphylactic shock, which may be caused by product impurities (11008).
Musculoskeletal ...As an injection, superoxide dismutase can cause pain at the injection site in some patients (2235).
Neurologic/CNS ...Superoxide dismutase may be prepared from bovine liver. Products made from contaminated or diseased organs might present a human health hazard. There is also concern that spleen extracts produced from cows in countries where bovine spongiform encephalitis (BSE) has been reported might be contaminated with diseased tissue (1825). Thus far, there have been no reports of BSE transfer to humans from contaminated SOD products.
General ...Orally, sweet orange juice or fruit seem to be well tolerated. Large amounts of sweet orange peel may be unsafe, especially for children. When inhaled, sweet orange essential oil seems to be generally well tolerated.
Gastrointestinal ...There have been reports of intestinal colic in children following ingestion of large amounts of sweet orange peel (11).
Neurologic/CNS ...There have been reports of convulsions in children following ingestion of large amounts of sweet orange peel (11).
