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FOR MEDICAL PROFESSIONALS

Please note that Turmeric refers to the whole Turmeric with an average Curcumin percentage of around 3%.

Curcumin refers to standardised 95% curcuminoids extracted from the whole Turmeric.

Turmeric and Curcumin are not interchangeable terms (regardless of the current practice of labelling products as "Turmeric/Curcumin").

Black pepper refers to freshly ground black pepper, not the ordinary pre-ground black pepper sold for use in pepper shakers.

Piperine, the primary active constituent in black pepper, is oxidized on exposure to air and is also degraded by light. So most table pepper will have little if any, remaining piperine.


Possible Medication Interactions
with Turmeric, Curcumin and Black Pepper


Metabolic pathways:

Black pepper is a moderate inhibitor of the cytochrome P450 pathway CYP3A4. Pepper also inhibits UDP-glucuronosyltransferase. Both of these are significant for many medications.

95% standardized curcumin extract is an inhibitor of CYP3A4 as well. However, the percentage of curcumin in whole turmeric isn’t high enough to be significant. Curcumin extract also inhibits sulfotransferase, CYP2C19, CYP2B6, UDP-glucuronosyltransferase and CYP2C9, in that order.[1]

 

Interactions with psychotropic medications:

Both turmeric and pepper are modest non-selective MAO inhibitors. As such, they may increase levels of serotonin and the other neurotransmitters.
In addition, some of the psychotropic medications are metabolized via CYP3A4.


Antibiotic interactions:

Although some antibiotics are metabolized via CYP3A4, there is no data to suggest problems with using turmeric and black pepper along with antibiotics, except for the fluoroquinolones. Curcumin has been shown to inhibit the mechanism of that class (oxidative burst). [2] Whole turmeric contains only a small percentage of curcumin, but caution seems like a good idea even so.

Steroid Interactions:

Most steroids are metabolized via CYP3A4, but years of both clinical observation in veterinary clinics and anecdotal experience among humans suggest that black pepper does not have a significant effect on half-life or serum AUC for the commonly prescribed steroids such as prednisone.

Potent topical steroids such as clobetasol and triamcinolone have not typically been a problem along with turmeric/pepper formulations. However, for patients with chronic infectious diseases where immunosuppressants may require caution, the combination of turmeric and pepper along with those steroids may increase the immunosuppressant action of the steroids. For example, the side effects of triamcinolone in psoriasis and clobetasol in lichen sclerosus may be increased  when turmeric/pepper formulations are being used, and especially with the use of high-concentrate curcumin extracts.

Blood pressure interactions:

Turmeric is a vasodilator with an action similar to prescription beta blockers. It is also, for some people and animals, a diuretic. Not everyone seems to respond that way, and the effect is transient. The calcium channel blockers are metabolized via CYP3A4, but years of anecdotal data have not revealed problems with the concurrent use of black pepper and CCB’s. A possible exception is nifedipine and its variants, as they appear to have a higher likelihood of toxicity if an overdose occurs.

Blood lipid interactions:

Most statins are metabolized via CYP3A4, but anecdotal experience in a large group suggests that statins are not ordinarily a problem along with black pepper.

Opioid interactions:

Many opioids are metabolized via CYP3A4, but most of them have short enough half-lives that turmeric and/or pepper can be used along with them by separating the consumption several hours away from the opioid. Turmeric appears to clear within 4-6 hours (anecdotal, but drawn from a 270,000+ member group).

Diabetes medication interactions:

Turmeric may reduce insulin resistance, a concern with Type II diabetes. There is little data to indicate that it would affect insulin production for type I diabetics. Some studies indicated, however, that it could help repair damage to the islets of Langerhans[3]. That could indirectly result in more insulin being available. In addition, some data suggests that it will improve glucose metabolism. Routine blood glucose monitoring would be appropriate even if the individual was not insulin-dependent.

The black pepper in Golden Paste is also a P-glycoprotein inhibitor, which can affect the metabolism of the sulfonylureas. And both turmeric and black pepper are non-selective beta blockers[4].

Anticoagulant interactions:

Turmeric inhibits both platelet aggregation and fibrin formation. Thus it would generally not be appropriate with any anticoagulant which doesn’t permit PT/INR monitoring. Prothrombin time can be monitored for Xarelto (rivaroxaban), but multiple factors are involved, including the requirement for a different reagent than that used for warfarin [5]. Anecdotal data suggests that PT/INR times do not change significantly with the use of whole turmeric, but caution is still suggested.

Hypothyroid medication interactions:

Levothyroxine (L-T(3)) and trilodo-L-thyronine (L-T(4)) have been found to upregulate expression of P-glycoprotein in vitro. The piperine in black pepper is a P-glycoprotein inhibitor. There is insufficient data on the degree of P-gp upregulation or inhibition to be able to say how or to what extent medications such as Synthroid are affected. However, in a very large group that includes both humans and animals, the common hypothyroid medications such as levothyroxine and liothyronine are being used along with a mixture of turmeric and black pepper, with no reported issues.

Cannabis:

With the new, widespread and increasingly legal use of cannabis and its derivatives, the potential for metabolic interactions has increased. CBD oil (even if only from hemp) is a potent CYP3A4 inhibitor and also an inhibitor of P-glycoprotein [6,7]. Its use along with curcumin extracts and black pepper (or pepper extracts such as Bioperine) poses a double problem if affected medications are in use. There isn’t enough data yet to do more than recommend caution. But there are concerns about amplified reactions in both people and dogs using CBD oil along with a combination of turmeric, black pepper and some medications.



Cuisines that use “chilli” (hot) peppers:

The capsaicin in hot peppers has the same effect on CYP3A4 and PgP as the piperine in black pepper, though it is not as potent[8]. Still, though, anything mentioned here about the use of black pepper may apply as well to cuisines that use large amounts of hot peppers.

Monoclonal antibodies:

Turmeric and black pepper appear to be safe with this class of drugs. In fact, curcumin has been conjugated with anti TAG 72, a monoclonal antibody specific to ovarian cancer. The combination was found to enhance the activity of cisplatin against resistant cancer cells [9].


Chemotherapy medications:

Curcumin extracts from turmeric (both as simple 95% standardized extracts and as nanoparticle formulations) have been trialled successfully with many chemotherapy medications (cisplatin, carboplatin, doxorubicin, etc). However, some of these drugs are also metabolized by CYP3A4 and some are affected by P-gp. Infusion concentrations may need to be adjusted to compensate for the metabolic inhibition[10-12]. In addition, curcumin was found to reduce doxorubicin-induced apoptosis in breast cancer cells (in vitro), so that should be taken into account[13].

The situation with cyclophosphamide is less clear. Curcumin has been shown to inhibit the effectiveness of cyclophosphamide in some circumstances[14]. However, it was also found to enhance the effect of cyclophosphamide against canine mammary cancer cells[15].

Radiotherapy:

Turmeric may help with side effects after radiotherapy. However, as a potent anti-inflammatory, it may also interfere with the inflammatory effect of radiotherapy on cancer cells. It is generally recommended not to have it in the diet during radiotherapy and to wait until blood cell counts are normal afterwards.

Gout medications:

Turmeric is widely promoted in the lay health groups as helpful with gout. That’s because it addresses some of the same metabolic interactions as the commonly prescribed allopurinol and others. Like 6-mercaptopurine (allopurinol's active metabolite), turmeric is a xanthine oxidase inhibitor, so it inhibits the conversion of oxypurines to uric acid. But turmeric may also be a modest ACE inhibitor, which has been shown to be an additional risk factor in the development of hypersensitive skin conditions such as Stevens-Johnson syndrome. Caution is probably called for, especially if the patient is in one of the high-risk ethnic groups with the HLA-B*5801 allele (Asians, blacks, Hawaiians/Pacific Islanders)[16].

Colchicine, another popular medication for gout, is cleared via the both of the metabolic pathways inhibited by the piperine in pepper—CYP3A4 and P-glycoprotein. So caution would be advised if the patient is using freshly ground pepper in any significant quantity in their cooking, or using it with turmeric. Since standardized curcumin extract is also a potent CYP3A4 inhibitor the same caution would apply for that. Fatal drug reactions have been reported with colchicine and potent inhibitors of CP3A4 and P-glycoprotein, especially with protease inhibitors (curcumin is an inhibitor of multiple proteases, including cyclooxygenase-2, which accounts for much of its anti-inflammatory activity)[17]. This drawback for colchicine is well known and widely publicized, but practitioners may not be aware of the potential interaction with curcumin, piperine and capsaicin.

Anti-fungals:

Ketoconazole is the standard benchmark for inhibition of CYP3A4. It and the other azoles will add to the inhibitory effect of the piperine in black pepper, the capsaicin in hot peppers and the curcumin in curcumin extracts. Unless other medications are in use that would be affected by CYP3A4, the azoles shouldn’t be a problem. In trials with fluconazole, curcumin “decreased proteinase secretion by 49% and 53%, respectively, in C. albicans and by 39% and 46%, respectively, in C. glabrata” [18].
The echinocandins do not have any metabolic interactions with the cytochrome P450 enzymes. In addition, curcumin has been trialled with caspofungin against Candida albicans and was found to work synergistically with it, using the same cell wall deformation mechanism [19].
Amphotericin B is less used now, but still valuable, especially in the veterinary setting against leishmaniasis. Since it’s metabolized via the kidneys, it has no metabolic interactions with piperine, capsaicin or curcumin. In addition, its side effects may be moderated by combination with curcumin [20].

Anticonvulsants:

Phenobarbital is metabolized via a different P450 pathway (CYP2C19) than the one affected by piperine or capsaicin. However, curcumin has a moderate inhibiting effect on CYP 2C19, something that may need to be considered in dosing phenobarb. The small percentage of curcumin in whole turmeric has not been a problem in clinical veterinary practice.

KBr/NaBr—Neither potassium bromide nor sodium bromide are approved for use in the US, but KBr is widely prescribed for canine seizures off-label. Potassium bromide is approved for human use in Germany. Both are excreted unchanged via the kidneys, so do not interact metabolically with turmeric, piperine, capsaicin or curcumin. No indication could be found after a search of PubMed, PubChem, and other sources to suggest any other interactions.

The dibenzazepines (carbamazepine, oxcarbazepine, eslicarbazepine) are both inducers and substrates of multiple cytochrome P450 pathways, so they have the potential to both be affected by piperine, capsaicin and curcumin, and to increase the rate of clearance of many drugs.

Specifically:
· Carbamazepine is an inducer of CYP3A4 and a substrate of it. Its clearance will be slowed by the use of capsaicin, turmeric, black pepper and curcumin, in increasing order.
· Oxcarbazepine is metabolized via CYP2C19, CYP3A4 and CYP3A5. At the same time, it is a potent inducer of CYP3A4 and CYP3A5. It is a pro-drug, metabolized to licarbazepine, the active drug. Concomitant use of moderate amounts of black pepper or large amounts of chilli peppers seems like to slow metabolism to licarbazepine.
· Eslicarbazepine is an inducer of CYP3A4 and UDP-glucuronosyltransferase. It is an inhibitor of CYP2C19. It is itself metabolized via hepatic hydrolysis to S-licarbazepine, the biologically active drug. Its metabolism will not be affected by turmeric, black pepper, chili peppers or curcumin, but consumption of those along with eslicarbazepine could affect other drugs prescribed along with it, if its dosage was adjusted to compensate for its induction of CYP3A4 and UPD-glucuronosyltransferase.

Gabapentin was originally marketed as an anticonvulsant but is now prescribed off-label for many other uses. It is excreted unchanged via the kidneys and therefore does not interact metabolically with turmeric, piperine, capsaicin or curcumin. While turmeric (particularly its sesquiterpene constituent curcumol) does interact with GABA receptors, gabapentin does not bind with GABA receptors or change GABA transport or metabolism. There does not appear to be any direct interaction between gabapentin, curcumin, piperine or capsaicin.

Diazepam and the other benzodiazepines are all metabolized via several of the cytochrome P450 enzymes, including CYP3A4 and CYP2C19. Since these are generally used for seizure control only in the emergency setting, the fact that they are P450 substrates may not be significant.

Brivaracetam is metabolized primarily via hydrolysis and secondarily via CYP2C19. Therefore, its clearance could be inhibited by curcumin extracts.


Sources:
1. Curcuminoids inhibit multiple human cytochromes P450 (CYP),  UDP-glucuronosyltransferase (UGT), and sulfotransferase (SULT) enzymes, while piperine is a relatively selective CYP3A4 inhibitor 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2574793/
2. Curcumin reduces the antimicrobial activity of ciprofloxacin against Salmonella Typhimurium and Salmonella Typhi 
https://academic.oup.com/jac/article/68/1/139/673708
3. Curcumin and Diabetes: A Systematic Review 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3857752/#sec9title

4. Clinically and pharmacologically relevant interactions of antidiabetic drugs
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821002/5. Laboratory assessment of rivaroxaban: a review 
https://thrombosisjournal.biomedcentral.com/articles/10.1186/1477-9560-11-11

6. Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: Role of phenolic hydroxyl groups in the resorcinol moiety
https://www.medicinalgenomics.com/wp-content/uploads/2013/11/Potent-inhibition-of-CYP3A-with-CBD.pdf

7.An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569602/

8. Curcumin, piperine and capsaicin: a comparative study of spice-mediated inhibition of human cytochrome P450 isozyme activities 
http://dmd.aspetjournals.org/content/early/2016/11/07/dmd.116.073213

9. Potential application of curcumin and its analogues in the treatment strategy of patients with primary epithelial ovarian cancer. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284673/

10. Curcumin enhances the effectiveness of cisplatin by suppressing CD133+ cancer stem cells in laryngeal carcinoma treatment 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3820845/

11. Curcumin-enhanced chemosensitivity of FDA-approved platinum (II)-based anti-cancer drugs involves downregulation of nuclear endonuclease G and NF-κB as well as induction of apoptosis and G2/M arrest. 
https://www.ncbi.nlm.nih.gov/pubmed/24438326

12. Co-delivery of doxorubicin and curcumin by pH-sensitive prodrug nanoparticle for combination therapy of cancer 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753416/
13. Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast cancer 
https://www.ncbi.nlm.nih.gov/pubmed/12097302
14. Effects of curcumin in combination with cyclophosphamide on canine mammary tumour cell lines 
http://vri.cz/docs/vetmed/59-11-553.pdf
15. Allopurinol: extra caution urged in high risk groups. 
https://www.medscape.com/viewarticle/895335

16. How does curcumin work with poor bioavailability? Clues from experimental and theoretical studies 
https://www.nature.com/articles/srep20872
17. Curcumin inhibits HIV-1 by promoting TAT protein degradation. 
https://www.nature.com/articles/srep27539
18. Curcumin as a promising anticandidal of clinical interest 
https://www.ncbi.nlm.nih.gov/pubmed/21358761
19. Curcumin Targets Cell Wall Integrity via Calcineurin-Mediated Signaling in Candida albicans 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910804/
20. Complexation of amphotericin B and curcumin with serum albumins: solubility and effect on erythrocyte membrane damage 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863302/