The Combination of Doxycycline and Methotrexate: Is it safe?

The Risks and Benefits of Using Doxycycline and MTX Together.

Both doxycycline and methotrexate have anti-inflammatory properties. Methotrexate is a powerful inhibitor of dihydrofolate reductase enzyme. Doxycycline is known to inhibit matrix metalloproteinases (MMP-1, MMP-8 and MMP-11) and to be immunomodulatory. Whether two drugs are combined one needs to consider whether the drugs have a potential harmful interaction. Methotrexate has several important drug interactions including various sulfa drugs, proton pump inhibitors, NSAIDS and others. All patients using MTX need to advise all physicians, pharmacists and health care workers about their use of this medication.

Some studies have suggested that doxycycline increases levels of oral methotrexate  by decreasing elimination. It may also be the doxycycline competes with methotrexate for binding sites with plamsa proteins and in turn increases. The combination of the two drugs has the potential to make MTX more powerful and in turn increase side effects.


In 1999, Tortajada-Ituren reported that doxycycline increased the toxicity of methtorexate in a patient using high dose methotrexate. In 2019, Arslan and colleagues reported a patient using low dose methotrexate who developed pancytopenia with the combination of low dose MTX and doxycycline.


In 2006, O’Dell and colleagues published a report of 66 patients with rheumatoid arthritis who were randomized to receive 100 mg doxycycline BID with methotrexate (N=24), 20 mg doxycycline BID with methotrexate (N=18) or placebo daily with methotrexate (N=24) for 2 years.

These studies showed that patients with the doxycycline-MTX combination groups had better responses in terms of treating their rheumatoid arthritis than patients in the methotrexate along group. There were however more patients in the high dose MTX - doxycycline who had to stop treatment because of toxic reactions. 2 of the patients in the high dose group had photosensitive reactions. One patient had an increased ALT liver enzyme reading. One patient had a heart attack. In the low dose doxycycline-MTX group two patients had an increased ALT liver enzyme reading.


Doxycycline has the potential to affect MTX blood levels and therefore affect potential toxicity. One must be careful using the combination and monitor blood parameters (CBC, AST, ALT) frequently


1) Tortajada-Ituren JJ et al , High-dose methotrexate-doxycycline interaction. Ann Pharmacother. 1999 Jul-Aug;33(7-8):804-8.

2) Arslan et al. Methotrexate and doxycycline interaction: a rare cause of pancytopenia.
BMJ Case Rep. 2019 May 31;12(5). pii: e229296. doi: 10.1136/bcr-2019-229296.

Dr. Jeff Donovan is a Canadian and US board certified dermatologist specializing exclusively in hair loss. To schedule a consultation, please call the Whistler office at 604.283.1887

Share This