Understanding how methotrexate works helps explain why it can cause unwanted effects. Researchers originally developed methotrexate in the 1940s as a cancer drug. It stops malignant (or cancerous) cells from rapidly multiplying and spreading by blocking their access to folate, a form of vitamin B, which these cells need to survive. I started methotrexate 2 evenings ago (6 pills q 7 days). After a full 6 hours of sleep, I am still extremely tired and have been sleeping in my recliner since getting up at 7:00am. It does seem to take ages to settle in my body and the tired feeling lasts for weeks after changing the dose. I take the folic every day, apart from the methoject day, on the advise of rheumy nurse to help with sickness. It does make a difference and after experimenting with days and times of injection find doing it last thing at night gets over worst of tiredness. I still hurt a lot and the. Does taking citalopram and seroquel together cause tiredness Tiredness when taking warfarin All the information, content and live chat provided on the site is intended to be for informational purposes only, and not a substitute for professional or medical advice. I too am on methotrexate and I don't remember what it used to be like to get through a day with energy. I feel I struggle through every day just to do the basic things. It does get me down but because I can't seem to function not because I am depressed. I feel useless and just so not normal. It is not normal to be hardly able to pick the kids up from school or do some simple housework. “Proteins called cytokines that are released during inflammatory reactions can cause fatigue, but also contributing can be conditions that are common among people with psoriatic arthritis, including anemia, obesity, diabetes, depression and sleep problems.” All information contained within the Johns Hopkins Arthritis Center website is intended for educational purposes only. Physicians and other health care professionals are encouraged to consult other sources and confirm the information contained within this site. Methotrexate is a powerful medication that can be used for many serious conditions. MTX is an antineoplastic (anticancer) drug that is used in protocols to treat all kinds of cancers such as leukemias, lymphomas, and breast cancers. Hi Jacey, yes I'd agree that mtx definitely causes fatigue. I feel unmotivated and fatigued pretty much all of the time and have made my mind up that I want my metoject reducing to 15mg again. Summary. Fatigue is found among people who take Methotrexate, especially for people who are female, 60+ old , have been taking the drug for 1 - 6 months, also take medication Enbrel, and have Psoriatic arthropathy.