Methotrexate is a medication primarily used to treat autoimmune conditions like rheumatoid arthritis and psoriasis, and certain types of cancer. It functions by reducing inflammation and slowing the growth of rapidly dividing cells. While not typically listed as a direct side effect, the relationship between methotrexate and weight changes is complex and warrants closer examination.
Obesity and Cancer: A Troubling Connection
Obesity has been identified as a pro-oncogenic factor, contributing to an increase in obesity-associated cancers such as breast, ovarian, prostate, and gastrointestinal cancers. Treating cancer patients is further complicated by the different physiological responses to chemotherapeutic agents in individuals with varying body weights.
The Anti-Obesity Effects of Methotrexate and Cyclophosphamide in Mice
A study by Myers et al. revealed that methotrexate and cyclophosphamide, both commonly prescribed drugs, exhibit anti-obesity effects in mice. These drugs, acting as anti-folate and DNA alkylating agents, respectively, caused significant weight loss at sub-lethal doses, despite their different mechanisms of action. This observation opens up intriguing questions about how these drugs function to reduce overweight and obesity.
The loss of adiposity indicates a negative energy balance, although the source of this imbalance was not directly identified in the study. One hypothesis is that energy expenditure increases outside the initial measurement window, potentially due to direct effects of methotrexate on uncoupled oxygen consumption. The impact of these drugs on muscle mass and quality also needs investigation, considering that some cancers and cancer-associated therapies can cause muscle wasting, which in turn affects energy balance.
The study also demonstrated a depletion of adipogenic precursors in obese mice treated with cyclophosphamide or methotrexate. While these drugs target dividing cells, including adipogenic precursors, the long-term effects on fat storage and metabolism, particularly in post-chemotherapy survivorship, require further investigation.
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Understanding Methotrexate: Uses, Precautions, and Side Effects
Methotrexate is used to treat autoimmune conditions, such as arthritis and psoriasis by decreasing inflammation, which can reduce pain and prevent long-term injury to the joints and skin. It may also be used to treat some types of cancer by slowing down the growth of cancer cells.
Important Considerations Before Taking Methotrexate
Before starting methotrexate, it's crucial to inform your healthcare team about any existing conditions, including:
- Dehydration
- Diabetes
- Fluid in the stomach area or lungs
- Frequent alcohol consumption
- Upcoming surgery, including dental surgery
- High cholesterol
- Immune system problems
- Inflammatory bowel disease
- Kidney or liver disease
- Low blood cell levels
- Lung disease
- Recent or ongoing radiation
- Recent or upcoming vaccine
- Stomach ulcers or other stomach/intestine problems
- Allergic reactions to methotrexate or other substances
- Pregnancy or breastfeeding
How to Use Methotrexate
Methotrexate is taken by mouth with water, as directed on the prescription label. For conditions like arthritis and psoriasis, it is typically taken ONCE A WEEK, either as a single dose or divided into 3 smaller doses taken 12 hours apart. It's crucial to understand why you are taking the medication, how often to take it, and the correct dosage. Taking methotrexate more often than directed can lead to serious side effects, even death.
Potential Interactions
Methotrexate can interact with various substances, including:
- Acitretin
- Live virus vaccines
- Probenecid
- Alcohol
- Aspirin and aspirin-like medications
- Certain antibiotics
- Medications for stomach problems
- Clozapine
- Cyclosporine
- Dapsone
- Folic acid
- Foscarnet
- NSAIDs
- Phenytoin
- Pyrimethamine
- Steroid medications
- Tacrolimus
- Theophylline
Monitoring and Precautions
Regular check-ups with your healthcare team are essential while taking methotrexate. Blood work may be required to monitor for any unwanted effects. If folic acid is also prescribed, your healthcare provider may advise skipping the folic acid dose on the day you take methotrexate.
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Methotrexate can increase sensitivity to the sun, so it's important to take precautions like wearing protective clothing and sunscreen. It can also increase the risk of infection, so it's crucial to avoid contact with sick individuals and promptly report any signs of infection to your healthcare team.
Common and Serious Side Effects
Possible side effects of methotrexate include:
- Allergic reactions
- Dry cough, shortness of breath
- Infection
- Kidney or liver injury
- Low red blood cell level
- Pain, tingling, or numbness in extremities
- Redness, blistering, peeling of the skin
- Stomach bleeding
- Severe stomach pain
- Unusual bruising or bleeding
- Diarrhea
- Dizziness
- Hair loss
- Nausea
- Mouth sores
- Skin reactions on sun-exposed areas
- Vomiting
Some side effects can be serious and require immediate medical attention.
The Patient Perspective: Weight Changes and Methotrexate
While the manufacturer doesn't list weight gain as a direct side effect, patient experiences and studies suggest that weight changes can occur. Some individuals report weight gain, while others experience weight loss.
Weight Gain Experiences
Elizabeth M., an RA patient, shared that the nausea and fatigue caused by methotrexate led her to consume more simple carbohydrates to boost her blood sugar, resulting in a 40-pound weight gain. Rebecca M. reported experiencing both hair loss and weight gain each time she was on methotrexate.
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Weight Loss Experiences
Conversely, some individuals experience weight loss due to side effects like decreased appetite, nausea, and upset stomach.
Other RA Medications and Weight Gain
Several other medications used to treat RA, such as adalimumab, pregabalin, etanercept, and prednisone, have also been associated with weight gain.
Managing Weight Changes and Side Effects
Maintaining a moderate weight is crucial for managing RA symptoms, regardless of medication use. Here are some helpful tips:
- Increase fiber intake
- Avoid packaged, high-fat, fried, and processed foods
- Reduce sugar intake
- Limit processed carbohydrates
- Stay active
- Decrease or eliminate alcohol intake
Folic acid supplements or anti-nausea medications may help manage other side effects from methotrexate.
Methotrexate and Adipose Tissue: A Deeper Dive
Recent research has explored the impact of methotrexate on brown and beige adipose tissue, which play a crucial role in regulating glucose and lipid homeostasis.
Methotrexate Promotes Browning of Adipose Tissue
A study presented evidence that methotrexate treatment increases the gene expression of thermogenic genes in brown and beige adipose tissues. Furthermore, mice treated with methotrexate exhibited cold resistance, improved glucose homeostasis, decreased inflammation, and reduced hepatosteatosis in high-fat diet states.
In Vitro Studies
In vitro experiments with 10T1/2 cells showed that methotrexate treatment increased mRNA levels of UCP1 and CIDEA, key markers of brown fat, without affecting cell viability. Similar effects were observed in cells differentiated into white fat.
In Vivo Studies
In vivo studies involving mice treated with methotrexate demonstrated increased cold tolerance compared to control mice. Histological and molecular analysis of adipose depots revealed decreased lipid accumulation and increased UCP1 staining in subcutaneous white adipose tissue (scWAT) and brown adipose tissue (BAT) of methotrexate-treated mice.
Effects on Metabolic Dysfunction
Methotrexate treatment was associated with decreased body weight in mice on a high-fat diet compared to control-treated mice. Molecular analysis of scWAT and BAT revealed increased expression of brown fat markers. Moreover, methotrexate treatment was accompanied by improved insulin sensitivity.
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