Metformin withdrawal effects
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Metformin Withdrawal Effects: Metabolic, Endocrine, and Behavioral Changes
Weight Gain and Metabolic Changes After Metformin Withdrawal
Stopping metformin can lead to weight gain, especially in women with polycystic ovary syndrome (PCOS). Short-term users of metformin gained a significant amount of weight after withdrawal, while long-term users also tended to gain weight, though to a lesser extent. Eating behaviors worsened in both groups after stopping the medication. However, waist circumference, insulin resistance (HOMA), and glucose homeostasis remained stable for at least six months after withdrawal, suggesting some lasting metabolic benefits from prior metformin use .
Endocrine and Reproductive Effects in PCOS
Withdrawal of metformin in PCOS patients led to a decrease in menstrual frequency and a borderline increase in androgen levels (androstenedione), particularly in those who had used metformin long-term. This indicates that some of the reproductive and hormonal benefits of metformin may diminish after stopping the drug .
Diabetes Risk After Metformin Discontinuation
In people at risk for diabetes, stopping metformin resulted in a temporary increase in diabetes diagnoses, suggesting that part of metformin’s protective effect is lost when the drug is withdrawn. However, even after stopping metformin, the overall risk of developing diabetes remained lower compared to those who never took the drug, indicating some sustained benefit beyond the period of active treatment .
Gut Hormones, Bile Acids, and Microbiota Changes
Metformin withdrawal in people with type 2 diabetes led to a reduction in the gut hormone GLP-1 and an increase in certain bile acids in the blood. These changes reversed when metformin was restarted. The composition of gut microbiota also shifted with metformin withdrawal, which may influence metabolic health and hormone levels .
Kidney Effects in Animal Studies
Animal studies show that metformin can cause changes in kidney structure and function, including signs of degeneration and increased markers of kidney dysfunction. Importantly, these negative effects improved after metformin was withdrawn, especially with longer periods off the drug, suggesting that kidney health can recover after stopping metformin .
Effects on Withdrawal Syndromes from Other Substances
Metformin has been studied for its effects on withdrawal symptoms from substances like methamphetamine and nicotine. In animal models, metformin reduced anxiety and depression-like behaviors during methamphetamine withdrawal, likely by affecting gut microbiota and brain chemistry 356. In lung cancer patients trying to quit smoking, metformin helped reduce symptoms of nicotine withdrawal such as depression, anxiety, cravings, and irritability, though some benefits did not persist long-term after stopping the drug .
Conclusion
Metformin withdrawal can lead to weight gain, worsened eating behaviors, and a partial loss of metabolic and reproductive benefits, especially in PCOS and diabetes-risk populations. Some protective effects, such as reduced diabetes risk, may persist after stopping the drug, but others—like improved menstrual regularity and gut hormone levels—may diminish. In animal studies, kidney function and structure improved after withdrawal. Metformin also shows promise in reducing withdrawal symptoms from addictive substances, with effects linked to gut microbiota and brain chemistry. Overall, the effects of metformin withdrawal are complex and depend on the condition being treated and the duration of prior use.
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