Do Not Take Central Nervous System Stimulants for Weight Loss!

Obesity, defined as having a body mass index (a measure of body fat based on a person’s height and weight) of 30 or higher,[1] is a chronic disease that affects more than one-third of Americans.[2] It is associated with an increased risk of serious health problems (including coronary heart disease, type 2 diabetes, hypertension and various types of cancer) and death.

Although lifestyle changes (such as reduced-calorie diet and increased physical activity) are the mainstay treatment for obesity, millions of Americans take weight-loss medications. Among these drugs are four oral prescription central nervous system stimulants that purportedly decrease weight by suppressing the appetite: benzphetamine (generic only),[3] diethylpropion (TENUATE, TENUATE DOSPAN),[4] phendimetrazine (BONTRIL PDM)[5] and phentermine (ADIPEX-P, LOMAIRA, QSYMIA).[6], [7] Notably, the Qsymia formulation is a combination of the antiseizure drug topiramate and the stimulant phentermine.

These medications have been approved by the Food and Drug Administration (FDA) for use in obese adults (and, in the case of Qsymia, overweight adults with at least one weight-related disease, such as hypertension or type 2 diabetes) who have not responded to lifestyle changes alone. The agency states that these drugs are to be used only in conjunction with lifestyle changes.

Public Citizen’s Health Research Group has designated these drugs as Do Not Use because their limited benefits are far outweighed by their multiple, serious adverse effects.

Meager, mostly short-term benefit

Except for Qsymia, these central nervous system stimulants were approved for obesity before 1985 — the year that obesity was recognized as a chronic condition — and were tested for short-term use (up to 12 weeks) only.[8] The magnitude of weight loss with these short-term weight-loss drugs is limited to a fraction of a pound a week. Additionally, this weight loss varied across clinical trials and was dependent, in part, on nondrug factors (including the type of subjects and the type of diet) used in these trials. Therefore, the labels of these drugs attest that “studies do not permit conclusions as to the relative importance of [these drug] and non-drug factors on weight loss.” The labeling further clarifies that the total weight-loss effect of these drugs over that of lifestyle changes alone must be “clinically limited,” because the natural history of obesity is measured in years and the trials were restricted to a few weeks.

In 2012, the FDA approved Qsymia for long-term treatment of obesity in adults. It is the most expensive of all weight-loss central nervous system stimulants.[9] The drug, which is started at a lower dose and then increased to a standard (higher) dose after two weeks, may not work for everyone. The labeling recommends either discontinuing low-dose Qsymia or taking the higher dose if the lower dose results in less than 3% loss of body weight after three months of use. The labeling also recommends that the higher dose be discontinued if it results in less than 3% loss of body weight after three months.

The two clinical trials that supported the approval of Qsymia showed a modest benefit. At best, 70% of the subjects who used the maximum dose of Qsymia (in conjunction with lifestyle changes) lost 5% or more of their body weight after a year of therapy, compared with up to 21% of those who took a placebo. A maximum of 48% of those who used the highest dose of Qsymia (in conjunction with lifestyle changes) lost 10% or more of their body weight after a year of therapy, compared with 7% of those taking a placebo.

Importantly, none of the trials supporting the approval of these drugs looked at clinical complications related to obesity (including heart disease and related death) to assess the long-term benefits of these drugs.[10]

Adverse effects

All four weight-loss drugs discussed in this article are classified as controlled substances in the U.S. because they can be abused or can be addictive.[11]

These drugs can raise heart rate and blood pressure, cause nervousness and insomnia and exacerbate hyperthyroidism (overactive thyroid) and glaucoma (buildup of pressure inside the eye). They also can have dangerous interactions with a group of antidepressants known as monoamine oxidase inhibitors, including isocarboxazid (MARPLAN). Except for Qsymia, the labeling of these drugs indicates that they should not be used in patients with a history of cardiovascular disease (such as coronary artery disease, irregular heart rhythm, stroke or uncontrolled hypertension).

When used by pregnant women, these drugs increase the risk of fetal harm. Qsymia in particular increases the risk of congenital cleft lip and palate.

These drugs, except Qsymia, can increase the risk of heart valve damage and can cause pulmonary hypertension (a potentially fatal condition that affects the arteries that carry blood from the heart to the lungs). Symptoms of this adverse effect include breathing difficulty, chest pain, fainting or swelling of the lower limbs.

However, Qsymia has been linked to cardiovascular risks due to the phentermine component of the drug, leading the European Medicines Agency (EMA) to refuse its approval in 2013.[12] The EMA also cited concerns over unclear long-term psychiatric (including depression and anxiety) and cognitive (including memory and attention) problems associated with the topiramate component of the drug. The EMA rightly noted that there was a high probability that, if approved, Qsymia would not be used strictly for the intended patients. Months before the EMA decision, we issued a statement opposing FDA approval of Qsymia for reasons similar to those cited by the European regulators.[13]

Additional serious adverse effects for Qsymia include seizure (if discontinued abruptly), metabolic acidosis and suicidal behavior and ideation. It also can cause low blood pressure in patients taking high blood pressure medications and low blood sugar in those taking medications for diabetes.

What You Can Do

You should never take any central nervous stimulant drug or any other drug to lose weight. You can lose weight effectively and safely by combining lifestyle changes with behavior-based weight loss interventions that include self-monitoring and behavior-change techniques, as well as counseling.[14]
 

References

[1] Centers for Disease Control and Prevention. Defining adult overweight and obesity. April 11, 2017. https://www.cdc.gov/obesity/adult/defining.html. Accessed June 4, 2019.

[2] Curry SJ, Krist AH, Owens DK, et al. Behavioral weight loss interventions to prevent obesity-related morbidity and mortality in adults US Preventive Services Task Force recommendation statement. JAMA. 2018;320(11):1163-1171.

[3] KVK-Tech Inc. Label: benzphetamine (generic only). December 2018. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=14d4589d-7f1c-4b6e-9557-59dad39b0960&type=display. Accessed June 4, 2019.

[4] KVK-Tech Inc. Label: diethylpropion. December 2018. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=3ecb7bd7-e04c-47fe-859a-8ba8a54f9aff&type=display. Accessed June 4, 2019.

[5] C.O. Truxton, Inc. Label: phendimetrazine. November 2018. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=b06b1320-d88d-4fd3-bf08-613d44d26504&type=display. Accessed June 4, 2019.

[6] KVK-Tech Inc. Label: phentermine (LOMAIRA). December 2018. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=cde9fb09-e5af-434d-8874-e4f9f974d893&type=display. Accessed June 4, 2019.

[7] Vivus, Inc. Label: phentermine and topiramate (QSYMIA). November 2018. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=40dd5602-53da-45ac-bb4b-15789aba40f9&type=display. Accessed June 4, 2019.

[8] Greenway FL, Caruso MK. Safety of obesity drugs. Expert Opin Drug Saf. 2005;4(6):1083-1095.

[9] Diet, drugs, devices, and surgery for weight management. Med Lett. 2018;60(1548):91-98.

[10] Topiramate + phentermine: An excessively dangerous appetite-suppressant combination. Prescrire Int. 2013;22(136):61-64.

[11] Greenway FL, Caruso MK. Safety of obesity drugs. Expert Opin Drug Saf. 2005;4(6):1083-1095.

[12] European Medicines Agency. Questions and answers on the refusal of the marketing authorisation for Qsiva (phentermine/topiramate). February 21, 2013. https://www.ema.europa.eu/en/documents/smop-initial/questions-answers-refusal-marketing-authorisation-qsiva-phentermine/topiramate_en.pdf. Accessed June 6, 2019.

[13] Statement of Dr. Sidney Wolfe, Director, Public Citizen’s Health Research Group re. FDA approval of diet drug Qnexa is reckless. July 18, 2012. https://www.citizen.org/news/fda-approval-of-diet-drug-qnexa-is-reckless/. Accessed June 6, 2019.

[14] Curry SJ, Krist AH, Owens DK, et al. Behavioral weight loss interventions to prevent obesity-related morbidity and mortality in adults US Preventive Services Task Force recommendation statement. JAMA. 2018;320(11):1163-1171.