What are the adverse effects of phentermine?

Adverse Effects of Phentermine

Phentermine causes a range of adverse effects primarily related to its sympathomimetic activity, with the most common being dry mouth, insomnia, constipation, headache, elevated blood pressure, elevated heart rate, and anxiety. 1, 2

Cardiovascular Side Effects

The cardiovascular effects are the most clinically significant concern:

• Elevated blood pressure and heart rate occur through norepinephrine release and sympathetic nervous system activation, though paradoxically, blood pressure often decreases during treatment due to weight loss 1
• Palpitations and tachycardia are common cardiovascular manifestations 1, 2
• Ischemic cardiac events including angina pectoris have been reported 1, 2
• Primary pulmonary hypertension is a serious but rare complication 2
• Valvular heart disease was historically associated with the fenfluramine-phentermine ("fen-phen") combination, but this risk was attributed to fenfluramine, not phentermine itself 1, 3

Critical caveat: The cardiovascular risks require baseline and ongoing monitoring of blood pressure and heart rate at every visit, and phentermine is contraindicated in patients with uncontrolled hypertension, history of cardiovascular disease, or coronary artery disease 1, 3

Central Nervous System Effects

Phentermine's stimulant properties produce multiple CNS side effects:

• Insomnia is one of the most frequent complaints, which is why dosing should occur early in the day 1, 4
• Headache occurs commonly across all studies 1, 5
• Overstimulation, restlessness, and anxiety reflect its amphetamine-like structure 1, 2
• Dizziness and tremor are reported in clinical trials 1, 2, 5
• Euphoria, dysphoria, and rarely psychosis can occur, particularly at higher doses 1, 2
• Depression-related and anxiety-related adverse events occurred in 4-8% of patients in combination therapy trials 5
• Cognitive impairment (concentration and memory problems) is more prominent with phentermine-topiramate combination 1

Important pitfall: Phentermine is contraindicated in patients with agitated states, anxiety disorders, or history of drug abuse due to its stimulant properties and potential for dependence 1

Gastrointestinal Effects

GI side effects are extremely common but generally mild:

• Dry mouth (xerostomia) is the most frequently reported adverse effect, occurring in 13-21% of patients 1, 5, 4
• Constipation affects 15-17% of patients 1, 5
• Unpleasant taste (dysgeusia) occurs in approximately 10% 1, 2, 5
• Diarrhea and other GI disturbances are less common 1, 2

Ocular Side Effects

Visual disturbances require immediate attention:

• Blurred vision can occur and should prompt immediate medical evaluation 3
• Acute myopia and ocular pain are particular concerns with phentermine-topiramate combination 1, 3
• Acute angle-closure glaucoma risk makes phentermine contraindicated in patients with glaucoma 1, 3

Monitoring recommendation: Patients should be questioned about visual disturbances at each visit and instructed to discontinue phentermine immediately if vision changes occur 3

Endocrine and Reproductive Effects

• Changes in libido and impotence have been reported 1, 2
• Pregnancy is an absolute contraindication due to teratogenic concerns, particularly with topiramate in combination products 1

Metabolic and Other Effects

• Paresthesia (tingling sensations) occurs in 14-21% of patients, more common with combination therapy 1, 5
• Urticaria (allergic skin reactions) can occur 1, 2
• Decreased bicarbonate and electrolyte disturbances may develop 1

Serious but Rare Adverse Events

The following require immediate discontinuation:

• Severe hypertension or hypertensive crisis, especially if combined with MAO inhibitors 1, 2
• Dyspnea and syncope 1
• Seizures in susceptible individuals 1
• Severe liver injury is extremely rare but documented 1

Withdrawal and Dependence

• Pharmacological tolerance, dependence, and withdrawal symptoms can develop with long-term use 1
• Phentermine is classified as a Schedule IV controlled substance due to abuse potential 1
• Abrupt discontinuation of higher doses should be avoided; tapering over at least one week is recommended 1

Drug Interactions Leading to Adverse Effects

Critical interactions that increase adverse event risk:

• MAO inhibitors are absolutely contraindicated; allow ≥14 days between discontinuation of MAOIs and phentermine initiation 1, 3
• Tramadol was the most frequently co-prescribed drug causing severe potential drug-drug interactions in one study 6
• Dextromethorphan commonly causes moderate interactions 6
• Other sympathomimetic amines should be avoided 1

Frequency and Severity Context

Most adverse effects are mild to moderate in intensity 4. In a Korean study, dry mouth and insomnia were the only statistically significant adverse events, and most side effects were well-tolerated 4. However, in clinical practice, approximately 4-7% of patients discontinue phentermine due to intolerable side effects, most commonly severe headaches, hypertension, depressive symptoms, breathlessness, palpitations, and irritability 7.

The unpredictability of individual response is a key clinical challenge—plasma phentermine concentrations do not correlate with side effect severity or efficacy, making it impossible to predict who will experience significant adverse effects 7.