Phentermine, sold under the brand name Adipex-P among others, is a medication used together with diet and exercise to treat obesity. It is available by itself or as the combination phentermine/topiramate. Phentermine is taken by mouth. Common side effects include a fast heart beat, high blood pressure, trouble sleeping, dizziness, and restlessness. Serious side effects may include abuse, but do not include pulmonary hypertension or valvular heart disease, as the latter complications were caused by the fenfluramine component of the "fen-phen" combination. Phentermine is a norepinephrine and dopamine releasing agent (NDRA) and produces stimulant, rewarding, and appetite suppressant effects. Chemically, it is a substituted amphetamine. Phentermine was approved for medical use in the United States in 1959. It is available as a generic medication. In 2023, it was the 168th most commonly prescribed medication in the United States, with more than 3 million prescriptions. Phentermine was withdrawn from the market in the United Kingdom in 2000, while the combination medication fen-phen, of which it was a part, was withdrawn from the market in 1997, due to side effects of fenfluramine.
Medical uses Phentermine is used for a short period of time to promote weight loss, if exercise and calorie reduction are not sufficient, and in addition to exercise and calorie reduction. Phentermine is approved for up to 12 weeks of use and most weight loss occurs in the first weeks. However, significant loss continues through the sixth month and has been shown to continue at a slower rate through the ninth month.
Contraindications Use is not recommended during pregnancy or breastfeeding, or with selective serotonin reuptake inhibitors (SSRIs) or monoamine oxidase inhibitors (MAOIs). Phentermine is contraindicated for users who:
have a history of drug abuse are allergic to sympathomimetic amine drugs are taking a monoamine oxidase inhibitor (MAOI) or have taken one within the last 14 days have cardiovascular disease, hyperthyroidism, or glaucoma are pregnant, planning to become pregnant, or breastfeeding.
Adverse effects Tolerance usually occurs; however, risks of dependence and addiction are considered negligible. People taking phentermine may be impaired when driving or operating machinery. Consumption of alcohol with phentermine may produce adverse effects. There is no evidence regarding whether or not phentermine is safe for pregnant women. Other adverse effects include:
Cardiovascular effects like palpitations, tachycardia, high blood pressure, precordial pain; rare cases of stroke, angina, myocardial infarction, cardiac failure and cardiac arrest have been reported. Central nervous system effects like overstimulation, restlessness, nervousness, insomnia, tremor, dizziness and headache; there are rare reports of euphoria followed by fatigue and depression, and very rarely, psychotic episodes and hallucinations. Gastrointestinal effects include nausea, vomiting, dry mouth, cramps, unpleasant taste, diarrhea, and constipation. Other adverse effects include trouble urinating, rash, impotence, changes in libido, and facial swelling.
Interactions Phentermine may decrease the effect of drugs like clonidine, methyldopa, and guanethidine. Drugs to treat hypothyroidism may increase the effect of phentermine.
Pharmacology
Pharmacodynamics
Monoamine releasing agent
Phentermine is a substrate of the monoamine transporters (MATs) and acts as a monoamine releasing agent (MRA), specifically as a norepinephrine–dopamine releasing agent (NDRA). It also acts as a norepinephrine–dopamine reuptake inhibitor (NDRI) to a lesser extent. The drug robustly and dose-dependently elevates brain norepinephrine and dopamine levels in animals. Phentermine is more potent in its effects on norepinephrine than on dopamine and the drug shows only weak effects on serotonin. Unlike many other amphetamines and MRAs, phentermine is completely inactive at the vesicular monoamine transporter 2 (VMAT2). Due to its actions on the catecholamines, phentermine produces effects including stimulation, rewarding effects, appetite suppression, and sympathomimetic effects in animals and humans. In terms of monoamine release in vitro using rat brain synaptosomes, phentermine is about 6-fold less potent than dextroamphetamine in the case of norepinephrine release, 11-fold less potent than dextroamphetamine in the case of dopamine release, and has a ratio of norepinephrine release versus dopamine release of about 6.6:1 compared to dextroamphetamine's ratio of about 3.5:1. It is more than 3-fold less potent than amphetamine in elevating brain dopamine and serotonin levels in rodents in vivo, is about 10-fold less potent than amphetamine in terms of self-administration in monkeys, and is a relatively weak reinforcer in rodents. Although phentermine induces the release of dopamine at sufficiently high concentrations in vitro and at sufficiently high doses in rodents and monkeys in vivo, it may result in only weak or negligible brain dopamine release in humans at typical clinical doses. This may be due to its selectivity for induction of norepinephrine over dopamine release and may be analogous to the case of ephedrine (which is at least 10-fold selective for induction of norepinephrine over dopamine release). The effects of phentermine may be more related to noradrenergic activation rather than dopaminergic activity. However, more research is needed to assess the preceding notions. As with other MRAs, phentermine produces dopaminergic neurotoxicity in rodents at high doses. It can also produce serotonergic neurotoxicity at very high doses in rodents. The clinical significance of these findings for humans, in which employed doses may be much lower, are unclear. The combination of phentermine with a serotonin releasing agent (SRA) like fenfluramine results in suppression of brain dopamine release by phentermine and marked attenuation or abolition of phentermine's stimulant and rewarding effects in animals and humans. Conversely, combined phentermine and fenfluramine administration synergistically enhances the appetite suppression of these drugs in animals and results in greater weight loss than either drug alone in humans. Fenfluramine produces serotonergic neurotoxicity in animals and addition of phentermine results in either no change or augmentation of this neurotoxicity.
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