Phentermine

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 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 3million 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 Phentermine was withdrawn from the market in the United Kingdom in 2000, while the combination medication fen-phen, of which it was a part, was withdrawn from the market in 1997 due to side effects of fenfluramine.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 or monoamine oxidase inhibitors.
Phentermine is contraindicated for users who:

have a history of drug abuse
are allergic to sympathomimetic amine drugs
are taking a monoamine oxidase inhibitor 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 currently 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 and acts as a monoamine releasing agent, specifically as a norepinephrine–dopamine releasing agent. It also acts as a norepinephrine–dopamine reuptake inhibitor 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. 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. 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 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.

Other actions

Phentermine has been found to be completely inactive as a ligand or agonist of the serotonin 5-HT₂ receptors, including of the serotonin 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors. This is in contrast to the serotonin releasing agents fenfluramine, norfenfluramine, and to a lesser extent chlorphentermine. However, another study found that phentermine was a weak human serotonin 5-HT_2C receptor partial agonist. In accordance with its lack of serotonin release and serotonin 5-HT_2B receptor agonism, phentermine appears to show no risk of primary pulmonary hypertension or valvular heart disease in humans.
Phentermine has been found to be active as an agonist of the rat and human trace amine-associated receptor 1. It appears to be a weak human TAAR1 partial agonist. The drug shows reduced activity as a TAAR1 agonist compared to amphetamine. TAAR1 agonism by amphetamines that possess this action may serve to auto-inhibit and constrain their effects.
Phentermine is a very weak monoamine oxidase inhibitor in vitro. It specifically inhibits monoamine oxidase A and monoamine oxidase B . However, its potency as a MAOI is far below its potency as a monoamine releasing agent. Relatedly, phentermine does not show neurochemical signs of MAOI activity in rodents in vivo. As such, the significance of phentermine as an MAOI in humans is questionable.

Pharmacokinetics

Absorption

The pharmacokinetics of phentermine are dose-dependent. Peak concentrations of phentermine are reached 6hours following oral administration of a dose of 15mg. The steady-state levels of phentermine with continuous administration have been found to be around 200ng/mL in clinical studies. The oral bioavailability of phentermine is not affected by intake of a high-fat meal.
Phentermine is a lipophilic amine that is rapidly absorbed through the gastrointestinal tract following oral ingestion. Its weakly basic nature facilitates absorption in the small intestine, where it exists primarily in a non-ionized form at physiological pH. Peak plasma concentrations can vary slightly based on formulation and gastric motility. The drug’s predictable absorption profile supports once-daily dosing in most therapeutic regimens.

Distribution

The volume of distribution of phentermine is 5L/kg. Its plasma protein binding is approximately 17.5%. This percentage of 17.5 suggests that a substantial portion of the drug remains unbound and pharmacologically active. Because of its lipophilicity and amphetamine-like structure, phentermine readily crosses the blood–brain barrier, contributing to its central nervous system stimulant effects, such as increased alertness and appetite suppression. Distribution into fatty tissues may contribute to a moderate duration of action despite limited metabolism.

Metabolism

Phentermine undergoes minimal metabolism. Only about 6% of an administered dose of phentermine is metabolized. It is metabolized to a minor extent by para-hydroxylation, N-oxidation, and N-hydroxylation, followed by conjugation.
Because phentermine’s metabolism is relatively minor, most of its pharmacologic activity is attributable to the parent compound rather than metabolites. The drug is not known to significantly induce or inhibit CYP450 enzymes, suggesting a low potential for clinically meaningful drug–drug interactions. Variations in metabolic rate due to hepatic function generally have less effect on overall clearance compared to renal factors.