Phentermine, sold under the brand name Adipex-P among others, is a

medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

used together with diet and

exercise Exercise or workout is physical activity that enhances or maintains fitness and overall health. It is performed for various reasons, including weight loss or maintenance, to aid growth and improve strength, develop muscles and the cardio ...

to treat

obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

. It is available by itself or as the combination phentermine/topiramate. Phentermine is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

. Common

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s include a fast heart beat,

high blood pressure Hypertension, also known as high blood pressure, is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms itself. It is, however, a major ri ...

, trouble sleeping,

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

, and restlessness. Serious side effects may include

abuse Abuse is the act of improper usage or treatment of a person or thing, often to unfairly or improperly gain benefit. Abuse can come in many forms, such as: physical or verbal maltreatment, injury, assault, violation, rape, unjust practices, ...

, but do not include

pulmonary hypertension Pulmonary hypertension (PH or PHTN) is a condition of increased blood pressure in the pulmonary artery, arteries of the lungs. Symptoms include dypsnea, shortness of breath, Syncope (medicine), fainting, tiredness, chest pain, pedal edema, swell ...

or valvular heart disease, as the latter complications were caused by the

fenfluramine Fenfluramine, sold under the brand name Fintepla, is a serotonergic medication used for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome. It was formerly used as an appetite suppressant in the treat ...

component of the " fen-phen" combination. Phentermine is a norepinephrine and dopamine releasing agent (NDRA) and produces

stimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition, ...

, rewarding, and

appetite suppressant An anorectic is a drug that reduces appetite, resulting in lower food consumption, leading to weight loss. These substances work by affecting the central nervous system or certain neurotransmitters to create a feeling of fullness or reduce the desi ...

effects. Chemically, it is a

substituted amphetamine Substituted amphetamines, or simply amphetamines, are a chemical class, class of compounds based upon the amphetamine structure; it includes all derivative (chemistry), derivative compounds which are formed by replacing, or substitution reacti ...

. Phentermine was approved for medical use in the United States in 1959. It is available as a

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

. In 2022, it was the 149th 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 A combination drug is a combination of two or more pharmaceutical drugs as active ingredients combined into a single dosage form, typically as a ''fixed-dose combination'', with each constituent standardized to specifications of a fixed dose. Fix ...

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 Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat (adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other conn ...

, 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 Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

breastfeeding Breastfeeding, also known as nursing, is the process where breast milk is fed to a child. Infants may suck the milk directly from the breast, or milk may be extracted with a Breast pump, pump and then fed to the infant. The World Health Orga ...

, or with

selective serotonin reuptake inhibitor Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs primarily work by blo ...

s (SSRIs) or

monoamine oxidase inhibitors Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, espe ...

(MAOIs). Phentermine is

contraindicated In medicine, a contraindication is a condition (a situation or factor) that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a rea ...

for users who: * have a history of

drug abuse Substance misuse, also known as drug misuse or, in older vernacular, substance abuse, is the use of a drug in amounts or by methods that are harmful to the individual or others. It is a form of substance-related disorder, differing definitions ...

* are allergic to sympathomimetic amine drugs * are taking a

monoamine oxidase inhibitor Monoamine oxidase inhibitors (MAOIs) are a drug class, class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressa ...

(MAOI) or have taken one within the last 14 days * have

cardiovascular disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...

hyperthyroidism Hyperthyroidism is a endocrine disease in which the thyroid gland produces excessive amounts of thyroid hormones. Thyrotoxicosis is a condition that occurs due to elevated levels of thyroid hormones of any cause and therefore includes hyperth ...

, or

glaucoma Glaucoma is a group of eye diseases that can lead to damage of the optic nerve. The optic nerve transmits visual information from the eye to the brain. Glaucoma may cause vision loss if left untreated. It has been called the "silent thief of ...

* are

pregnant Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

, planning to become pregnant, or

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 Palpitations occur when a person becomes aware of their heartbeat. The heartbeat may feel hard, fast, or uneven in their chest. Symptoms include a very fast or irregular heartbeat. Palpitations are a sensory symptom. They are often described as ...

tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ...

, 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 A norepinephrine–dopamine reuptake inhibitor (NDRI) is a type of drug that inhibits the reuptake of the monoamine neurotransmitters norepinephrine and dopamine and thereby increases extracellular levels of these neurotransmitters and nor ...

(NDRI) to a lesser extent. The drug robustly and dose-dependently elevates brain

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...

and

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

levels in animals. Phentermine is more potent in its effects on norepinephrine than on dopamine and the drug shows only weak effects on

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

. Unlike many other

amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

s 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 Stimulation is the encouragement of development or the cause of activity in general. For example, "The press provides stimulation of political discourse." An interesting or fun activity can be described as "stimulating", regardless of its physic ...

, 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 Dextroamphetamine (international nonproprietary name, INN: dexamfetamine) is a potent central nervous system (CNS) stimulant and enantiomer of amphetamine that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narc ...

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 Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

'', is about 10-fold less potent than amphetamine in terms of

self-administration Self-administration is, in its Medicine, medical sense, the process of a subject administering a Pharmacology, pharmacological substance to themself. A clinical example of this is the subcutaneous "self-injection" of insulin by a Diabetes, diabetic ...

in monkeys, and is a relatively weak reinforcer in rodents. Although phentermine induces the release of dopamine at sufficiently high concentrations ''

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

'' 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 Ephedrine is a central nervous system (CNS) stimulant and sympathomimetic agent that is often used to prevent hypotension, low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred ...

(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 Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic pathways, Dopaminergic brain pathways facil ...

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

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

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 In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of the

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 (SRAs)

, 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 pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

( = 1,394nM, V_max = 66%). 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 (PPH) or valvular heart disease (VHD) in humans. Phentermine has been found to be active as an agonist of the rat and human trace amine-associated receptor 1 (TAAR1). It appears to be a weak human TAAR1

( = 5,470nM and = 68% in one study). The drug shows reduced activity as a TAAR1 agonist compared to

. TAAR1 agonism by amphetamines that possess this action may serve to auto-inhibit and constrain their effects. Phentermine is a very weak

(MAOI) ''

''. It specifically inhibits monoamine oxidase A (MAO-A) ( = 85,000–143,000nM) and monoamine oxidase B (MAO-B) ( = 285,000nM). 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 ''

''. As such, the significance of phentermine as an MAOI in humans is questionable.

Pharmacokinetics

Absorption

The

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific su ...

of phentermine are dose-dependent. Peak concentrations of phentermine are reached 6hours following

oral administration Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

of a dose of 15mg. The

steady-state In systems theory, a system or a process is in a steady state if the variables (called state variables) which define the behavior of the system or the process are unchanging in time. In continuous time, this means that for those properties ''p'' ...

levels of phentermine with continuous administration have been found to be around 200ng/mL in clinical studies. The oral

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

of phentermine is not affected by intake of a high-fat meal.

Distribution

The volume of distribution of phentermine is 5L/kg. Its plasma protein binding is approximately 17.5%.

Metabolism

Phentermine undergoes minimal

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

. Only about 6% of an administered dose of phentermine is metabolized. It is metabolized to a minor extent by ''para''- hydroxylation, ''N''-

oxidation Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...

, and ''N''-hydroxylation, followed by

conjugation Conjugation or conjugate may refer to: Linguistics *Grammatical conjugation, the modification of a verb from its basic form *Emotive conjugation or Russell's conjugation, the use of loaded language Mathematics *Complex conjugation, the change o ...

Elimination

The drug is eliminated mainly in

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

. It is excreted 62 to 85% unchanged in urine. The

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

of phentermine is 20 to 25hours. The elimination of phentermine is modified by urine acidicity or pH. In the case of acidic urine (pH < 5), the elimination half-life of phentermine has been found to be 7 to 8hours. The clearance of phentermine is 8.79L/h.

History

In 1959, phentermine first received approval from the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) as an appetite suppressant. Eventually a hydrochloride salt and a

resin A resin is a solid or highly viscous liquid that can be converted into a polymer. Resins may be biological or synthetic in origin, but are typically harvested from plants. Resins are mixtures of organic compounds, predominantly terpenes. Commo ...

form became available. Phentermine was marketed with

or dexfenfluramine as a combination appetite suppressant and fat burning agent under the popular name fen-phen. In 1997, after 24 cases of heart valve disease in fen-phen users, fenfluramine and dexfenfluramine were voluntarily taken off the market at the request of the FDA. Studies later showed nearly 30% of people taking fenfluramine or dexfenfluramine for up to 24 months had abnormal valve findings. Phentermine is still available by itself in most countries, including the US. However, because it is similar to

, it is classified as a controlled substance in many countries. Internationally, phentermine is a schedule IV drug under the

Convention on Psychotropic Substances The Convention on Psychotropic Substances of 1971 is a United Nations treaty designed to control psychoactive drugs such as amphetamine-type stimulants, barbiturates, benzodiazepines, and psychedelics signed in Vienna, Austria on 21 February ...

. In the United States, it is classified as a Schedule IV controlled substance under the

Controlled Substances Act The Controlled Substances Act (CSA) is the statute establishing federal government of the United States, federal drug policy of the United States, U.S. drug policy under which the manufacture, importation, possession, use, and distribution of ...

. In contrast, amphetamine preparations are classified as Schedule II controlled substances. A company called Vivus developed a

combination drug A combination drug is a combination of two or more pharmaceutical drugs as active ingredients combined into a single dosage form, typically as a ''fixed-dose combination'', with each constituent standardized to specifications of a fixed dose. Fix ...

, phentermine/topiramate that it originally called Qnexa and then called Qsymia, which was invented and used off-label by Thomas Najarian, who opened a weight-clinic in Los Osos, California in 2001; Najarian had previously worked at Interneuron Pharmaceuticals, which had developed one of the fen-phen drugs previously withdrawn from the market. The FDA rejected the combination drug in 2010 due to concerns over its safety. In 2012 the FDA approved it after Vivus re-applied with further safety data. At the time, one obesity specialist estimated that around 70% of his colleagues were already prescribing the combination off-label.

Chemistry

Phentermine, also known as α,α-dimethylphenethylamine or as α-methylamphetamine, is a

substituted phenethylamine Substituted phenethylamines (or simply phenethylamines) are a chemical class of organic compounds that are based upon the phenethylamine structure; the class is composed of all the derivative (chemistry), derivative compounds of phenethylamine ...

and

. It is the

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

of amphetamine in which a second

methyl group In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated a ...

is present at the alpha carbon. The drug is a positional isomer of

methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug use, recreational or Performance-enhancing substance, performance-enhancing drug and less commonly as a secon ...

(''N''-methylamphetamine) and of other methylamphetamines such as 4-methylamphetamine.

Derivatives

A number of derivatives of phentermine exist, including cericlamine, chlorphentermine, cloforex, clortermine, etolorex, mephentermine, 3,4-methylenedioxyphentermine (MDPH), 3,4-methylenedioxy-''N''-methylphentermine (MDMP or MDMPH), and pentorex, among others. Some of these drugs, including chlorphentermine, cloforex, clortermine, and mephentermine, have been marketed as

pharmaceutical drug Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the ...

s similarly to phentermine, for instance as

Society and culture

Etymology

The term ‘phentermine' is contracted from phenyl- tertiary-butyl amine.

Brand names

Phentermine is marketed under many brand names and formulations worldwide, including Acxion, Adipex, Adipex-P, Duromine, Elvenir, Fastin, Ionamin, Lomaira (phentermine hydrochloride), Panbesy, Qsymia (phentermine and topiramate), Razin, Redusa, Sentis, Suprenza, and Terfamex.

References

External links

* {{Authority control 5-HT2C agonists Amphetamine Anorectics Anti-obesity drugs Carbonic anhydrase activators Norepinephrine-dopamine releasing agents Phentermines TAAR1 agonists Wikipedia medicine articles ready to translate Withdrawn drugs