Levoamphetamine is a

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, ...

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 ...

which is used in the treatment of certain

medical condition A disease is a particular abnormal condition that adversely affects the structure or function (biology), function of all or part of an organism and is not immediately due to any external injury. Diseases are often known to be medical condi ...

s. It was previously marketed by itself under the brand name Cydril, but is now available only in

combination In mathematics, a combination is a selection of items from a set that has distinct members, such that the order of selection does not matter (unlike permutations). For example, given three fruits, say an apple, an orange and a pear, there are ...

with

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 varying ratios under brand names like Adderall and Evekeo. The drug is known to increase

wakefulness Wakefulness is a daily recurring brain state and state of consciousness in which an individual is conscious and engages in coherent cognition, cognitive and behavioral responses to the external world. Being awake is the opposite of being asleep, ...

and

concentration In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', '' molar concentration'', '' number concentration'', ...

in association with decreased

appetite Appetite is the desire to eat food items, usually due to hunger. Appealing foods can stimulate appetite even when hunger is absent, although appetite can be greatly reduced by satiety. Appetite exists in all higher life-forms, and serves to reg ...

and

fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...

. Pharmaceuticals that contain levoamphetamine are currently indicated and prescribed for the treatment of

attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...

(ADHD),

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 ...

, and

narcolepsy Narcolepsy is a chronic neurological disorder that impairs the ability to regulate sleep–wake cycles, and specifically impacts REM (rapid eye movement) sleep. The symptoms of narcolepsy include excessive daytime sleepiness (EDS), sleep-r ...

in some countries. Levoamphetamine 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 ...

. Levoamphetamine acts as a releasing agent of the

monoamine neurotransmitter Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin. All monoamines ...

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 ...

. It is similar to

in its ability to release norepinephrine and in its sympathomimetic effects but is a few times weaker than dextroamphetamine in its capacity to release dopamine and in its

psychostimulant 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 ...

effects. Levoamphetamine is the

levorotatory Optical rotation, also known as polarization rotation or circular birefringence, is the rotation of the orientation of the plane of polarization about the optical axis of linearly polarized light as it travels through certain materials. Circul ...

stereoisomer In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in ...

of the

racemic In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...

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 ...

molecule, whereas dextroamphetamine is the dextrorotatory isomer. Levoamphetamine was first introduced in the form of

racemic 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 ...

under the brand name Benzedrine in 1935 and as an enantiopure drug under the brand name Cydril in the 1970s. While

pharmaceutical formulation Pharmaceutical formulation, in pharmaceutics, is the process in which different chemical substances, including the active drug, are combined to produce a final medicinal product. The word ''formulation'' is often used in a way that includes dos ...

s containing enantiopure levoamphetamine are no longer manufactured,

levomethamphetamine Levomethamphetamine (International Nonproprietary Name, INN: levmetamfetamine) is an optical isomer of methamphetamine primarily used as a Topical decongestant, topical nasal decongestant. Levomethamphetamine is used to treat nasal congestion f ...

(levmetamfetamine) is still marketed and sold

over-the-counter Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid pres ...

as a

nasal decongestant A decongestant, or nasal decongestant, is a type of pharmaceutical drug that is used to relieve nasal congestion in the upper respiratory tract. The active ingredient in most decongestants is either pseudoephedrine or phenylephrine (the latter o ...

. In addition to being used in pharmaceutical drugs itself, levoamphetamine is a known active metabolite of certain other drugs, such as

selegiline Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl, Zelapar, and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It has also been studied and us ...

(L-deprenyl).

Medical uses

Levoamphetamine has been used in the treatment of

(ADHD) both alone and in combination with

at different ratios. Levoamphetamine on its own has been found to be effective in the treatment of ADHD in multiple

clinical studies Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

conducted in the 1970s. The clinical dosages and potencies of levoamphetamine and dextroamphetamine in the treatment of ADHD have been fairly similar in these older studies.

Available forms

Racemic amphetamine

The first patented amphetamine brand, Benzedrine, was a

(i.e., equal parts) mixture of the free bases or the more stable sulfate salts of both amphetamine enantiomers (levoamphetamine and dextroamphetamine) that was introduced in the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

in 1934 as an inhaler for treating

nasal congestion Nasal congestion is the partial or complete blockage of nasal passages, leading to impaired nasal breathing, usually due to membranes lining the nose becoming swollen from inflammation of blood vessels. Background In about 85% of cases, nasal ...

. It was later realized that the amphetamine enantiomers could treat

, and

ADHD Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple ...

. Because of the greater

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

effect of the dextrorotatory enantiomer (i.e.,

), sold as Dexedrine, prescription of the Benzedrine brand fell and was eventually discontinued. However, in 2012,

amphetamine sulfate was reintroduced as the Evekeo brand name.

Adderall

Adderall Adderall and Mydayis are trade names for a combination drug containing four salts of amphetamine. The mixture is composed of equal parts racemic amphetamine and dextroamphetamine, which produces a (3:1) ratio between dextroamphetamine and l ...

is a 3.1:1 mixture of dextro- to levo- amphetamine base equivalent pharmaceutical that contains equal amounts (by weight) of four salts: dextroamphetamine sulfate, amphetamine sulfate, dextroamphetamine saccharate and amphetamine (D,L)-aspartate monohydrate. This result is a 76% dextroamphetamine to 24% levoamphetamine, or to ratio.

Evekeo

Evekeo is an

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

-approved medication that contains racemic amphetamine sulfate (i.e., 50% levoamphetamine sulfate and 50% dextroamphetamine sulfate). It is approved for the treatment of

, ADHD, and exogenous obesity. The orally disintegrating tablets are approved for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents aged six to 17 years of age.

Other forms

Products using amphetamine base are now marketed. ''Dyanavel XR'', a liquid suspension form became available in 2015, and contains about 24% levoamphetamine. ''Adzenys XR'', an orally dissolving tablet came to market in 2016 and contains 25% levoamphetamine.

Side effects

Levoamphetamine can produce sympathomimetic

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 ...

Pharmacology

Pharmacodynamics

Levoamphetamine, similarly to

, acts as a reuptake inhibitor and releasing agent of

and

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 ...

''. However, there are differences in potency between the two compounds. Levoamphetamine is either similar in potency or somewhat more potent in inducing the release of norepinephrine than dextroamphetamine, whereas dextroamphetamine is approximately 4-fold more potent in inducing the release of dopamine than levoamphetamine. In addition, as a reuptake inhibitor, levoamphetamine is about 3- to 7-fold less potent than dextroamphetamine in inhibiting dopamine reuptake but is only about 2-fold less potent in inhibiting norepinephrine reuptake. Dextroamphetamine is very weak as a reuptake inhibitor of

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, ...

, whereas levoamphetamine is essentially inactive in this regard. Levoamphetamine and dextroamphetamine are both also relatively weak reversible

inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...

s of

monoamine oxidase Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The fi ...

(MAO) and hence can inhibit

catecholamine A catecholamine (; abbreviated CA), most typically a 3,4-dihydroxyphenethylamine, is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Cate ...

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 ...

. However, this action may not occur significantly at clinical doses and may only be relevant to high doses. In rodent studies, both dextroamphetamine and levoamphetamine dose-dependently induce the release of dopamine in the

striatum The striatum (: striata) or corpus striatum is a cluster of interconnected nuclei that make up the largest structure of the subcortical basal ganglia. The striatum is a critical component of the motor and reward systems; receives glutamat ...

and norepinephrine in the

prefrontal cortex In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. It is the association cortex in the frontal lobe. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, ...

. Dextroamphetamine is about 3- to 5-fold more potent in increasing striatal dopamine levels as levoamphetamine 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 ...

'', whereas the two enantiomers are about equally effective in terms of increasing prefrontal norepinephrine levels. Dextroamphetamine has greater effects on dopamine levels than on norepinephrine levels, whereas levoamphetamine has relatively more balanced effects on dopamine and norepinephrine levels. As with rodent studies, levoamphetamine and dextroamphetamine have been found to be similarly potent in elevating norepinephrine levels in

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...

in monkeys. By an uncertain

mechanism Mechanism may refer to: *Mechanism (economics), a set of rules for a game designed to achieve a certain outcome **Mechanism design, the study of such mechanisms *Mechanism (engineering), rigid bodies connected by joints in order to accomplish a ...

, the striatal dopamine release of dextroamphetamine in rodents appears to be prolonged by levoamphetamine when the two enantiomers are administered at a 3:1 ratio (though not at a 1:1 ratio). The

-releasing effects of levoamphetamine and dextroamphetamine in rodents have a fast onset of action, with a peak of effect after about 30 to 45minutes, are large in magnitude (e.g., 700–1,500% of baseline for dopamine and 400–450% of baseline for norepinephrine), and decline relatively rapidly after the effects reach their maximum. The magnitudes of the effects of amphetamines are greater than those of classical reuptake inhibitors like

atomoxetine Atomoxetine, formerly sold under the brand name Strattera, is a selective norepinephrine reuptake inhibitor (sNRI) medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, cognitive disengagement syndr ...

and

bupropion Bupropion, formerly called amfebutamone, and sold under the brand name Wellbutrin among others, is an atypical antidepressant that is indicated in the treatment of major depressive disorder, seasonal affective disorder, and to support smo ...

. In addition, unlike with reuptake inhibitors, there is no dose–effect

ceiling A ceiling is an overhead interior roof that covers the upper limits of a room. It is not generally considered a structural element, but a finished surface concealing the underside of the roof structure or the floor of a story above. Ceilings can ...

in the case of amphetamines. Although dextroamphetamine is more potent than levoamphetamine, both enantiomers can maximally increase striatal dopamine release by more than 5,000% of baseline. This is in contrast to reuptake inhibitors like bupropion and vanoxerine, which have 5- to 10-fold smaller maximal impacts on dopamine levels and, in contrast to amphetamines, were not experienced as stimulating or

euphoric Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and danci ...

. Dextroamphetamine has greater potency in producing stimulant-like effects in rodents and non-human primates than levoamphetamine. Some rodent studies have found it to be 5- to 10-fold more potent in its stimulant-like effects than levoamphetamine. Levoamphetamine is also less potent than dextroamphetamine in its

anorectic 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 in rodents. Dextroamphetamine is about 4-fold more potent than levoamphetamine in motivating

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 about 2- to 3-fold more potent than levoamphetamine in terms of positive reinforcing effects in humans. Potency ratios of dextroamphetamine versus levoamphetamine with single doses of 5 to 80mg in terms of psychological effects in humans 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 ...

, activation, euphoria, reduction of hyperactivity, and exacerbation of

psychosis In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...

have ranged from 1:1 to 4:1 in a variety of older clinical studies. With very large doses, ranging from 270 to 640mg, the potency ratios of dextroamphetamine and levoamphetamine in stimulating locomotor activity and inducing amphetamine psychosis in humans have ranged from 1:1 to 2:1 in a couple studies. The differences in potency and dopamine versus norepinephrine release between dextroamphetamine and levoamphetamine are suggestive of dopamine being the primary neurochemical mediator responsible for the stimulant and euphoric effects of these agents. In addition to inducing norepinephrine release in the brain, levoamphetamine and dextroamphetamine induce the release of

epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands a ...

(adrenaline) in the

peripheral A peripheral device, or simply peripheral, is an auxiliary hardware device that a computer uses to transfer information externally. A peripheral is a hardware component that is accessible to and controlled by a computer but is not a core compo ...

sympathetic nervous system The sympathetic nervous system (SNS or SANS, sympathetic autonomic nervous system, to differentiate it from the somatic nervous system) is one of the three divisions of the autonomic nervous system, the others being the parasympathetic nervous sy ...

and this is related to their

cardiovascular In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...

effects. Although levoamphetamine is less potent than dextroamphetamine as a stimulant, it is approximately

equipotent In mathematics, two set (mathematics), sets or class (mathematics), classes ''A'' and ''B'' are equinumerous if there exists a one-to-one correspondence (or bijection) between them, that is, if there exists a function (mathematics), function from ...

with dextroamphetamine in producing various peripheral effects, including

vasoconstriction Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vesse ...

, vasopression, and other cardiovascular effects. Similarly to dextroamphetamine, levoamphetamine has been found to improve symptoms in an

animal model An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...

of ADHD, the spontaneously hypertensive rat (SHR), including improving sustained attention and reducing overactivity and

impulsivity In psychology, impulsivity (or impulsiveness) is a tendency to act on a whim, displaying behavior characterized by little or no forethought, reflection, or consideration of the consequences. Impulsive actions are typically "poorly conceived, pre ...

. These findings parallel the clinical results in which both levoamphetamine and dextroamphetamine have been found to be effective in the treatment of ADHD in humans. Unlike the case of dextroamphetamine versus dextromethamphetamine, in which the latter is more effective than the former, levoamphetamine is substantially more potent as a dopamine releaser and stimulant than

. Conversely, levoamphetamine, levomethamphetamine, and dextroamphetamine are all similar in their potencies as norepinephrine releasers. In addition to its catecholamine-releasing activity, levoamphetamine is also an

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

trace amine-associated receptor 1 Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the ''TAAR1'' gene. TAAR1 is a primarily intracellular amine-activated and G protein-coupled receptor (GPCR) that is p ...

(TAAR1). Levoamphetamine has also been found to act as a catecholaminergic activity enhancer (CAE), notably at much lower concentrations than its catecholamine releasing activity. It is similarly potent to selegiline and levomethamphetamine but is more potent than dextromethamphetamine and dextroamphetamine in this action. The CAE effects of such agents may be mediated by TAAR1 agonism.

Pharmacokinetics

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 levoamphetamine have been studied. Usually this has been orally in

with

at different ratios. The pharmacokinetics of levoamphetamine have also been studied as a

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

Absorption

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 levoamphetamine has been found to be similar to that of dextroamphetamine. The time to peak levels of levoamphetamine with immediate-release (IR) formulations of

ranges from 2.5 to 3.5hours and with extended-release (ER) formulations ranges from 5.3 to 8.2hours depending on the formulation and the study. For comparison, the time to peak levels of

with IR formulations ranges from 2.4 to 3.3hours and with ER formulations ranges from 4.0 to 8.0hours. The

peak Peak or The Peak may refer to: Basic meanings Geology * Mountain peak ** Pyramidal peak, a mountaintop that has been sculpted by erosion to form a point Mathematics * Peak hour or rush hour, in traffic congestion * Peak (geometry), an (''n''-3)-d ...

levels of levoamphetamine are proportionally similar to those of dextroamphetamine with administration of amphetamine at varying ratios. With a single oral dose of 10mg racemic amphetamine (a 1:1 ratio of enantiomers, or 5mg dextroamphetamine and 5mg levoamphetamine), peak levels of dextroamphetamine were 14.7ng/mL and peak levels of levoamphetamine were 12.0ng/mL in one study. Food does not affect the peak levels or overall exposure to levoamphetamine or dextroamphetamine with IR racemic amphetamine. However, time to peak levels was delayed from 2.5hours (range 1.5–6hours) to 4.5hours (range 2.5–8.0hours). During oral

therapy at a dosage of 10mg/day, circulating levels of levoamphetamine have been found to be 6 to 8ng/mL and levels of

have been reported to be 9 to 14ng/mL. Although levels of levoamphetamine and levomethamphetamine are relatively low at typical doses of selegiline, they could be clinically relevant and may contribute to the effects and

s of selegiline.

Distribution

The

volume of distribution In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...

of both levoamphetamine and dextroamphetamine is about 3 to 4L/kg. The

plasma protein binding Plasma protein binding refers to the degree to which medications attach to blood proteins within the blood plasma. A drug's efficacy may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse o ...

of levoamphetamine is 31.7%, whereas that of dextroamphetamine was 29.0% in the same study.

Metabolism

Levoamphetamine and dextroamphetamine are

metabolized 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 ...

via

CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2 ...

-mediated

hydroxylation In chemistry, hydroxylation refers to the installation of a hydroxyl group () into an organic compound. Hydroxylations generate alcohols and phenols, which are very common functional groups. Hydroxylation confers some degree of water-solubility ...

to produce 4-hydroxyamphetamine and additionally via

oxidative 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 ...

deamination Deamination is the removal of an amino group from a molecule. Enzymes that catalysis, catalyse this reaction are called deaminases. In the human body, deamination takes place primarily in the liver; however, it can also occur in the kidney. In s ...

. There are several enzymes involved in the metabolism of amphetamine, of which CYP2D6 is one. Levoamphetamine seems to be metabolized somewhat less efficiently than dextroamphetamine. The pharmacokinetics of levoamphetamine generated as a

from

have been found not to significantly vary in CYP2D6

poor metabolizer Pharmacogenomics, often abbreviated "PGx," is the study of the role of the genome in drug response. Its name ('' pharmaco-'' + ''genomics'') reflects its combining of pharmacology and genomics. Pharmacogenomics analyzes how the genetic makeup o ...

s versus extensive metabolizers, suggesting that CYP2D6 may be minimally involved in the clinical metabolism of levoamphetamine.

Elimination

The mean

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 levoamphetamine ranges from 11.7 to 15.2hours in different studies. Its half-life is somewhat longer than that of dextroamphetamine, with a difference of about 1 to 2hours. For comparison, in the same studies that reported the preceding values for levoamphetamine's half-life, the half-life of dextroamphetamine ranged from 10.0 to 12.4hours. The elimination of amphetamine is highly dependent on

urinary The human urinary system, also known as the urinary tract or renal system, consists of the kidneys, ureters, bladder, and the urethra. The purpose of the urinary system is to eliminate waste from the body, regulate blood volume and blood pressu ...

pH. Urinary acidifying agents like

ascorbic acid Ascorbic acid is an organic compound with formula , originally called hexuronic acid. It is a white solid, but impure samples can appear yellowish. It dissolves freely in water to give mildly acidic solutions. It is a mild reducing agent. Asco ...

and

ammonium chloride Ammonium chloride is an inorganic chemical compound with the chemical formula , also written as . It is an ammonium salt of hydrogen chloride. It consists of ammonium cations and chloride anions . It is a white crystalline salt (chemistry), sal ...

increase amphetamine

excretion Excretion is elimination of metabolic waste, which is an essential process in all organisms. In vertebrates, this is primarily carried out by the lungs, Kidney (vertebrates), kidneys, and skin. This is in contrast with secretion, where the substa ...

and reduce its elimination half-life, whereas urinary alkalinizing agents like

acetazolamide Acetazolamide, sold under the trade name Diamox among others, is a medication used to treat glaucoma, epilepsy, acute mountain sickness, periodic paralysis, idiopathic intracranial hypertension (raised brain pressure of unclear cause), heart f ...

enhance renal tubular reabsorption and extend its half-life. The urinary excretion of unchanged amphetamine is 70% on average with a urinary pH of 6.6 and 17 to 43% at a urinary pH of greater than 6.7. With

at an oral dose of 10mg, levoamphetamine and

are eliminated in urine and recovery of levoamphetamine is 9 to 30% (or about 1–3mg) while that of levomethamphetamine is 20 to 60% (or about 2–6mg).

Chemistry

Levoamphetamine 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 also known as L-α-methyl-β-phenylethylamine or as (2''R'')-1-phenylpropan-2-amine. Levoamphetamine is the

of the amphetamine molecule.

Racemic In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...

amphetamine contains two

optical isomer In chemistry, a molecule or ion is called chiral () if it cannot be superposed on its mirror image by any combination of rotations, translations, and some conformational changes. This geometric property is called chirality (). The terms are de ...

s in equal amounts,

(the dextrorotatory enantiomer) and levoamphetamine.

History

The origin of the amphetamine

s comes from ephedra. This plant, also known as "ma huang", is an

herb Herbs are a widely distributed and widespread group of plants, excluding vegetables, with savory or aromatic properties that are used for flavoring and garnishing food, for medicinal purposes, or for fragrances. Culinary use typically distingu ...

which has been used for thousands of years in

traditional Chinese medicine Traditional Chinese medicine (TCM) is an alternative medicine, alternative medical practice drawn from traditional medicine in China. A large share of its claims are pseudoscientific, with the majority of treatments having no robust evidence ...

as a stimulant and antiasthmatic

medicine Medicine is the science and Praxis (process), practice of caring for patients, managing the Medical diagnosis, diagnosis, prognosis, Preventive medicine, prevention, therapy, treatment, Palliative care, palliation of their injury or disease, ...

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 ...

((1''R'',2''S'')-β-hydroxy-''N''-methylamphetamine), an analogue and

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 ...

and the major pharmacologically active constituent of ephedra, was first isolated from the plant in 1885. Another plant, known as ''

Catha edulis Khat (''Catha edulis''), also known as Bushman's tea, especially in South Africa, is a flowering plant native to eastern and southeastern Africa. It has a history of cultivation originating in the Harari Region, Harar area (present day easter ...

'' (khat), also naturally contains amphetamines, specifically

cathine Cathine, also known as -norpseudoephedrine or as (+)-norpseudoephedrine, is a psychoactive drug of the phenethylamine and amphetamine groups which acts as a stimulant. Along with cathinone, it is found naturally in ''Catha edulis'' (khat), and ...

((1''S'',2''S'')-β-hydroxyamphetamine) and

cathinone Cathinone (; also known as β-ketoamphetamine) is a monoamine alkaloid found in the shrub ''Catha edulis'' (khat) and is chemically similar to ephedrine, cathine, methcathinone and other amphetamines. It is probably the main contributor to t ...

(β-ketoamphetamine). It has a long history of use for its stimulant effects in

Eastern Africa East Africa, also known as Eastern Africa or the East of Africa, is a region at the eastern edge of the Africa, African continent, distinguished by its unique geographical, historical, and cultural landscape. Defined in varying scopes, the regi ...

and the

Arabian Peninsula The Arabian Peninsula (, , or , , ) or Arabia, is a peninsula in West Asia, situated north-east of Africa on the Arabian plate. At , comparable in size to India, the Arabian Peninsula is the largest peninsula in the world. Geographically, the ...

. However, cathine was not isolated from khat until 1930 and cathinone was not isolated from the plant until 1975. Amphetamine, which is a

racemic mixture In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...

and levoamphetamine, was first discovered in 1887, shortly after the isolation of ephedrine. However, it was not until 1927 that amphetamine was synthesized by Gordon Alles and was studied by him in animals and humans. This led to the discovery of the stimulating effects of amphetamine in humans in 1929 after Alles injected himself with 50mg of the drug. Levoamphetamine was first introduced in the form of racemic amphetamine (a 1:1 combination of levoamphetamine and dextroamphetamine) under the brand name Benzedrine in 1935. It was indicated for the treatment of

, mild depression,

parkinsonism Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), Rigidity (neurology), rigidity, and balance disorder, postural instability. Both hypokinetic features (bradykinesia and akinesia) and hyperkinetic f ...

, and a variety of other conditions. Dextroamphetamine was found to be the more potent of the two

enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

s of amphetamine and was introduced as an enantiopure drug under the brand name Dexedrine in 1937. Consequent to its lower potency, levoamphetamine has received far less attention than racemic amphetamine or dextroamphetamine. Levoamphetamine was studied in the treatment of

(ADHD) in the 1970s and was found to be clinically effective for this condition similarly to dextroamphetamine. As a result, it was marketed as an enantiopure drug under the brand name Cydril for the treatment of ADHD in the 1970s. However, it was reported in 1976 that racemic amphetamine was less effective than dextroamphetamine in treating ADHD. As a result of this study, use of racemic amphetamine in the treatment of ADHD dramatically declined in favor of dextroamphetamine. Enantiopure levoamphetamine was eventually discontinued and is no longer available today.

Society and culture

Legal status

Levoamphetamine is a

controlled substance A controlled substance is generally a drug or chemical whose manufacture, possession and use is regulated by a government, such as illicitly used drugs or prescription medications that are designated by law. Some treaties, notably the Sing ...

in the

Philippines The Philippines, officially the Republic of the Philippines, is an Archipelagic state, archipelagic country in Southeast Asia. Located in the western Pacific Ocean, it consists of List of islands of the Philippines, 7,641 islands, with a tot ...

Recreational use

Misuse of enantiopure levoamphetamine and

is reportedly not known. However, rare cases of misuse of levomethamphetamine, which is available

as a

, actually have been reported. Due to their lower

efficacy Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as '' effectiveness'', and it has often been used synonymously, although in pharmacology a distinction is now often made betwee ...

in stimulating dopamine release and their reduced potency as

s, levoamphetamine and levomethamphetamine would theoretically be expected to have less misuse potential than the corresponding

and dextromethamphetamine forms.

Research

Levoamphetamine as an enantiopure drug has been studied in the past in a variety of contexts. These include its effects in and/or treatment of mood, " minimal brain dysfunction",

, " hyperkinetic syndrome" and

aggression Aggression is behavior aimed at opposing or attacking something or someone. Though often done with the intent to cause harm, some might channel it into creative and practical outlets. It may occur either reactively or without provocation. In h ...

sleep Sleep is a state of reduced mental and physical activity in which consciousness is altered and certain Sensory nervous system, sensory activity is inhibited. During sleep, there is a marked decrease in muscle activity and interactions with th ...

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

Tourette's syndrome Tourette syndrome (TS), or simply Tourette's, is a common neurodevelopmental disorder that begins in childhood or adolescence. It is characterized by multiple movement (motor) tics and at least one vocal (phonic) tic. Common tics are blinki ...

, and

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

, among others. Levoamphetamine has been studied in the treatment of

multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...

in more modern studies and has been reported to improve

cognition Cognition is the "mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...

and

memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembe ...

in this condition as well. It was under development for this indication under the name levafetamine and the developmental code name ''C-105'' and reached phase 2

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s, but development was discontinued sometime after 2008.

Other drugs

Selegiline

Levoamphetamine is a major active metabolite of

(L-deprenyl; ''N''-propargyl-L-methamphetamine). Selegiline is 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), specifically a selective

of monoamine oxidase B (MAO-B) at lower doses and a dual inhibitor of both

monoamine oxidase A Monoamine oxidase A, also known as MAO-A, is an enzyme ( E.C. 1.4.3.4) that in humans is encoded by the ''MAOA'' gene. This gene is one of two neighboring gene family members that encode mitochondrial enzymes which catalyze the oxidative dea ...

(MAO-A) and MAO-B at higher doses. It also has additional activities, such as acting as a catecholaminergic activity enhancer (CAE), possibly via

agonism Agonism (from Greek 'struggle') is a political and social theory that emphasizes the potentially positive aspects of certain forms of conflict. It accepts a permanent place for such conflict in the political sphere, but seeks to show how indivi ...

of the TAAR1, and having potential neuroprotective effects. Selegiline is clinically used as an

antiparkinsonian agent In the management of Parkinson's disease, due to the chronic nature of Parkinson's disease (PD), a broad-based program is needed that includes patient and family education, support-group services, general wellness maintenance, exercise, and nutr ...

in the treatment of

and as an

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

in the treatment of

major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...

. In addition to levoamphetamine, selegiline also metabolizes into

. With a 10mg oral dose of selegiline, about 2 to 6mg levomethamphetamine and 1 to 3mg levoamphetamine is excreted 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 ...

. As levoamphetamine and levomethamphetamine are

and/or dopamine releasing agents, they may contribute to the effects and

s of selegiline. This may particularly include

and sympathomimetic effects of selegiline. Other selective MAO-B inhibitors that do not metabolize into amphetamine metabolites or have associated cardiovascular effects, such as

rasagiline Rasagiline, sold under the brand name Azilect among others, is a medication which is used in the treatment of Parkinson's disease. It is used as a monotherapy to treat symptoms in early Parkinson's disease or as an adjunct therapy in more advan ...

, have also been developed and introduced. Because selegiline metabolizes into levoamphetamine and levomethamphetamine, people taking selegiline can erroneously test positive for amphetamines on

drug test A drug test (also often toxicology screen or tox screen) is a technical analysis of a biological specimen, for example urine, hair, blood, breath, sweat, or saliva, oral fluid/saliva—to determine the presence or absence of specified parent ...

Notes

References

External links

* {{Portal bar, Medicine, Chemistry, Biology Amphetamine Antihypotensive agents Drugs acting on the nervous system Enantiopure drugs Euphoriants Human drug metabolites Monoaminergic activity enhancers Norepinephrine-dopamine releasing agents Selegiline Stimulants Substituted amphetamines Sympathomimetics TAAR1 agonists VMAT inhibitors Wakefulness-promoting agents