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Levoamphetamine is a stimulant medication which is used in the treatment of certain medical conditions. It was previously marketed by itself under the brand name Cydril, but is now available only in combination drug with dextroamphetamine in varying ratios under brand names such as Adderall. The drug is known to increase wakefulness and attention in association with decreased appetite and fatigue. Pharmaceuticals that contain levoamphetamine are currently indicated and prescribed for the treatment of attention deficit hyperactivity disorder (ADHD), obesity, and narcolepsy in some countries. (2026). 9780128002124, Elsevier. ISBN 9780128002124 Levoamphetamine is taken by mouth.
Levoamphetamine acts as a releasing agent of the monoamine neurotransmitters norepinephrine and dopamine. It is similar to dextroamphetamine 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 effects. Levoamphetamine is the levorotatory stereoisomer of the racemate amphetamine molecule, whereas dextroamphetamine is the dextrorotatory isomer.
Levoamphetamine was first introduced in the form of racemic amphetamine under the brand name Benzedrine in 1935 and as an enantiopure drug under the brand name Cydril in the 1970s. While pharmaceutical formulations containing enantiopure levoamphetamine are no longer manufactured, levomethamphetamine (levmetamfetamine) is still marketed and sold over-the-counter as a decongestant. In addition to being used in pharmaceutical drugs itself, levoamphetamine is a known active metabolite of certain other drugs, such as selegiline (L-deprenyl).
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| Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs: | ||||||
Levoamphetamine, similarly to dextroamphetamine, acts as a reuptake inhibitor and releasing agent of norepinephrine and dopamine in vitro. 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, whereas levoamphetamine is essentially inactive in this regard. Levoamphetamine and dextroamphetamine are both also relatively weak reversible enzyme inhibitor of monoamine oxidase (MAO) and hence can inhibit catecholamine metabolism. 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 dependence induce the release of dopamine in the striatum and norepinephrine in the prefrontal cortex. Dextroamphetamine is about 3- to 5-fold more potent in increasing striatal dopamine levels as levoamphetamine in rodents in vivo, 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 in monkeys. (1989). 9781489909084, Springer US. ISBN 9781489909084 By an uncertain mechanism, 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 catecholamine-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 and bupropion. In addition, unlike with reuptake inhibitors, there is no dose–effect ceiling 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 euphoriant.
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. (1978). 9781475705126, Springer US. ISBN 9781475705126 Levoamphetamine is also less potent than dextroamphetamine in its anorectic effects in rodents. Dextroamphetamine is about 4-fold more potent than levoamphetamine in motivating self-administration 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 stimulant, wakefulness, activation, euphoria, reduction of hyperactivity, and exacerbation of psychosis 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 hyperlocomotion 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) in the peripheral sympathetic nervous system and this is related to their cardiovascular effects. Although levoamphetamine is less potent than dextroamphetamine as a stimulant, it is approximately equipotent with dextroamphetamine in producing various peripheral effects, including vasoconstriction, vasopressor, and other cardiovascular effects.
Similarly to dextroamphetamine, levoamphetamine has been found to improve symptoms in an animal model of ADHD, the spontaneously hypertensive rat (SHR), including improving sustained attention and reducing hyperactivity and impulsivity. (2026). 9783031210532, Springer International Publishing. ISBN 9783031210532 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 levomethamphetamine. 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 of the trace amine-associated receptor 1 (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.
The time to peak levels of levoamphetamine with immediate-release (IR) formulations of amphetamine 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 dextroamphetamine with IR formulations ranges from 2.4 to 3.3hours and with ER formulations ranges from 4.0 to 8.0hours. The peak 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 selegiline therapy at a dosage of 10mg/day, circulating levels of levoamphetamine have been found to be 6 to 8ng/mL and levels of levomethamphetamine 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 of selegiline.
The plasma protein binding of levoamphetamine is 31.7%, whereas that of dextroamphetamine was 29.0% in the same study.
The pharmacokinetics of levoamphetamine generated as a metabolite from selegiline have been found not to significantly vary in CYP2D6 versus extensive metabolizers, suggesting that CYP2D6 may be minimally involved in the clinical metabolism of levoamphetamine.
The elimination of amphetamine is highly dependent on urine pH. Acidifier like ascorbic acid and ammonium chloride increase amphetamine excretion and reduce its elimination half-life, whereas urinary alkalinizing agents like acetazolamide enhance 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 selegiline at an oral dose of 10mg, levoamphetamine and levomethamphetamine 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).
Amphetamine, which is a racemate of dextroamphetamine 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 narcolepsy, mild depression, parkinsonism, and a variety of other conditions. Dextroamphetamine was found to be the more potent of the two 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 attention deficit hyperactivity disorder (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.
In addition to levoamphetamine, selegiline also metabolizes into levomethamphetamine. With a 10mg oral dose of selegiline, about 2 to 6mg levomethamphetamine and 1 to 3mg levoamphetamine is excretion in urine. As levoamphetamine and levomethamphetamine are norepinephrine and/or dopamine releasing agents, they may contribute to the effects and of selegiline. (1996). 9783211828915 ISBN 9783211828915 This may particularly include cardiovascular 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, have also been developed and introduced.
Because selegiline metabolizes into levoamphetamine and levomethamphetamine, people taking selegiline can erroneously test positive for amphetamines on .
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