Levoamphetamine has been used in the treatment ofattention deficit hyperactivity disorder (ADHD) both alone and in combination withdextroamphetamine at different ratios.[10][12] Levoamphetamine on its own has been found to be effective in the treatment of ADHD in multipleclinical studies conducted in the 1970s.[10][12] The clinical dosages andpotencies of levoamphetamine and dextroamphetamine in the treatment of ADHD have been fairly similar in these older studies.[10][12]
The first patented amphetamine brand,Benzedrine, was aracemic (i.e., equal parts) mixture of thefree bases or the more stablesulfate salts of both amphetamine enantiomers (levoamphetamine and dextroamphetamine) that was introduced in the United States in 1934 as an inhaler for treatingnasal congestion.[2] It was later realized that the amphetamine enantiomers could treatobesity,narcolepsy, and ADHD.[2][3] Because of the greatercentral nervous system effect of thedextrorotatory enantiomer (i.e.,dextroamphetamine), sold as Dexedrine, prescription of the Benzedrine brand fell and was eventually discontinued.[18] However, in 2012, racemic amphetamine sulfate was reintroduced as the Evekeo brand name.[3][19]
Adderall 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, or3⁄4 to1⁄4 ratio.[20][21]
Evekeo is anFDA-approved medication that contains racemic amphetamine sulfate.[3] It is approved for the treatment of narcolepsy, ADHD, and exogenous obesity.[3] The orally disintegrating tablets are approved for the treatment of ADHD in children and adolescents aged six to 17 years of age.[22]
Products using amphetamine base are now marketed. Dyanavel XR, a liquid suspension form became available in 2015, and contains about 24% levoamphetamine.[23] Adzenys XR, an orally disintegrating tablet, came to market in 2016 and contains 25% levoamphetamine.[24][25]
Levoamphetamine, similarly todextroamphetamine, acts as areuptake inhibitor andreleasing agent ofnorepinephrine anddopaminein vitro.[10][14] However, there are differences inpotency between the two compounds.[10][14] 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.[10] 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.[10] Dextroamphetamine is very weak as a reuptake inhibitor ofserotonin, whereas levoamphetamine is essentially inactive in this regard.[10] Levoamphetamine and dextroamphetamine are both also relatively weakreversibleinhibitors ofmonoamine oxidase (MAO) and hence can inhibitcatecholaminemetabolism.[10][35][36][37] However, this action may not occur significantly at clinical doses and may only be relevant to high doses.[35]
In rodent studies, both dextroamphetamine and levoamphetaminedose-dependently induce the release of dopamine in thestriatum and norepinephrine in theprefrontal cortex.[10] Dextroamphetamine is about 3- to 5-fold more potent in increasing striatal dopamine levels as levoamphetamine in rodentsin vivo, whereas the two enantiomers are about equally effective in terms of increasing prefrontal norepinephrine levels.[10] Dextroamphetamine has greater effects on dopamine levels than on norepinephrine levels, whereas levoamphetamine has relatively more balanced effects on dopamine and norepinephrine levels.[10] As with rodent studies, levoamphetamine and dextroamphetamine have been found to be similarly potent in elevating norepinephrine levels incerebrospinal fluid in monkeys.[38][39] By an uncertainmechanism, 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).[10]
Thecatecholamine-releasing effects of levoamphetamine and dextroamphetamine in rodents have a fastonset 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.[10] The magnitudes of the effects of amphetamines are greater than those of classical reuptake inhibitors likeatomoxetine andbupropion.[10] In addition, unlike with reuptake inhibitors, there is nodose–effectceiling in the case of amphetamines.[10] Although dextroamphetamine is more potent than levoamphetamine, both enantiomers can maximally increase striatal dopamine release by more than 5,000% of baseline.[10][40] This is in contrast to reuptake inhibitors like bupropion andvanoxerine, which have 5- to 10-fold smaller maximal impacts on dopamine levels and, in contrast to amphetamines, were not experienced as stimulating oreuphoric.[10]
Dextroamphetamine has greater potency in producing stimulant-like effects in rodents and non-human primates than levoamphetamine.[10] Some rodent studies have found it to be 5- to 10-fold more potent in its stimulant-like effects than levoamphetamine.[14][41][42] Levoamphetamine is also less potent than dextroamphetamine in itsanorectic effects in rodents.[14][43] Dextroamphetamine is about 4-fold more potent than levoamphetamine in motivatingself-administration in monkeys and is about 2- to 3-fold more potent than levoamphetamine in terms ofpositive reinforcing effects in humans.[10][7][44] Potency ratios of dextroamphetamine versus levoamphetamine with single doses of 5 to 80mg in terms of psychological effects in humans includingstimulation,wakefulness, activation, euphoria,reduction of hyperactivity, and exacerbation ofpsychosis have ranged from 1:1 to 4:1 in a variety of older clinical studies.[12][note 2][45] With very large doses, ranging from 270 to 640mg, the potency ratios of dextroamphetamine and levoamphetamine instimulating locomotor activity and inducingamphetamine psychosis in humans have ranged from 1:1 to 2:1 in a couple studies.[12] 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.[10]
In addition to inducing norepinephrine release in the brain, levoamphetamine and dextroamphetamine induce the release ofepinephrine (adrenaline) in theperipheralsympathetic nervous system and this is related to theircardiovascular effects.[10] Although levoamphetamine is less potent than dextroamphetamine as a stimulant, it is approximatelyequipotent with dextroamphetamine in producing various peripheral effects, includingvasoconstriction,vasopression, and other cardiovascular effects.[14]
Unlike the case of dextroamphetamine versusdextromethamphetamine, in which the latter is more effective than the former, levoamphetamine is substantially more potent as a dopamine releaser and stimulant thanlevomethamphetamine.[35][50] Conversely, levoamphetamine, levomethamphetamine, and dextroamphetamine are all similar in their potencies as norepinephrine releasers.[35][50]
In addition to its catecholamine-releasing activity, levoamphetamine is also anagonist of thetrace amine-associated receptor 1 (TAAR1).[51][52] Levoamphetamine has also been found to act as acatecholaminergic activity enhancer (CAE), notably at much lower concentrations than its catecholamine releasing activity.[53][54][55][56] It is similarly potent to selegiline and levomethamphetamine but is more potent than dextromethamphetamine and dextroamphetamine in this action.[55] The CAE effects of such agents may be mediated by TAAR1 agonism.[57][56]
The oralbioavailability of levoamphetamine has been found to be similar to that of dextroamphetamine.[58]
Thetime to peak levels of levoamphetamine withimmediate-release (IR) formulations ofamphetamine ranges from 2.5 to 3.5hours and withextended-release (ER) formulations ranges from 5.3 to 8.2hours depending on the formulation and the study.[5][58] For comparison, the time to peak levels ofdextroamphetamine with IR formulations ranges from 2.4 to 3.3hours and with ER formulations ranges from 4.0 to 8.0hours.[5][58] Thepeak levels of levoamphetamine are proportionally similar to those of dextroamphetamine with administration of amphetamine at varying ratios.[5] 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.[5]
Food does not affect the peak levels or overall exposure to levoamphetamine or dextroamphetamine with IR racemic amphetamine.[3] However, time to peak levels was delayed from 2.5hours (range 1.5–6hours) to 4.5hours (range 2.5–8.0hours).[3]
During oralselegiline therapy at a dosage of 10mg/day, circulating levels of levoamphetamine have been found to be 6 to 8ng/mL and levels oflevomethamphetamine have been reported to be 9 to 14ng/mL.[7] 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 andside effects of selegiline.[7]
Levoamphetamine and dextroamphetamine aremetabolized viaCYP2D6-mediatedhydroxylation to produce4-hydroxyamphetamine and additionally viaoxidativedeamination.[3] There are several enzymes involved in the metabolism of amphetamine, of which CYP2D6 is one.[3] Levoamphetamine seems to be metabolized somewhat less efficiently than dextroamphetamine.[58]
The pharmacokinetics of levoamphetamine generated as ametabolite fromselegiline have been found not to significantly vary in CYP2D6poor metabolizers versusextensive metabolizers, suggesting that CYP2D6 may be minimally involved in the clinical metabolism of levoamphetamine.[17][59]
The meanelimination half-life of levoamphetamine ranges from 11.7 to 15.2hours in different studies.[5][58][3] Its half-life is somewhat longer than that of dextroamphetamine, with a difference of about 1 to 2hours.[5][6][58] 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.[5][58][3]
Withselegiline at an oral dose of 10mg, levoamphetamine andlevomethamphetamine 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).[7]
Amphetamine, which is aracemic mixture ofdextroamphetamine and levoamphetamine, was first discovered in 1887, shortly after the isolation of ephedrine.[65][60] However, it was not until 1927 that amphetamine wassynthesized byGordon Alles and was studied by him in animals and humans.[10] This led to the discovery of the stimulating effects of amphetamine in humans in 1929 after Alles injected himself with 50mg of the drug.[65][10] 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.[10] It was indicated for the treatment ofnarcolepsy, milddepression,parkinsonism, and a variety of other conditions.[10] Dextroamphetamine was found to be the morepotent of the twoenantiomers of amphetamine and was introduced as an enantiopure drug under the brand name Dexedrine in 1937.[10] Consequent to its lower potency, levoamphetamine has received far less attention than racemic amphetamine or dextroamphetamine.[10]
Levoamphetamine was studied in the treatment ofattention deficit hyperactivity disorder (ADHD) in the 1970s and was found to be clinically effective for this condition similarly to dextroamphetamine.[10] As a result, it was marketed as anenantiopure drug under the brand name Cydril for the treatment of ADHD in the 1970s.[10][15] However, it was reported in 1976 that racemic amphetamine was less effective than dextroamphetamine in treating ADHD.[10] As a result of this study, use of racemic amphetamine in the treatment of ADHD dramatically declined in favor of dextroamphetamine.[10] Enantiopure levoamphetamine was eventually discontinued and is no longer available today.[10]
Because selegiline metabolizes into levoamphetamine and levomethamphetamine, people taking selegiline can erroneously test positive for amphetamines ondrug tests.[98][99]
^Smith & Davis (1977) reviewed 11clinical studies of dextroamphetamine and levoamphetamine including doses and potency ratios in terms of a variety of psychological and behavioral effects.[12] The summaries of these studies are in Table 1 of the paper.[12]
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Notes: (1) TAAR1 activity of ligands varies significantly between species. Some agents that are TAAR1 ligands in some species are not in other species. This navbox includes all TAAR1 ligands regardless of species. (2) See the individual pages for references, as well as theList of trace amines,TAAR, andTAAR1 pages. See also:Receptor/signaling modulators
