Levoamphetamine
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 with dextroamphetamine in varying ratios under brand names such as Adderall. The drug is known to increase wakefulness and concentration in association with decreased appetite and fatigue. Pharmaceuticals that contain levoamphetamine are currently indicated and prescribed for the treatment of attention deficit hyperactivity disorder, obesity, and narcolepsy in some countries. 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 racemic 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 is still marketed and sold over-the-counter as a nasal decongestant. In addition to being used in pharmaceutical drugs itself, levoamphetamine is a known active metabolite of certain other drugs, such as selegiline.
Medical uses
Levoamphetamine has been used in the treatment of attention deficit hyperactivity disorder both alone and in combination with dextroamphetamine at different ratios. Levoamphetamine on its own has been found to be effective in the treatment of ADHD in multiple clinical studies 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 racemic mixture of the free bases or the more stable sulfate salts of both amphetamine enantiomers that was introduced in the United States in 1934 as an inhaler for treating nasal congestion. It was later realized that the amphetamine enantiomers could treat obesity, narcolepsy, and ADHD. Because of the greater central nervous system effect of the dextrorotatory enantiomer, sold as Dexedrine, prescription of the Benzedrine brand fell and was eventually discontinued. However, in 2012, racemic amphetamine sulfate was reintroduced as the Evekeo brand name.Adderall
is a 3.1:1 mixture of dextro- to levo- amphetamine base equivalent pharmaceutical that contains equal amounts of four salts: dextroamphetamine sulfate, amphetamine sulfate, dextroamphetamine saccharate and amphetamine -aspartate monohydrate. This result is a 76% dextroamphetamine to 24% levoamphetamine, or to ratio.Evekeo
Evekeo is an FDA-approved medication that contains racemic amphetamine sulfate. It is approved for the treatment of narcolepsy, ADHD, and exogenous obesity. The orally disintegrating tablets are approved for the treatment of 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 disintegrating tablet, came to market in 2016 and contains 25% levoamphetamine.Side effects
Levoamphetamine can produce sympathomimetic side effects.Pharmacology
Pharmacodynamics
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 inhibitors of monoamine oxidase 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-dependently 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. 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.
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, 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 euphoric.
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 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 stimulation, 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 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 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, vasopression, and other cardiovascular effects.
Similarly to dextroamphetamine, levoamphetamine has been found to improve symptoms in an animal model of ADHD, the spontaneously hypertensive rat, including improving sustained attention and reducing overactivity and impulsivity. 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. Levoamphetamine has also been found to act as a catecholaminergic activity enhancer, 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.