Levoamphetamine: Difference between revisions

Levoamphetamine
Clinical data
Trade names	Cydril, Adderall, Evekeo, others
Other names	l-Amphetamine, Levamfetamine
Routes of; administration	Oral (as part of Adderall, Evekeo, and generic amphetamine sulfate)
Drug class	Amphetamine; Stimulant; Sympathomimetic; Norepinephrine releasing agent; TAAR1 agonist
Legal status
Legal status	US: Schedule II;
Pharmacokinetic data
Protein binding	31.7%
Elimination half-life	12.0–15.2 hours
Identifiers
	IUPAC name (2R)-1-Phenylpropan-2-amine;
CAS Number	156-34-3 ;
PubChem CID	32893;
IUPHAR/BPS	2146;
ChemSpider	30477 ;
UNII	R87US8P740;
ChEBI	CHEBI:42724 ;
ChEMBL	ChEMBL19393 ;
CompTox Dashboard (EPA)	DTXSID20166016 ;
ECHA InfoCard	100.005.320
Chemical and physical data
Formula	C9H13N
Molar mass	135.210 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C[C@@H](N)Cc1ccccc1;
	InChI InChI=1S/C9H13N/c1-8(10)7-9-5-3-2-4-6-9/h2-6,8H,7,10H2,1H3/t8-/m1/s1 ; Key:KWTSXDURSIMDCE-MRVPVSSYSA-N ;

Browse history interactively

← Previous edit Next edit →

Content deleted Content added

VisualWikitext

Inline

Revision as of 02:04, 8 July 2024

Levoamphetamine^{[note 1]} is a stimulant medication which is used in the treatment of certain medical conditions.^[8] 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 like Adderall and Evekeo.^[8]^[5] The drug is known to increase wakefulness and concentration in association with decreased appetite and fatigue.^[9]^[10] Pharmaceuticals that contain levoamphetamine are currently indicated and prescribed for the treatment of attention deficit hyperactivity disorder (ADHD), obesity, and narcolepsy in some countries.^[8]^[8]^[5]^[11] Levoamphetamine is taken by mouth.^[8]^[5]

Levoamphetamine acts as a releasing agent of the monoamine neurotransmitters norepinephrine and dopamine.^[8] It is similar to dextroamphetamine in its ability to release norepinephrine and in its sympathomimetic effects but is several times weaker than dextroamphetamine in its capacity to release dopamine and in its psychostimulant effects.^[8]^[12]^[10] Levoamphetamine is the levorotatory stereoisomer of the racemic amphetamine molecule, whereas dextroamphetamine is the dextrorotatory isomer.^[8]^[5]

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 by the 1970s.^[8]^[13] While pharmaceutical formulations containing enantiopure levoamphetamine are no longer manufactured,^[8] levomethamphetamine (levmetamfetamine) is still marketed and sold over-the-counter as a nasal decongestant.^[14] In addition to being used in pharmaceutical drugs itself, levoamphetamine is a known active metabolite of certain other drugs, such as selegiline (L-deprenyl).^[15]

Medical uses

Levoamphetamine has been used in the treatment of attention deficit hyperactivity disorder (ADHD) both alone and in combination with dextroamphetamine at different ratios.^[8]^[10] Levoamphetamine on its own has been found to be effective in the treatment of ADHD in multiple clinical studies conducted in the 1970s.^[8]^[10] The clinical dosages and potencies of levoamphetamine and dextroamphetamine in the treatment of ADHD have been fairly similar in these older studies.^[8]^[10]

Available forms

Racemic amphetamine

The first patented amphetamine brand, Benzedrine, was a racemic (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 in 1934 as an inhaler for treating nasal congestion.^[2] It was later realized that the amphetamine enantiomers could treat obesity, narcolepsy, and ADHD.^[2]^[3] Because of the greater central nervous system effect of the dextrorotatory enantiomer (i.e., dextroamphetamine), sold as Dexedrine, prescription of the Benzedrine brand fell and was eventually discontinued.^[16] However, in 2012, racemic amphetamine sulfate was reintroduced as the Evekeo brand name.^[3]^[17]

Adderall

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, or 3⁄4 to 1⁄4 ratio.^[18]^[19]

Evekeo

Evekeo is an FDA-approved medication that contains racemic amphetamine sulfate (i.e., 50% levoamphetamine sulfate and 50% dextroamphetamine 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 attention deficit hyperactivity disorder (ADHD) in children and adolescents aged six to 17 years of age.^[20]

Other forms

Products using amphetamine base are now marketed. Dyanavel XR, a liquid suspension form became available in 2015, and contains about 24% levoamphetamine.^[21] Adzenys XR, an orally dissolving tablet came to market in 2016 and contains 25% levoamphetamine.^[22]^[23]

Pharmacology

Pharmacodynamics

Levoamphetamine, similarly to dextroamphetamine, acts as a reuptake inhibitor and releasing agent of norepinephrine and dopamine in vitro.^[8]^[12] However, there are differences in potency between the two compounds.^[8]^[12] 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.^[8] 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.^[8] Dextroamphetamine is very weak as a reuptake inhibitor of serotonin, whereas levoamphetamine is essentially inactive in this regard.^[8] Levoamphetamine and dextroamphetamine are both also relatively weak reversible inhibitors of monoamine oxidase (MAO).^[8]^[24]^[25]

In rodent studies, both dextroamphetamine and levoamphetamine dose-dependently induce the release of dopamine in the striatum and norepinephrine in the prefrontal cortex.^[8] 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.^[8] Dextroamphetamine has greater effects on dopamine levels than on norepinephrine levels, whereas levoamphetamine has relatively more balanced effects on dopamine and norepinephrine levels.^[8] As with rodent studies, levoamphetamine and dextroamphetamine have been found to be similarly potent in elevating norepinephrine levels in cerebrospinal fluid in monkeys.^[26]^[27] 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).^[8]

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 45 minutes, 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.^[8] The magnitudes of the effects of amphetamines are greater than those of classical reuptake inhibitors like atomoxetine and bupropion.^[8] In addition, unlike with reuptake inhibitors, there is no dose–effect ceiling in the case of amphetamines.^[8] Although dextroamphetamine is more potent than levoamphetamine, both enantiomers can maximally increase striatal dopamine release by more than 5,000% of baseline.^[8]^[28] 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.^[8]

Dextroamphetamine has greater potency in producing stimulant-like effects in rodents and non-human primates than levoamphetamine.^[8] Some rodent studies have found it to be 5- to 10-fold more potent in its stimulant-like effects than levoamphetamine.^[12]^[29]^[30] Levoamphetamine is also less potent than dextroamphetamine in its anorectic effects in rodents.^[12]^[31] 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.^[8]^[15]^[32] Potency ratios of dextroamphetamine versus levoamphetamine with single doses of 5 to 80 mg 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.^[10]^{[note 2]}^[33] With very large doses, ranging from 270 to 640 mg, 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.^[10] 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.^[8]

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.^[8] 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.^[12]

Similarly to dextroamphetamine, levoamphetamine has been found to improve symptoms in a animal model of ADHD, the spontaneously hypertensive rat (SHR), including improving sustained attention and reducing overactivity and impulsivity.^[34]^[35]^[36]^[37] 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.^[8]^[10]

Pharmacokinetics

The pharmacokinetics of levoamphetamine have been studied.^[5] Usually this has been orally in combination with dextroamphetamine at different ratios.^[5] The pharmacokinetics of levoamphetamine have also been studied as a metabolite of selegiline.^[15]^[38]

Absorption

The time to peak levels of levoamphetamine with immediate-release (IR) formulations of amphetamine ranges from 2.5 to 3.5 hours and with extended-release (ER) formulations ranges from 5.3 to 8.2 hours depending on the formulation and the study.^[5] For comparison, the time to peak levels of dextroamphetamine with IR formulations ranges from 2.4 to 3.3 hours and with ER formulations ranges from 4.0 to 8.0 hours.^[5] The peak levels of levoamphetamine are proportionally similar to those of dextroamphetamine with administration of amphetamine at different ratios.^[5] With a single oral dose of 10 mg racemic amphetamine (a 1:1 ratio of enantiomers, or 5 mg dextroamphetamine and 5 mg levoamphetamine), peak levels of dextroamphetamine were 14.7 ng/mL and peak levels of levoamphetamine were 12.0 ng/mL in one study.^[5]

During oral selegiline therapy at a dosage of 10 mg/day, circulating levels of levoamphetamine have been found to be 6 to 8 ng/mL and levels of levomethamphetamine have been reported to be 9 to 14 ng/mL.^[15] 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 side effects of selegiline.^[15]

Distribution

The plasma protein binding of levoamphetamine is 31.7%, whereas that of dextroamphetamine was 29.0% in the same study.^[4]

Metabolism

The pharmacokinetics of levoamphetamine generated as a metabolite from selegiline have been found not to significantly vary in CYP2D6 poor metabolizers versus extensive metabolizers, suggesting that CYP2D6 is minimally involved in the metabolism of levoamphetamine.^[38]^[39]

Elimination

The mean elimination half-life of levoamphetamine ranges from 12.0 to 15.2 hours in different studies.^[5] For comparison, the mean elimination half-life of dextroamphetamine ranges from 10.1 to 12.4 hours in different studies.^[5]

With selegiline at a oral dose of 10 mg, levoamphetamine and levomethamphetamine are eliminated in urine and recovery of levoamphetamine is 9 to 30% (or about 1–3 mg) while that of levomethamphetamine is 20 to 60% (or about 2–6 mg).^[15]

Chemistry

Levoamphetamine is a substituted phenethylamine and amphetamine. It is also known as L-α-methyl-β-phenylethylamine or as (2R)-1-phenylpropan-2-amine.^[6] Levoamphetamine is the levorotatory stereoisomer of the amphetamine molecule. Racemic amphetamine contains two optical isomers in equal amounts, dextroamphetamine (the dextrorotatory enantiomer) and levoamphetamine.^[18]^[19]

History

Amphetamine, a racemic mixture of dextroamphetamine and levoamphetamine, was first discovered in 1910.^[8] However, it was not until 1927 that amphetamine was synthesized by Gordon Alles and was studied by him in animals and humans.^[8] This eventually led to the discovery of the stimulating effects of amphetamine in humans.^[8] 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.^[8] It was indicated for the treatment of narcolepsy, mild depression, parkinsonism, and a variety of other conditions.^[8] Dextroamphetamine was found to be the more potent of the two enantiomers of amphetamine and was introduced as an enantiopure drug under the brand name Dexedrine in 1937.^[8] Consequent to its lower potency, levoamphetamine has received far less attention than racemic amphetamine or dextroamphetamine.^[8]

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.^[8] As a result, it was marketed as an enantiopure drug under the brand name Cydril for the treatment of ADHD in the 1970s.^[8]^[13] However, it was reported in 1976 that racemic amphetamine was less effective than dextroamphetamine in treating ADHD.^[8] As a result of this study, use of racemic amphetamine in the treatment of ADHD dramatically declined in favor of dextroamphetamine.^[8] Enantiopure levoamphetamine was eventually discontinued and is no longer available today.^[8]

Research

Levoamphetamine as an enantiopure drug has been studied in the past in a variety of contexts.^[9] These include its effects in and/or treatment of mood,^[9] "minimal brain dysfunction",^[40] narcolepsy,^[9]^[41] "hyperkinetic syndrome" and aggression,^[42]^[13] sleep,^[43]^[44] schizophrenia,^[45] wakefulness,^[46] Tourette's syndrome,^[47] and Parkinson's disease, among others.^[9]^[48] Levoamphetamine has been studied in the treatment of multiple sclerosis in more modern studies and has been reported to improve cognition and memory as well.^[49]^[50]^[51]^[52]^[53]^[54]

Notes

^ Synonyms and alternate spellings include: (2R)-1-phenylpropan-2-amine (IUPAC name), levamfetamine (International Nonproprietary Name [INN]), (R)-amphetamine, (−)-amphetamine, l-amphetamine, and L-amphetamine.^[6]^[7]
^ Smith & Davis (1977) reviewed 11 clinical studies of dextroamphetamine and levoamphetamine including potency ratios in terms of a variety of psychological and behavioral effects.^[10] The summaries of these studies are in Table 1 of the paper.^[10]

References

^ CID 32893 from PubChem
^ ^a ^b ^c Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present – a pharmacological and clinical perspective". J. Psychopharmacol. 27 (6): 479–496. doi:10.1177/0269881113482532. PMC 3666194. PMID 23539642.
^ ^a ^b ^c ^d ^e "Evekeo- amphetamine sulfate tablet". DailyMed. 14 August 2019. Retrieved 7 April 2020.
^ ^a ^b Losacker M, Roehrich J, Hess C (October 2021). "Enantioselective determination of plasma protein binding of common amphetamine-type stimulants". J Pharm Biomed Anal. 205: 114317. doi:10.1016/j.jpba.2021.114317. PMID 34419812. Amphetamine-type stimulants (ATS) like amphetamine ('speed'), methamphetamine ('crystal meth') and 3,4-methylenedioxy-N-methylamphetamine (MDMA, 'ecstasy') represent some of the most frequently abused drugs worldwide. [...] The enantiomers of these four compounds exhibit different pharmacokinetic and pharmacodynamic properties. According to the free drug theory, the pharmacological properties of a substance are dependent on its plasma protein binding (PPB). However, data on PPB of stimulant enantiomers in humans are rare or non-existent. [...] For (R)-amphetamine a slightly but significantly higher PPB was found compared to the (S)-enantiomer (31.7 % vs 29.0 %).
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m Markowitz JS, Patrick KS (October 2017). "The Clinical Pharmacokinetics of Amphetamines Utilized in the Treatment of Attention-Deficit/Hyperactivity Disorder". J Child Adolesc Psychopharmacol. 27 (8): 678–689. doi:10.1089/cap.2017.0071. PMID 28910145.
^ ^a ^b ^c "L-Amphetamine". PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. 30 December 2017. Retrieved 2 January 2018.
^ "R(-)amphetamine". IUPHAR/BPS Guide to Pharmacology. International Union of Basic and Clinical Pharmacology. Retrieved 2 January 2018.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u ^v ^w ^x ^y ^z ^aa ^ab ^ac ^ad ^ae ^af ^ag ^ah ^ai ^aj ^ak ^al ^am ^an ^ao ^ap ^aq ^ar ^as Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present--a pharmacological and clinical perspective". J Psychopharmacol. 27 (6): 479–496. doi:10.1177/0269881113482532. PMC 3666194. PMID 23539642. As a molecule with a single chiral centre, amphetamine exists in two optically active forms, i.e. the dextro- (or d-) and levo- (or l-) isomers or enantiomers (Figure 1). Smith, Kline and French synthesised both isomers, and in 1937 commenced marketing of d-amphetamine, which was the more potent of the two isomers, under the trade name of Dexedrine®. [...] Although l-amphetamine (Cydril®) achieved far less attention than either the racemate or d-isomer, clinical trials conducted in the 1970s demonstrated that both isomers of amphetamine were clinically effective in treating ADHD (Arnold et al., 1972, 1973, 1976). The use of Benzedrine to treat ADHD declined dramatically after Gross (1976) reported that the racemate was significantly less clinically effective than Dexedrine. Currently, the only use of l-amphetamine in ADHD medications is in mixed salts/mixed enantiomers amphetamine (MES-amphetamine), which consists of a 3:1 enantiomeric mixture d-amphetamine:l-amphetamine salts that is available in both immediate-release (Adderall®, generic) and extended-release (Adderall XR®, generic) formulations.
^ ^a ^b ^c ^d ^e Silverstone T, Wells B (1980). "Clinical Psychopharmacology of Amphetamine and Related Compounds". Amphetamines and Related Stimulants: Chemical, Biological, Clinical, and Sociological Aspects. CRC Press. pp. 147–160. doi:10.1201/9780429279843-10. ISBN 978-0-429-27984-3. A comparison of dextroamphetamine and levoamphetamine revealed that the dextrorotatory isomer was the more potent in elevating mood in normal subjects, being at least twice as potent as the levo form.35 [...] Narcolepsy was one of the first conditions to be treated successfully with amphetamine3 and remains one of the few (some would say the only) clinical indications for its use. While the required oral dose of dextroamphetamine (Dexedrine®) ranges from 5 to 120 mg/day, most patients respond to 10 mg two to four times daily. [...] The closely related compound methylphenidate (Ritalin®), 20 mg two to four times daily, has been shown to be as effective as dextroamphetamine but with less likelihood of causing side effects.61 The same is true of levoamphetamine.62 [...] Nevertheless, as amphetamine has an action on dopaminergic pathways it was considered worthwhile to examine the effects of amphetamine under controlled conditions.95 Twenty patients, all on other anti-Parkinsonian drugs, were studied. There was some subjective improvement in a proportion (less than half) of the patients when they received either dextroamphetamine or levoamphetamine, but there was little objective improvement. The authors remarked that amphetamine was unlikely to have worked anyway in Parkinson's disease as it acts mainly by releasing dopamine and noradrenaline from presynaptic neurons; as the underlying pathology involves a reduction of presynaptic dopamine, there would be insufficient dopamine for amphetamine to release.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j Smith RC, Davis JM (June 1977). "Comparative effects of d-amphetamine, l-amphetamine, and methylphenidate on mood in man". Psychopharmacology (Berl). 53 (1): 1–12. doi:10.1007/BF00426687. PMID 407607. The comparative effects of d-amphetamine, l-amphetamine, and methylphenidate were assessed in 16 normal subjects, using a double-blind, crossover placebo-controlled design. Within the dose range tested, the efficacy ratio of d-amphetamine:l-amphetamine was about 2:1, and graphic presentation of dose response scores indicated a relatively small difference in potency between the amphetamine isomers. [...] The efficacy ratios for d-amphetamine:l-amphetamine on increasing euphoric mood in man were similar to the previously reported ratios of these two isomers in inducing or exacerbating psychosis in humans. [...] The results of this study indicate that d-AMP is about 2 times as effective as l-AMP [...] in increasing euphoric and activating moods in man. [...] the relatively small efficacy ratios of about 2:1 that we report here for the euphoric effects of d- vs. l-AMP in our normal subjects are similar to those recently reported by other studies using different groups of subjects—Van Kamen et al. (1976) in depressed patients and Janowsky and Davis (1976) in acute psychotics. [...] Moreover, the 2:1 ratio of d- and l-AMP effects on euphoric mood is very similar to the ratios (1.3:1 to 2.1:1) which have been reported for the efficacy of amphetamine isomers on other classes of behavior in man—for example, the activation of psychosis and the treatment of hyperkinetic children (see Table 1). [...] Table 1. Some previous studies comparing effects of d-amphetamine, l-amphetamine, and methylphenidate in man. [...]
^ Simola, Nicola; Carta, Manolo (2016). "Amphetamine Usage, Misuse, and Addiction Processes". Neuropathology of Drug Addictions and Substance Misuse. Elsevier. p. 14–24. doi:10.1016/b978-0-12-800212-4.00002-9. ISBN 978-0-12-800212-4.
^ ^a ^b ^c ^d ^e ^f Biel, J. H.; Bopp, B. A. (1978). "Amphetamines: Structure-Activity Relationships". Stimulants. Boston, MA: Springer US. p. 1–39. doi:10.1007/978-1-4757-0510-2_1. ISBN 978-1-4757-0512-6. Snyder and his colleagues (1970b; Taylor and Snyder, 1970; Coyle and Snyder, 1969) have compared the effects of the two amphetamine isomers on norepinephrine and dopamine uptake by synaptosomes from the rat hypothalamus and corpus striatum, respectively. The dextro isomer was ten times more potent than the levo isomer in inhibiting norepinephrine uptake but the two isomers were equipotent in inhibiting dopamine uptake. The marked difference in the potency (tenfold) of the two isomers in increasing locomotor activity contrasted with a relatively small (twofold) difference in potency in eliciting stereotyped behavior. [...] The dextro isomers of both amphetamine and methamphetamine are considerably more potent as stimulants than the levo isomers. Depending on the parameter measured, the potency difference may range from two- to tenfold (Taylor and Snyder, 1970; Snyder et at., 1970b; Svensson, 1971; Roth et at., 1954; Van Rossum, 1970; Moore, 1963). The anorexic activity of the dextro isomers also exceeds that of the levo isomers (Lawlor et at., 1969). However, the two isomers are approximately equipotent in eliciting certain peripheral effects, such as the vasoconstriction, vasopressor, and other cardiovascular effects (Roth et at., 1954; Swanson et at., 1943).The dextro isomers of both amphetamine and methamphetamine are considerably more potent as stimulants than the levo isomers. Depending on the parameter measured, the potency difference may range from two- to tenfold (Taylor and Snyder, 1970; Snyder et at., 1970b; Svensson, 1971; Roth et at., 1954; Van Rossum, 1970; Moore, 1963). The anorexic activity of the dextro isomers also exceeds that of the levo isomers (Lawlor et at., 1969). However, the two isomers are approximately equipotent in eliciting certain peripheral effects, such as the vasoconstriction, vasopressor, and other cardiovascular effects (Roth et at., 1954; Swanson et at., 1943).
^ ^a ^b ^c Arnold LE, Wender PH, McCloskey K, Snyder SH (December 1972). "Levoamphetamine and dextroamphetamine: comparative efficacy in the hyperkinetic syndrome. Assessment by target symptoms". Arch Gen Psychiatry. 27 (6): 816–22. doi:10.1001/archpsyc.1972.01750300078015. PMID 4564954.
^ Barkholtz HM, Hadzima R, Miles A (July 2023). "Pharmacology of R-(-)-Methamphetamine in Humans: A Systematic Review of the Literature". ACS Pharmacol Transl Sci. 6 (7): 914–924. doi:10.1021/acsptsci.3c00019. PMC 10353062. PMID 37470013.
^ ^a ^b ^c ^d ^e ^f Heinonen EH, Lammintausta R (1991). "A review of the pharmacology of selegiline". Acta Neurol Scand Suppl. 136: 44–59. doi:10.1111/j.1600-0404.1991.tb05020.x. PMID 1686954. In humans, the three metabolites, l-MA, l-A and DES have been identified in plasma and urine after single and multiple doses of selegiline (193). The urine recovery after a 10 mg daily dose of selegiline has been 9–30 % as l-A, 20–60 % as l-MA and about 1 % as DES. During continuous treatment the serum concentrations of l-A have been 6–8 ng/ml, that of l–MA, 9–14 ng/ml and that of DES, 1–7 ng/ml depending on the sampling time, and the corresponding CSF concentrations, 6–7 ng/ml, 14–15 ng/ml and 0.7–1 ng/ml respectively (193). [...] It is also important to recognise the different properties of the two amphetamine isomers (Fig. 4). The basic pharmacological action of d- or l- amphetamine is the release of catecholamines from the presynaptic neuron. On higher concentration, uptake of catecholamines takes place and, at even higher concentrations, reversible inhibition of MAO. The DA releasing effect of l-A is about 10 times less than that of d-form (198). The uptake of DA is reported to be about 4–5 times less by the l-form in the rat brain (199, 200), while inhibition of uptake of NA has been reported to be two times weaker by the l-form, or to be equipotent with the d-form. d-A is a five times more potent inhibitor of MAO-A (201) and about 3–5 times more potent in inducing increase of blood pressure (202), stereotypic locomotor behaviour in rats (203) and self-administration in monkeys (204).
^ "Benzedrine: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 4 September 2015.
^ "Evekeo: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 11 August 2015.
^ ^a ^b "Adderall XR- dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate and amphetamine aspartate capsule, extended release". DailyMed. 17 July 2019. Retrieved 7 April 2020.
^ ^a ^b "Adderall- dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate tablet". DailyMed. 8 November 2019. Retrieved 7 April 2020.
^ "Evekeo ODT- amphetamine sulfate tablet, orally disintegrating". DailyMed. 20 February 2020. Retrieved 7 April 2020.
^ "Dyanavel XR Prescribing Information". January 2017. Retrieved 14 May 2017.
^ "Adzenys XR-ODT- amphetamine tablet, orally disintegrating". DailyMed. 22 January 2020. Retrieved 7 April 2020. Adzenys XR-ODT (amphetamine extended-release orally disintegrating tablet) contains a 3 to 1 ratio of d- to l-amphetamine, a central nervous system stimulant.
^ "Adzenys ER- amphetamine suspension, extended release". DailyMed. 21 January 2020. Retrieved 7 April 2020.
^ Clarke, D (1980). "Amphetamine and monoamine oxidase inhibition: an old idea gains new acceptance". Trends in Pharmacological Sciences. 1 (2): 312–313. doi:10.1016/0165-6147(80)90032-2.
^ Miller HH, Clarke DE (1978). "In vitro inhibition of monoamine oxidase types A and B by d- and l-amphetamine". Commun Psychopharmacol. 2 (4): 319–325. PMID 729356.
^ Ziegler, Michael G. (1989). "Catecholamine Measurement in Behavioral Research". Handbook of Research Methods in Cardiovascular Behavioral Medicine. Boston, MA: Springer US. p. 167–183. doi:10.1007/978-1-4899-0906-0_11. ISBN 978-1-4899-0908-4.
^ Ziegler, Michael G.; Raymond Lake, C.; Ebert, Michael H. (1979). "Norepinephrine elevations in cerebrospinal fluid after d- and l-amphetamine". European Journal of Pharmacology. 57 (2–3): 127–133. doi:10.1016/0014-2999(79)90358-3.
^ Cheetham, S. C., Kulkarni, R. S., Rowley, H. L., & Heal, D. J. (2007). The SH rat model of ADHD has profoundly different catecholaminergic responses to amphetamine’s enantiomers compared with Sprague-Dawleys. Society for Neurosciences. https://scholar.google.com/scholar?cluster=850792164327952775
^ Segal DS (October 1975). "Behavioral characterization of d- and l-amphetamine: neurochemical implications". Science. 190 (4213): 475–477. doi:10.1126/science.1166317. PMID 1166317.
^ Taylor KM, Snyder SH (June 1970). "Amphetamine: differentiation by d and l isomers of behavior involving brain norepinephrine or dopamine". Science. 168 (3938): 1487–1489. doi:10.1126/science.168.3938.1487. PMID 5463064.
^ Lawlor RB, Trivedi MC, Yelnosky J (June 1969). "A determination of the anorexigenic potential of dl-amphetamine, d-amphetamine, l-amphetamine and phentermine". Arch Int Pharmacodyn Ther. 179 (2): 401–407. PMID 5367311.
^ Balster RL, Schuster CR (1973). "A comparison of d-amphetamine, l-amphetamine, and methamphetamine self-administration in rhesus monkeys". Pharmacol Biochem Behav. 1 (1): 67–71. doi:10.1016/0091-3057(73)90057-9. PMID 4204513.
^ Van Kammen DP, Murphy DL (November 1975). "Attenuation of the euphoriant and activating effects of d- and l-amphetamine by lithium carbonate treatment". Psychopharmacologia. 44 (3): 215–224. doi:10.1007/BF00428897. PMID 1824. Seven of nine depressed patients experienced a 4.3-fold increase in rated euphoria and activation following 30 mg d-amphetamine in a replicated dose, double blind study. d-Amphetamine was 2 to 2.3-fold more effective in producing activation, euphoria, and antidepressant effects than the same dose of l-amphetamine.
^ Kantak KM (May 2022). "Rodent models of attention-deficit hyperactivity disorder: An updated framework for model validation and therapeutic drug discovery". Pharmacol Biochem Behav. 216: 173378. doi:10.1016/j.pbb.2022.173378. PMID 35367465.
^ Teal, Laura B.; Ingram, Shalonda M.; Bubser, Michael; McClure, Elliott; Jones, Carrie K. (2023). "The Evolving Role of Animal Models in the Discovery and Development of Novel Treatments for Psychiatric Disorders". Drug Development in Psychiatry. Vol. 30. Cham: Springer International Publishing. p. 37–99. doi:10.1007/978-3-031-21054-9_3. ISBN 978-3-031-21053-2.
^ Sagvolden T (March 2011). "Impulsiveness, overactivity, and poorer sustained attention improve by chronic treatment with low doses of l-amphetamine in an animal model of Attention-Deficit/Hyperactivity Disorder (ADHD)". Behav Brain Funct. 7: 6. doi:10.1186/1744-9081-7-6. PMC 3086861. PMID 21450079.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Sagvolden T, Xu T (January 2008). "l-Amphetamine improves poor sustained attention while d-amphetamine reduces overactivity and impulsiveness as well as improves sustained attention in an animal model of Attention-Deficit/Hyperactivity Disorder (ADHD)". Behav Brain Funct. 4: 3. doi:10.1186/1744-9081-4-3. PMC 2265273. PMID 18215285.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ ^a ^b Kraemer T, Maurer HH (April 2002). "Toxicokinetics of amphetamines: metabolism and toxicokinetic data of designer drugs, amphetamine, methamphetamine, and their N-alkyl derivatives". Ther Drug Monit. 24 (2): 277–89. doi:10.1097/00007691-200204000-00009. PMID 11897973. [...] in vivo studies with five poor and eight extensive metabolizers by Scheinin et al (61) showed that CYP2D6 polymorphism was not crucial for the disposition of selegiline. These authors did not find significant differences in the pharmacokinetic parameters of selegiline, desmethylselegiline, and R(−)- amphetamine between poor metabolizers and extensive metabolizers. However, the area under the serum concentration-time curve values of R(−)-methamphetamine were, on average, 46% higher in poor metabolizers than in extensive metabolizers.
^ Scheinin H, Anttila M, Dahl ML, Karnani H, Nyman L, Taavitsainen P, Pelkonen O, Bertilsson L (October 1998). "CYP2D6 polymorphism is not crucial for the disposition of selegiline". Clin Pharmacol Ther. 64 (4): 402–411. doi:10.1016/S0009-9236(98)90071-6. PMID 9797797.
^ Arnold LE, Huestis RD, Smeltzer DJ, Scheib J, Wemmer D, Colner G (March 1976). "Levoamphetamine vs dextroamphetamine in minimal brain dysfunction. Replication, time response, and differential effect by diagnostic group and family rating". Arch Gen Psychiatry. 33 (3): 292–301. doi:10.1001/archpsyc.1976.01770030012002. PMID 769721.
^ Parkes JD, Fenton GW (December 1973). "Levo(-) amphetamine and dextro(+) amphetamine in the treatment of narcolepsy". J Neurol Neurosurg Psychiatry. 36 (6): 1076–81. doi:10.1136/jnnp.36.6.1076. PMC 1083612. PMID 4359162.
^ Arnold LE, Kirilcuk V, Corson SA, Corson EO (February 1973). "Levoamphetamine and dextroamphetamine: differential effect on aggression and hyperkinesis in children and dogs". Am J Psychiatry. 130 (2): 165–70. doi:10.1176/ajp.130.2.165. PMID 4568123.
^ Gillin JC, van Kammen DP, Graves J, Murphy D (October 1975). "Differential effects of D- and L-amphetamine on the sleep of depressed patients". Life Sci. 17 (8): 1223–1240. doi:10.1016/0024-3205(75)90132-0. PMID 172755.
^ Hartmann E, Cravens J (November 1976). "Sleep: effects of d- and l-amphetamine in man and in rat". Psychopharmacology (Berl). 50 (2): 171–175. doi:10.1007/BF00430488. PMID 826958.
^ Janowsky DS, Davis JM (March 1976). "Methylphenidate, dextroamphetamine, and levamfetamine. Effects on schizophrenic symptoms". Arch Gen Psychiatry. 33 (3): 304–308. doi:10.1001/archpsyc.1976.01770030024003. PMID 769722.
^ Hartmann E, Orzack MH, Branconnier R (July 1977). "Sleep deprivation deficits and their reversal by d- and l-amphetamine". Psychopharmacology (Berl). 53 (2): 185–189. doi:10.1007/BF00426490. PMID 408844.
^ Caine ED, Ludlow CL, Polinsky RJ, Ebert MH (March 1984). "Provocative drug testing in Tourette's syndrome: d- and l-amphetamine and haloperidol". J Am Acad Child Psychiatry. 23 (2): 147–152. doi:10.1097/00004583-198403000-00005. PMID 6585416.
^ Parkes JD, Tarsy D, Marsden CD, Bovill KT, Phipps JA, Rose P, Asselman P (March 1975). "Amphetamines in the treatment of Parkinson's disease". J Neurol Neurosurg Psychiatry. 38 (3): 232–7. doi:10.1136/jnnp.38.3.232. PMC 491901. PMID 1097600.
^ Patti F (November 2012). "Treatment of cognitive impairment in patients with multiple sclerosis". Expert Opin Investig Drugs. 21 (11): 1679–1699. doi:10.1517/13543784.2012.716036. PMID 22876911.
^ Lovera J, Kovner B (October 2012). "Cognitive impairment in multiple sclerosis". Curr Neurol Neurosci Rep. 12 (5): 618–627. doi:10.1007/s11910-012-0294-3. PMC 4581520. PMID 22791241.
^ Roy S, Benedict RH, Drake AS, Weinstock-Guttman B (March 2016). "Impact of Pharmacotherapy on Cognitive Dysfunction in Patients with Multiple Sclerosis". CNS Drugs. 30 (3): 209–225. doi:10.1007/s40263-016-0319-6. PMID 26884145.
^ Morrow SA, Kaushik T, Zarevics P, Erlanger D, Bear MF, Munschauer FE, Benedict RH (July 2009). "The effects of L-amphetamine sulfate on cognition in MS patients: results of a randomized controlled trial". J Neurol. 256 (7): 1095–102. doi:10.1007/s00415-009-5074-x. PMID 19263186.
^ Benedict RH, Munschauer F, Zarevics P, Erlanger D, Rowe V, Feaster T, Carpenter RL (June 2008). "Effects of l-amphetamine sulfate on cognitive function in multiple sclerosis patients". J Neurol. 255 (6): 848–852. doi:10.1007/s00415-008-0760-7. PMID 18481035.
^ Sumowski JF, Chiaravalloti N, Erlanger D, Kaushik T, Benedict RH, DeLuca J (September 2011). "L-amphetamine improves memory in MS patients with objective memory impairment". Mult Scler. 17 (9): 1141–1145. doi:10.1177/1352458511404585. PMID 21561956.

External links

"Amphetamine". MedlinePlus.

[8] Synonyms and alternate spellings include: (2R)-1-phenylpropan-2-amine (IUPAC name), levamfetamine (International Nonproprietary Name [INN]), (R)-amphetamine, (−)-amphetamine, l-amphetamine, and L-amphetamine.^[6]^[7]

[smith-davis-1977-review-34] Smith & Davis (1977) reviewed 11 clinical studies of dextroamphetamine and levoamphetamine including potency ratios in terms of a variety of psychological and behavioral effects.^[10] The summaries of these studies are in Table 1 of the paper.^[10]

[1] CID 32893 from PubChem

[Amph_Uses-2] Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present – a pharmacological and clinical perspective". J. Psychopharmacol. 27 (6): 479–496. doi:10.1177/0269881113482532. PMC 3666194. PMID 23539642.

[Evekeo_FDA_label-3] "Evekeo- amphetamine sulfate tablet". DailyMed. 14 August 2019. Retrieved 7 April 2020.

[LosackerRoehrich2021-4] Losacker M, Roehrich J, Hess C (October 2021). "Enantioselective determination of plasma protein binding of common amphetamine-type stimulants". J Pharm Biomed Anal. 205: 114317. doi:10.1016/j.jpba.2021.114317. PMID 34419812. Amphetamine-type stimulants (ATS) like amphetamine ('speed'), methamphetamine ('crystal meth') and 3,4-methylenedioxy-N-methylamphetamine (MDMA, 'ecstasy') represent some of the most frequently abused drugs worldwide. [...] The enantiomers of these four compounds exhibit different pharmacokinetic and pharmacodynamic properties. According to the free drug theory, the pharmacological properties of a substance are dependent on its plasma protein binding (PPB). However, data on PPB of stimulant enantiomers in humans are rare or non-existent. [...] For (R)-amphetamine a slightly but significantly higher PPB was found compared to the (S)-enantiomer (31.7 % vs 29.0 %).

[MarkowitzPatrick2017-5] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m Markowitz JS, Patrick KS (October 2017). "The Clinical Pharmacokinetics of Amphetamines Utilized in the Treatment of Attention-Deficit/Hyperactivity Disorder". J Child Adolesc Psychopharmacol. 27 (8): 678–689. doi:10.1089/cap.2017.0071. PMID 28910145.

[PubChem-6] "L-Amphetamine". PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. 30 December 2017. Retrieved 2 January 2018.

[IUPHAR-7] "R(-)amphetamine". IUPHAR/BPS Guide to Pharmacology. International Union of Basic and Clinical Pharmacology. Retrieved 2 January 2018.

[HealSmithGosden2013-9] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u ^v ^w ^x ^y ^z ^aa ^ab ^ac ^ad ^ae ^af ^ag ^ah ^ai ^aj ^ak ^al ^am ^an ^ao ^ap ^aq ^ar ^as Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present--a pharmacological and clinical perspective". J Psychopharmacol. 27 (6): 479–496. doi:10.1177/0269881113482532. PMC 3666194. PMID 23539642. As a molecule with a single chiral centre, amphetamine exists in two optically active forms, i.e. the dextro- (or d-) and levo- (or l-) isomers or enantiomers (Figure 1). Smith, Kline and French synthesised both isomers, and in 1937 commenced marketing of d-amphetamine, which was the more potent of the two isomers, under the trade name of Dexedrine®. [...] Although l-amphetamine (Cydril®) achieved far less attention than either the racemate or d-isomer, clinical trials conducted in the 1970s demonstrated that both isomers of amphetamine were clinically effective in treating ADHD (Arnold et al., 1972, 1973, 1976). The use of Benzedrine to treat ADHD declined dramatically after Gross (1976) reported that the racemate was significantly less clinically effective than Dexedrine. Currently, the only use of l-amphetamine in ADHD medications is in mixed salts/mixed enantiomers amphetamine (MES-amphetamine), which consists of a 3:1 enantiomeric mixture d-amphetamine:l-amphetamine salts that is available in both immediate-release (Adderall®, generic) and extended-release (Adderall XR®, generic) formulations.

[SilverstoneWells1980-10] Silverstone T, Wells B (1980). "Clinical Psychopharmacology of Amphetamine and Related Compounds". Amphetamines and Related Stimulants: Chemical, Biological, Clinical, and Sociological Aspects. CRC Press. pp. 147–160. doi:10.1201/9780429279843-10. ISBN 978-0-429-27984-3. A comparison of dextroamphetamine and levoamphetamine revealed that the dextrorotatory isomer was the more potent in elevating mood in normal subjects, being at least twice as potent as the levo form.35 [...] Narcolepsy was one of the first conditions to be treated successfully with amphetamine3 and remains one of the few (some would say the only) clinical indications for its use. While the required oral dose of dextroamphetamine (Dexedrine®) ranges from 5 to 120 mg/day, most patients respond to 10 mg two to four times daily. [...] The closely related compound methylphenidate (Ritalin®), 20 mg two to four times daily, has been shown to be as effective as dextroamphetamine but with less likelihood of causing side effects.61 The same is true of levoamphetamine.62 [...] Nevertheless, as amphetamine has an action on dopaminergic pathways it was considered worthwhile to examine the effects of amphetamine under controlled conditions.95 Twenty patients, all on other anti-Parkinsonian drugs, were studied. There was some subjective improvement in a proportion (less than half) of the patients when they received either dextroamphetamine or levoamphetamine, but there was little objective improvement. The authors remarked that amphetamine was unlikely to have worked anyway in Parkinson's disease as it acts mainly by releasing dopamine and noradrenaline from presynaptic neurons; as the underlying pathology involves a reduction of presynaptic dopamine, there would be insufficient dopamine for amphetamine to release.

[SmithDavis1977-11] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j Smith RC, Davis JM (June 1977). "Comparative effects of d-amphetamine, l-amphetamine, and methylphenidate on mood in man". Psychopharmacology (Berl). 53 (1): 1–12. doi:10.1007/BF00426687. PMID 407607. The comparative effects of d-amphetamine, l-amphetamine, and methylphenidate were assessed in 16 normal subjects, using a double-blind, crossover placebo-controlled design. Within the dose range tested, the efficacy ratio of d-amphetamine:l-amphetamine was about 2:1, and graphic presentation of dose response scores indicated a relatively small difference in potency between the amphetamine isomers. [...] The efficacy ratios for d-amphetamine:l-amphetamine on increasing euphoric mood in man were similar to the previously reported ratios of these two isomers in inducing or exacerbating psychosis in humans. [...] The results of this study indicate that d-AMP is about 2 times as effective as l-AMP [...] in increasing euphoric and activating moods in man. [...] the relatively small efficacy ratios of about 2:1 that we report here for the euphoric effects of d- vs. l-AMP in our normal subjects are similar to those recently reported by other studies using different groups of subjects—Van Kamen et al. (1976) in depressed patients and Janowsky and Davis (1976) in acute psychotics. [...] Moreover, the 2:1 ratio of d- and l-AMP effects on euphoric mood is very similar to the ratios (1.3:1 to 2.1:1) which have been reported for the efficacy of amphetamine isomers on other classes of behavior in man—for example, the activation of psychosis and the treatment of hyperkinetic children (see Table 1). [...] Table 1. Some previous studies comparing effects of d-amphetamine, l-amphetamine, and methylphenidate in man. [...]

[SimolaCarta2016-12] Simola, Nicola; Carta, Manolo (2016). "Amphetamine Usage, Misuse, and Addiction Processes". Neuropathology of Drug Addictions and Substance Misuse. Elsevier. p. 14–24. doi:10.1016/b978-0-12-800212-4.00002-9. ISBN 978-0-12-800212-4.

[BielBopp1978-13] ^ ^a ^b ^c ^d ^e ^f Biel, J. H.; Bopp, B. A. (1978). "Amphetamines: Structure-Activity Relationships". Stimulants. Boston, MA: Springer US. p. 1–39. doi:10.1007/978-1-4757-0510-2_1. ISBN 978-1-4757-0512-6. Snyder and his colleagues (1970b; Taylor and Snyder, 1970; Coyle and Snyder, 1969) have compared the effects of the two amphetamine isomers on norepinephrine and dopamine uptake by synaptosomes from the rat hypothalamus and corpus striatum, respectively. The dextro isomer was ten times more potent than the levo isomer in inhibiting norepinephrine uptake but the two isomers were equipotent in inhibiting dopamine uptake. The marked difference in the potency (tenfold) of the two isomers in increasing locomotor activity contrasted with a relatively small (twofold) difference in potency in eliciting stereotyped behavior. [...] The dextro isomers of both amphetamine and methamphetamine are considerably more potent as stimulants than the levo isomers. Depending on the parameter measured, the potency difference may range from two- to tenfold (Taylor and Snyder, 1970; Snyder et at., 1970b; Svensson, 1971; Roth et at., 1954; Van Rossum, 1970; Moore, 1963). The anorexic activity of the dextro isomers also exceeds that of the levo isomers (Lawlor et at., 1969). However, the two isomers are approximately equipotent in eliciting certain peripheral effects, such as the vasoconstriction, vasopressor, and other cardiovascular effects (Roth et at., 1954; Swanson et at., 1943).The dextro isomers of both amphetamine and methamphetamine are considerably more potent as stimulants than the levo isomers. Depending on the parameter measured, the potency difference may range from two- to tenfold (Taylor and Snyder, 1970; Snyder et at., 1970b; Svensson, 1971; Roth et at., 1954; Van Rossum, 1970; Moore, 1963). The anorexic activity of the dextro isomers also exceeds that of the levo isomers (Lawlor et at., 1969). However, the two isomers are approximately equipotent in eliciting certain peripheral effects, such as the vasoconstriction, vasopressor, and other cardiovascular effects (Roth et at., 1954; Swanson et at., 1943).

[ArnoldWenderMcCloskey1972-14] Arnold LE, Wender PH, McCloskey K, Snyder SH (December 1972). "Levoamphetamine and dextroamphetamine: comparative efficacy in the hyperkinetic syndrome. Assessment by target symptoms". Arch Gen Psychiatry. 27 (6): 816–22. doi:10.1001/archpsyc.1972.01750300078015. PMID 4564954.

[BarkholtzHadzimaMiles2023-15] Barkholtz HM, Hadzima R, Miles A (July 2023). "Pharmacology of R-(-)-Methamphetamine in Humans: A Systematic Review of the Literature". ACS Pharmacol Transl Sci. 6 (7): 914–924. doi:10.1021/acsptsci.3c00019. PMC 10353062. PMID 37470013.

[HeinonenLammintausta1991-16] ^ ^a ^b ^c ^d ^e ^f Heinonen EH, Lammintausta R (1991). "A review of the pharmacology of selegiline". Acta Neurol Scand Suppl. 136: 44–59. doi:10.1111/j.1600-0404.1991.tb05020.x. PMID 1686954. In humans, the three metabolites, l-MA, l-A and DES have been identified in plasma and urine after single and multiple doses of selegiline (193). The urine recovery after a 10 mg daily dose of selegiline has been 9–30 % as l-A, 20–60 % as l-MA and about 1 % as DES. During continuous treatment the serum concentrations of l-A have been 6–8 ng/ml, that of l–MA, 9–14 ng/ml and that of DES, 1–7 ng/ml depending on the sampling time, and the corresponding CSF concentrations, 6–7 ng/ml, 14–15 ng/ml and 0.7–1 ng/ml respectively (193). [...] It is also important to recognise the different properties of the two amphetamine isomers (Fig. 4). The basic pharmacological action of d- or l- amphetamine is the release of catecholamines from the presynaptic neuron. On higher concentration, uptake of catecholamines takes place and, at even higher concentrations, reversible inhibition of MAO. The DA releasing effect of l-A is about 10 times less than that of d-form (198). The uptake of DA is reported to be about 4–5 times less by the l-form in the rat brain (199, 200), while inhibition of uptake of NA has been reported to be two times weaker by the l-form, or to be equipotent with the d-form. d-A is a five times more potent inhibitor of MAO-A (201) and about 3–5 times more potent in inducing increase of blood pressure (202), stereotypic locomotor behaviour in rats (203) and self-administration in monkeys (204).

[Racemic_amph_-_FDA_Benzedrine_status-17] "Benzedrine: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 4 September 2015.

[Racemic_amph_-_FDA_Evekeo_status-18] "Evekeo: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 11 August 2015.

[Adderall_XR_FDA_label-19] "Adderall XR- dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate and amphetamine aspartate capsule, extended release". DailyMed. 17 July 2019. Retrieved 7 April 2020.

[Adderall_FDA_label-20] "Adderall- dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate tablet". DailyMed. 8 November 2019. Retrieved 7 April 2020.

[Evekeo_ODT_FDA_label-21] "Evekeo ODT- amphetamine sulfate tablet, orally disintegrating". DailyMed. 20 February 2020. Retrieved 7 April 2020.

[Dyanavel-22] "Dyanavel XR Prescribing Information". January 2017. Retrieved 14 May 2017.

[Adzenys-23] "Adzenys XR-ODT- amphetamine tablet, orally disintegrating". DailyMed. 22 January 2020. Retrieved 7 April 2020. Adzenys XR-ODT (amphetamine extended-release orally disintegrating tablet) contains a 3 to 1 ratio of d- to l-amphetamine, a central nervous system stimulant.

[24] "Adzenys ER- amphetamine suspension, extended release". DailyMed. 21 January 2020. Retrieved 7 April 2020.

[Clarke1980-25] Clarke, D (1980). "Amphetamine and monoamine oxidase inhibition: an old idea gains new acceptance". Trends in Pharmacological Sciences. 1 (2): 312–313. doi:10.1016/0165-6147(80)90032-2.

[MillerClarke1978-26] Miller HH, Clarke DE (1978). "In vitro inhibition of monoamine oxidase types A and B by d- and l-amphetamine". Commun Psychopharmacol. 2 (4): 319–325. PMID 729356.

[Ziegler1989-27] Ziegler, Michael G. (1989). "Catecholamine Measurement in Behavioral Research". Handbook of Research Methods in Cardiovascular Behavioral Medicine. Boston, MA: Springer US. p. 167–183. doi:10.1007/978-1-4899-0906-0_11. ISBN 978-1-4899-0908-4.

[ZieglerRaymondLakeEbert1979-28] Ziegler, Michael G.; Raymond Lake, C.; Ebert, Michael H. (1979). "Norepinephrine elevations in cerebrospinal fluid after d- and l-amphetamine". European Journal of Pharmacology. 57 (2–3): 127–133. doi:10.1016/0014-2999(79)90358-3.

[CeethamKulkarniRowley2007-29] Cheetham, S. C., Kulkarni, R. S., Rowley, H. L., & Heal, D. J. (2007). The SH rat model of ADHD has profoundly different catecholaminergic responses to amphetamine’s enantiomers compared with Sprague-Dawleys. Society for Neurosciences. https://scholar.google.com/scholar?cluster=850792164327952775

[Segal1975-30] Segal DS (October 1975). "Behavioral characterization of d- and l-amphetamine: neurochemical implications". Science. 190 (4213): 475–477. doi:10.1126/science.1166317. PMID 1166317.

[TaylorSnyder1970-31] Taylor KM, Snyder SH (June 1970). "Amphetamine: differentiation by d and l isomers of behavior involving brain norepinephrine or dopamine". Science. 168 (3938): 1487–1489. doi:10.1126/science.168.3938.1487. PMID 5463064.

[LawlorTrivediYelnosky1969-32] Lawlor RB, Trivedi MC, Yelnosky J (June 1969). "A determination of the anorexigenic potential of dl-amphetamine, d-amphetamine, l-amphetamine and phentermine". Arch Int Pharmacodyn Ther. 179 (2): 401–407. PMID 5367311.

[BalsterSchuster1973-33] Balster RL, Schuster CR (1973). "A comparison of d-amphetamine, l-amphetamine, and methamphetamine self-administration in rhesus monkeys". Pharmacol Biochem Behav. 1 (1): 67–71. doi:10.1016/0091-3057(73)90057-9. PMID 4204513.

[VanKammenMurphy1975-35] Van Kammen DP, Murphy DL (November 1975). "Attenuation of the euphoriant and activating effects of d- and l-amphetamine by lithium carbonate treatment". Psychopharmacologia. 44 (3): 215–224. doi:10.1007/BF00428897. PMID 1824. Seven of nine depressed patients experienced a 4.3-fold increase in rated euphoria and activation following 30 mg d-amphetamine in a replicated dose, double blind study. d-Amphetamine was 2 to 2.3-fold more effective in producing activation, euphoria, and antidepressant effects than the same dose of l-amphetamine.

[Kantak2022-36] Kantak KM (May 2022). "Rodent models of attention-deficit hyperactivity disorder: An updated framework for model validation and therapeutic drug discovery". Pharmacol Biochem Behav. 216: 173378. doi:10.1016/j.pbb.2022.173378. PMID 35367465.

[TealIngramBubser2023-37] Teal, Laura B.; Ingram, Shalonda M.; Bubser, Michael; McClure, Elliott; Jones, Carrie K. (2023). "The Evolving Role of Animal Models in the Discovery and Development of Novel Treatments for Psychiatric Disorders". Drug Development in Psychiatry. Vol. 30. Cham: Springer International Publishing. p. 37–99. doi:10.1007/978-3-031-21054-9_3. ISBN 978-3-031-21053-2.

[Sagvolden2011-38] Sagvolden T (March 2011). "Impulsiveness, overactivity, and poorer sustained attention improve by chronic treatment with low doses of l-amphetamine in an animal model of Attention-Deficit/Hyperactivity Disorder (ADHD)". Behav Brain Funct. 7: 6. doi:10.1186/1744-9081-7-6. PMC 3086861. PMID 21450079.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[SagvoldenXu2008-39] Sagvolden T, Xu T (January 2008). "l-Amphetamine improves poor sustained attention while d-amphetamine reduces overactivity and impulsiveness as well as improves sustained attention in an animal model of Attention-Deficit/Hyperactivity Disorder (ADHD)". Behav Brain Funct. 4: 3. doi:10.1186/1744-9081-4-3. PMC 2265273. PMID 18215285.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[KraemerMaurer2002-40] Kraemer T, Maurer HH (April 2002). "Toxicokinetics of amphetamines: metabolism and toxicokinetic data of designer drugs, amphetamine, methamphetamine, and their N-alkyl derivatives". Ther Drug Monit. 24 (2): 277–89. doi:10.1097/00007691-200204000-00009. PMID 11897973. [...] in vivo studies with five poor and eight extensive metabolizers by Scheinin et al (61) showed that CYP2D6 polymorphism was not crucial for the disposition of selegiline. These authors did not find significant differences in the pharmacokinetic parameters of selegiline, desmethylselegiline, and R(−)- amphetamine between poor metabolizers and extensive metabolizers. However, the area under the serum concentration-time curve values of R(−)-methamphetamine were, on average, 46% higher in poor metabolizers than in extensive metabolizers.

[ScheininAnttilaDahl1998-41] Scheinin H, Anttila M, Dahl ML, Karnani H, Nyman L, Taavitsainen P, Pelkonen O, Bertilsson L (October 1998). "CYP2D6 polymorphism is not crucial for the disposition of selegiline". Clin Pharmacol Ther. 64 (4): 402–411. doi:10.1016/S0009-9236(98)90071-6. PMID 9797797.

[ArnoldHuestisSmeltzer1976-42] Arnold LE, Huestis RD, Smeltzer DJ, Scheib J, Wemmer D, Colner G (March 1976). "Levoamphetamine vs dextroamphetamine in minimal brain dysfunction. Replication, time response, and differential effect by diagnostic group and family rating". Arch Gen Psychiatry. 33 (3): 292–301. doi:10.1001/archpsyc.1976.01770030012002. PMID 769721.

[ParkesFenton1973-43] Parkes JD, Fenton GW (December 1973). "Levo(-) amphetamine and dextro(+) amphetamine in the treatment of narcolepsy". J Neurol Neurosurg Psychiatry. 36 (6): 1076–81. doi:10.1136/jnnp.36.6.1076. PMC 1083612. PMID 4359162.

[ArnoldKirilcukCorson1973-44] Arnold LE, Kirilcuk V, Corson SA, Corson EO (February 1973). "Levoamphetamine and dextroamphetamine: differential effect on aggression and hyperkinesis in children and dogs". Am J Psychiatry. 130 (2): 165–70. doi:10.1176/ajp.130.2.165. PMID 4568123.

[GillinvanKammenGraves1975-45] Gillin JC, van Kammen DP, Graves J, Murphy D (October 1975). "Differential effects of D- and L-amphetamine on the sleep of depressed patients". Life Sci. 17 (8): 1223–1240. doi:10.1016/0024-3205(75)90132-0. PMID 172755.

[HartmannCravens1976-46] Hartmann E, Cravens J (November 1976). "Sleep: effects of d- and l-amphetamine in man and in rat". Psychopharmacology (Berl). 50 (2): 171–175. doi:10.1007/BF00430488. PMID 826958.

[JanowskyDavis1976-47] Janowsky DS, Davis JM (March 1976). "Methylphenidate, dextroamphetamine, and levamfetamine. Effects on schizophrenic symptoms". Arch Gen Psychiatry. 33 (3): 304–308. doi:10.1001/archpsyc.1976.01770030024003. PMID 769722.

[HartmannOrzackBranconnier1977-48] Hartmann E, Orzack MH, Branconnier R (July 1977). "Sleep deprivation deficits and their reversal by d- and l-amphetamine". Psychopharmacology (Berl). 53 (2): 185–189. doi:10.1007/BF00426490. PMID 408844.

[CaineLudlowPolinsky1984-49] Caine ED, Ludlow CL, Polinsky RJ, Ebert MH (March 1984). "Provocative drug testing in Tourette's syndrome: d- and l-amphetamine and haloperidol". J Am Acad Child Psychiatry. 23 (2): 147–152. doi:10.1097/00004583-198403000-00005. PMID 6585416.

[ParkesTarsyMarsden1975-50] Parkes JD, Tarsy D, Marsden CD, Bovill KT, Phipps JA, Rose P, Asselman P (March 1975). "Amphetamines in the treatment of Parkinson's disease". J Neurol Neurosurg Psychiatry. 38 (3): 232–7. doi:10.1136/jnnp.38.3.232. PMC 491901. PMID 1097600.

[Patti2012-51] Patti F (November 2012). "Treatment of cognitive impairment in patients with multiple sclerosis". Expert Opin Investig Drugs. 21 (11): 1679–1699. doi:10.1517/13543784.2012.716036. PMID 22876911.

[LoveraKovner2012-52] Lovera J, Kovner B (October 2012). "Cognitive impairment in multiple sclerosis". Curr Neurol Neurosci Rep. 12 (5): 618–627. doi:10.1007/s11910-012-0294-3. PMC 4581520. PMID 22791241.

[RoyBenedictDrake2016-53] Roy S, Benedict RH, Drake AS, Weinstock-Guttman B (March 2016). "Impact of Pharmacotherapy on Cognitive Dysfunction in Patients with Multiple Sclerosis". CNS Drugs. 30 (3): 209–225. doi:10.1007/s40263-016-0319-6. PMID 26884145.

[MorrowKaushikVarevics2009-54] Morrow SA, Kaushik T, Zarevics P, Erlanger D, Bear MF, Munschauer FE, Benedict RH (July 2009). "The effects of L-amphetamine sulfate on cognition in MS patients: results of a randomized controlled trial". J Neurol. 256 (7): 1095–102. doi:10.1007/s00415-009-5074-x. PMID 19263186.

[BenedictMunschauerZarevics2008-55] Benedict RH, Munschauer F, Zarevics P, Erlanger D, Rowe V, Feaster T, Carpenter RL (June 2008). "Effects of l-amphetamine sulfate on cognitive function in multiple sclerosis patients". J Neurol. 255 (6): 848–852. doi:10.1007/s00415-008-0760-7. PMID 18481035.

[SumowskiChiaravallotiErlanger2011-56] Sumowski JF, Chiaravalloti N, Erlanger D, Kaushik T, Benedict RH, DeLuca J (September 2011). "L-amphetamine improves memory in MS patients with objective memory impairment". Mult Scler. 17 (9): 1141–1145. doi:10.1177/1352458511404585. PMID 21561956.

[1]

[2]

[3]

[4]

[5]

[6]

[note 1]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[note 2]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[7]

@@ Line 3: / Line 3: @@
 {{For|the [[racemate]]|Amphetamine}}
 {{Use dmy dates|date=November 2018}}
-{{Chembox
+{{Drugbox
+| Verifiedfields =
-| Watchedfields = changed
+| Watchedfields =
-| verifiedrevid = 612823596
+| verifiedrevid =
-| ImageFile = L-amphetamine.svg
+| IUPAC_name = (2''R'')-1-Phenylpropan-2-amine<ref name="PubChem">{{Cite web|title = L-Amphetamine|url = https://pubchem.ncbi.nlm.nih.gov/compound/32893| work=PubChem Compound | publisher=United States National Library of Medicine&nbsp;– National Center for Biotechnology Information |access-date = 2 January 2018|date = 30 December 2017}}</ref>
-| ImageFile_Ref = {{chemboximage|correct|??}}
+| image = L-amphetamine.svg
-| ImageSize = 244
+| width = 250px
-| ImageName = Stereo, Kekulé, skeletal formula of levoamphetamine
-| PIN = (2''R'')-1-Phenylpropan-2-amine<ref name="Pubchem">{{Cite web|title = L-Amphetamine|url = https://pubchem.ncbi.nlm.nih.gov/compound/32893| work=PubChem Compound | publisher=United States National Library of Medicine&nbsp;– National Center for Biotechnology Information |access-date = 2 January 2018|date = 30 December 2017}}</ref>
+<!-- Clinical data -->
-| OtherNames = l-Amphetamine, Levamfetamine<ref>{{PubChem|32893}}</ref>
+| tradename = Cydril, Adderall, Evekeo, others
-|Section1={{Chembox Identifiers
+| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
+| pregnancy_US = <!-- A / B / C / D / X -->
+| pregnancy_category =
+| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
+| legal_CA =
+| legal_UK =
+| legal_US = Schedule II
+| legal_status =
+| routes_of_administration = [[Oral route|Oral]] (as part of [[Adderall]], Evekeo, and generic amphetamine sulfate<ref name="Amph Uses" /><ref name="Evekeo FDA label" />)
+| class = [[Amphetamine-type stimulant|Amphetamine]]; [[Stimulant]]; [[Sympathomimetic]]; [[Norepinephrine releasing agent]]; [[TAAR1 agonist]]
+<!-- Pharmacokinetic data -->
+| bioavailability =
+| protein_bound = 31.7%<ref name="LosackerRoehrich2021" />
+| metabolism =
+| elimination_half-life = 12.0–15.2{{nbsp}}hours<ref name="MarkowitzPatrick2017" />
+| excretion =
+<!-- Identifiers -->
+| CAS_number_Ref = {{cascite|correct|??}}
+| CAS_number = 156-34-3
+| CAS_supplemental =
+| ATC_prefix =
+| ATC_suffix =
+| ATC_supplemental =
+| PubChem = 32893
 | IUPHAR_ligand = 2146
+| DrugBank_Ref =
-| CASNo_Ref = {{cascite|correct|??}}
-| CASNo = 156-34-3
+| DrugBank =
+| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
+| ChemSpiderID = 30477
 | UNII_Ref = {{fdacite|correct|FDA}}
 | UNII = R87US8P740
-| PubChem = 32893
+| KEGG =
-| ChemSpiderID = 30477
-| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
-| EINECS = 205-850-8
-| ChEBI = 42724
 | ChEBI_Ref = {{ebicite|correct|EBI}}
-| ChEMBL = 19393
+| ChEBI = 42724
 | ChEMBL_Ref = {{ebicite|correct|EBI}}
-| Beilstein = 2432739
+| ChEMBL = 19393
+| synonyms = l-Amphetamine, Levamfetamine<ref>{{PubChem|32893}}</ref>
-| Gmelin = 1125855
+<!-- Chemical data -->
+| C=9 | N=1 | H=13
 | SMILES = C[C@@H](N)Cc1ccccc1
-| SMILES1 = C[C@@H](N)CC1=CC=CC=C1
 | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
 | StdInChI = 1S/C9H13N/c1-8(10)7-9-5-3-2-4-6-9/h2-6,8H,7,10H2,1H3/t8-/m1/s1
 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
 | StdInChIKey = KWTSXDURSIMDCE-MRVPVSSYSA-N
- }}
-|Section2={{Chembox Properties
-| C=9 | N=1 | H=13
-| MolarMass = 135.2062 g mol<sup>−1</sup>
-| LogP = 1.789
- }}
-|Section3={{Chembox Pharmacology
-| AdminRoutes = [[Oral route|Oral]] (as part of [[Adderall]], Evekeo, and generic amphetamine sulfate<ref name="Amph Uses" /><ref name="Evekeo FDA label" />)
-| Legal_US = Schedule II
- }}
 }}
+<!-- Definition and medical uses -->
+'''Levoamphetamine'''{{#tag:ref|Synonyms and alternate spellings include: '''{{nowrap|(2''R'')-1-phenylpropan-2-amine}}''' ([[International Union of Pure and Applied Chemistry|IUPAC]] name), '''levamfetamine''' ([[International Nonproprietary Name|International Nonproprietary Name [INN]]]), '''{{nowrap|(''R'')-amphetamine}}''', '''{{nowrap|(&minus;)-amphetamine}}''', '''{{nowrap|l-amphetamine}}''', and {{nowrap|'''<small>L</small>-amphetamine}}'''.<ref name="PubChem" /><ref name="IUPHAR">{{cite web|title=R(-)amphetamine|url=http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2146|website=IUPHAR/BPS Guide to Pharmacology|publisher=International Union of Basic and Clinical Pharmacology|access-date=2 January 2018}}</ref>| group = "note" }} is a [[stimulant]] [[medication]] which is used in the treatment of certain [[medical condition]]s.<ref name="HealSmithGosden2013">{{cite journal | vauthors = Heal DJ, Smith SL, Gosden J, Nutt DJ | title = Amphetamine, past and present--a pharmacological and clinical perspective | journal = J Psychopharmacol | volume = 27 | issue = 6 | pages = 479–496 | date = June 2013 | pmid = 23539642 | pmc = 3666194 | doi = 10.1177/0269881113482532 | url = | quote = As a molecule with a single chiral centre, amphetamine exists in two optically active forms, i.e. the dextro- (or d-) and levo- (or l-) isomers or enantiomers (Figure 1). Smith, Kline and French synthesised both isomers, and in 1937 commenced marketing of d-amphetamine, which was the more potent of the two isomers, under the trade name of Dexedrine®. [...] Although l-amphetamine (Cydril®) achieved far less attention than either the racemate or d-isomer, clinical trials conducted in the 1970s demonstrated that both isomers of amphetamine were clinically effective in treating ADHD (Arnold et al., 1972, 1973, 1976). The use of Benzedrine to treat ADHD declined dramatically after Gross (1976) reported that the racemate was significantly less clinically effective than Dexedrine. Currently, the only use of l-amphetamine in ADHD medications is in mixed salts/mixed enantiomers amphetamine (MES-amphetamine), which consists of a 3:1 enantiomeric mixture d-amphetamine:l-amphetamine salts that is available in both immediate-release (Adderall®, generic) and extended-release (Adderall XR®, generic) formulations.}}</ref> It was previously marketed by itself under the brand name '''Cydril''', but is now available only in [[combination drug|combination]] with [[dextroamphetamine]] in varying ratios under brand names like '''Adderall''' and '''Evekeo'''.<ref name="HealSmithGosden2013" /><ref name="MarkowitzPatrick2017">{{cite journal | vauthors = Markowitz JS, Patrick KS | title = The Clinical Pharmacokinetics of Amphetamines Utilized in the Treatment of Attention-Deficit/Hyperactivity Disorder | journal = J Child Adolesc Psychopharmacol | volume = 27 | issue = 8 | pages = 678–689 | date = October 2017 | pmid = 28910145 | doi = 10.1089/cap.2017.0071 | url = }}</ref> The drug is known to increase [[wakefulness]] and [[attention|concentration]] in association with decreased [[appetite]] and [[Fatigue (medical)|fatigue]].<ref name="SilverstoneWells1980" /><ref name="SmithDavis1977" /> Pharmaceuticals that contain levoamphetamine are currently indicated and prescribed for the treatment of [[attention deficit hyperactivity disorder]] (ADHD), [[obesity]], and [[narcolepsy]] in some countries.<ref name="HealSmithGosden2013" /><ref name="HealSmithGosden2013" /><ref name="MarkowitzPatrick2017" /><ref name="SimolaCarta2016">{{cite book | last=Simola | first=Nicola | last2=Carta | first2=Manolo | title=Neuropathology of Drug Addictions and Substance Misuse | chapter=Amphetamine Usage, Misuse, and Addiction Processes | publisher=Elsevier | date=2016 | isbn=978-0-12-800212-4 | doi=10.1016/b978-0-12-800212-4.00002-9 | page=14–24}}</ref> Levoamphetamine is taken [[oral administration|by mouth]].<ref name="HealSmithGosden2013" /><ref name="MarkowitzPatrick2017" />
+<!-- Mechanism of action and chemistry -->
-'''Levoamphetamine'''{{#tag:ref|Synonyms and alternate spellings include: '''{{nowrap|(2''R'')-1-phenylpropan-2-amine}}''' ([[International Union of Pure and Applied Chemistry|IUPAC]] name), '''levamfetamine''' ([[International Nonproprietary Name|International Nonproprietary Name [INN]]]), '''{{nowrap|(''R'')-amphetamine}}''', '''{{nowrap|(&minus;)-amphetamine}}''', '''{{nowrap|l-amphetamine}}''', and {{nowrap|'''<small>L</small>-amphetamine}}'''.<ref name="Pubchem" /><ref name="IUPHAR">{{cite web|title=R(-)amphetamine|url=http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2146|website=IUPHAR/BPS Guide to Pharmacology|publisher=International Union of Basic and Clinical Pharmacology|access-date=2 January 2018}}</ref>| group = "note" }} is a [[central nervous system]] (CNS) [[stimulant]] known to increase [[wakefulness]] and [[attention|concentration]] in association with decreased [[appetite]] and [[Fatigue (medical)|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.
+Levoamphetamine acts as a [[releasing agent]] of the [[monoamine neurotransmitter]]s [[norepinephrine]] and [[dopamine]].<ref name="HealSmithGosden2013" /> It is similar to [[dextroamphetamine]] in its ability to release norepinephrine and in its [[sympathomimetic]] effects but is several times weaker than dextroamphetamine in its capacity to release dopamine and in its [[psychostimulant]] effects.<ref name="HealSmithGosden2013" /><ref name="BielBopp1978" /><ref name="SmithDavis1977" /> Levoamphetamine is the [[levorotatory]] [[stereoisomer]] of the [[racemate|racemic]] [[amphetamine]] molecule, whereas dextroamphetamine is the [[dextrorotatory]] isomer.<ref name="HealSmithGosden2013" /><ref name="MarkowitzPatrick2017" />
+<!-- History, society, and culture -->
-Levoamphetamine is the [[Dextrorotation and levorotation|levorotatory]] [[stereoisomer]] of the [[amphetamine]] molecule. While pharmaceutical formulations containing [[Enantiopure drug|enantiopure]] levoamphetamine are no longer manufactured, [[levomethamphetamine]] (levmetamfetamine) is still marketed and sold [[over-the-counter]] as a [[Decongestant|nasal decongestant]].
+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''' by the 1970s.<ref name="HealSmithGosden2013" /><ref name="ArnoldWenderMcCloskey1972" /> While [[pharmaceutical formulation]]s containing enantiopure levoamphetamine are no longer manufactured,<ref name="HealSmithGosden2013" /> [[levomethamphetamine]] (levmetamfetamine) is still marketed and sold [[over-the-counter]] as a [[decongestant|nasal decongestant]].<ref name="BarkholtzHadzimaMiles2023">{{cite journal | vauthors = Barkholtz HM, Hadzima R, Miles A | title = Pharmacology of R-(-)-Methamphetamine in Humans: A Systematic Review of the Literature | journal = ACS Pharmacol Transl Sci | volume = 6 | issue = 7 | pages = 914–924 | date = July 2023 | pmid = 37470013 | pmc = 10353062 | doi = 10.1021/acsptsci.3c00019 | url = }}</ref> In addition to being used in pharmaceutical drugs itself, levoamphetamine is a known [[active metabolite]] of certain other drugs, such as [[selegiline]] (<small>L</small>-deprenyl).<ref name="HeinonenLammintausta1991">{{cite journal | vauthors = Heinonen EH, Lammintausta R | title = A review of the pharmacology of selegiline | journal = Acta Neurol Scand Suppl | volume = 136 | issue = | pages = 44–59 | date = 1991 | pmid = 1686954 | doi = 10.1111/j.1600-0404.1991.tb05020.x | url = | quote = In humans, the three metabolites, l-MA, l-A and DES have been identified in plasma and urine after single and multiple doses of selegiline (193). The urine recovery after a 10 mg daily dose of selegiline has been 9–30 % as l-A, 20–60 % as l-MA and about 1 % as DES. During continuous treatment the serum concentrations of l-A have been 6–8 ng/ml, that of l–MA, 9–14 ng/ml and that of DES, 1–7 ng/ml depending on the sampling time, and the corresponding CSF concentrations, 6–7 ng/ml, 14–15 ng/ml and 0.7–1 ng/ml respectively (193). [...] It is also important to recognise the different properties of the two amphetamine isomers (Fig. 4). The basic pharmacological action of d- or l- amphetamine is the release of catecholamines from the presynaptic neuron. On higher concentration, uptake of catecholamines takes place and, at even higher concentrations, reversible inhibition of MAO. The DA releasing effect of l-A is about 10 times less than that of d-form (198). The uptake of DA is reported to be about 4–5 times less by the l-form in the rat brain (199, 200), while inhibition of uptake of NA has been reported to be two times weaker by the l-form, or to be equipotent with the d-form. d-A is a five times more potent inhibitor of MAO-A (201) and about 3–5 times more potent in inducing increase of blood pressure (202), stereotypic locomotor behaviour in rats (203) and self-administration in monkeys (204).}}</ref>
-== Chemistry ==
+==Medical uses==
+Levoamphetamine has been used in the treatment of [[attention deficit hyperactivity disorder]] (ADHD) both alone and in combination with [[dextroamphetamine]] at different ratios.<ref name="HealSmithGosden2013" /><ref name="SmithDavis1977" /> Levoamphetamine on its own has been found to be effective in the treatment of ADHD in multiple [[clinical study|clinical studies]] conducted in the 1970s.<ref name="HealSmithGosden2013" /><ref name="SmithDavis1977" /> The clinical dosages and [[potency (pharmacology)|potencies]] of levoamphetamine and dextroamphetamine in the treatment of ADHD have been fairly similar in these older studies.<ref name="HealSmithGosden2013" /><ref name="SmithDavis1977" />
-Levoamphetamine is the levorotatory stereoisomer of the amphetamine molecule. [[Racemic]] amphetamine contains two [[enantiomer|optical isomer]]s, [[dextroamphetamine]], and levoamphetamine.<ref name="Adderall XR FDA label" /><ref name="Adderall FDA label" />
+===Available forms===
-== Formulations ==
-=== Racemic amphetamine ===
+====Racemic amphetamine====
-The first patented amphetamine brand, [[History of Benzedrine|Benzedrine]], was a [[racemic]] (i.e., equal parts) mixture of the [[free base]]s or the more stable [[sulfate salt]]s of both amphetamine enantiomers (levoamphetamine and dextroamphetamine) that was introduced in the [[United States]] in 1934 as an inhaler for treating [[nasal congestion]].<ref name="Amph Uses">{{cite journal |vauthors=Heal DJ, Smith SL, Gosden J, Nutt DJ | title = Amphetamine, past and present – a pharmacological and clinical perspective | journal = J. Psychopharmacol. | volume = 27 | issue = 6 | pages = 479–496 |date=June 2013 | pmid = 23539642 | pmc = 3666194 | doi = 10.1177/0269881113482532}}</ref> It was later realized that the amphetamine enantiomers could treat [[obesity]], [[narcolepsy]], and [[ADHD]].<ref name="Amph Uses" /><ref name="Evekeo FDA label" /> Because of the greater [[central nervous system]] effect of the [[dextrorotatory]] enantiomer (i.e., [[dextroamphetamine]]), sold as Dexedrine, prescription of the Benzedrine brand fell and was eventually discontinued.<ref name="Racemic amph - FDA Benzedrine status">{{cite web | title=Benzedrine: FDA-Approved Drugs | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=083900 | website=U.S. [[Food and Drug Administration]] (FDA) | access-date=4 September 2015}}</ref> However, in 2012, [[Racemic mixture|racemic]] amphetamine sulfate was reintroduced as the Evekeo brandname.<ref name="Evekeo FDA label" /><ref name="Racemic amph - FDA Evekeo status">{{cite web | title=Evekeo: FDA-Approved Drugs | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=200166 | website=U.S. [[Food and Drug Administration]] (FDA) | access-date=11 August 2015}}</ref>
+The first patented amphetamine brand, [[History of Benzedrine|Benzedrine]], was a [[racemic]] (i.e., equal parts) mixture of the [[free base]]s or the more stable [[sulfate salt]]s of both amphetamine enantiomers (levoamphetamine and dextroamphetamine) that was introduced in the [[United States]] in 1934 as an inhaler for treating [[nasal congestion]].<ref name="Amph Uses">{{cite journal |vauthors=Heal DJ, Smith SL, Gosden J, Nutt DJ | title = Amphetamine, past and present – a pharmacological and clinical perspective | journal = J. Psychopharmacol. | volume = 27 | issue = 6 | pages = 479–496 |date=June 2013 | pmid = 23539642 | pmc = 3666194 | doi = 10.1177/0269881113482532}}</ref> It was later realized that the amphetamine enantiomers could treat [[obesity]], [[narcolepsy]], and [[ADHD]].<ref name="Amph Uses" /><ref name="Evekeo FDA label" /> Because of the greater [[central nervous system]] effect of the [[dextrorotatory]] enantiomer (i.e., [[dextroamphetamine]]), sold as Dexedrine, prescription of the Benzedrine brand fell and was eventually discontinued.<ref name="Racemic amph - FDA Benzedrine status">{{cite web | title=Benzedrine: FDA-Approved Drugs | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=083900 | website=U.S. [[Food and Drug Administration]] (FDA) | access-date=4 September 2015}}</ref> However, in 2012, [[Racemic mixture|racemic]] amphetamine sulfate was reintroduced as the Evekeo brand name.<ref name="Evekeo FDA label" /><ref name="Racemic amph - FDA Evekeo status">{{cite web | title=Evekeo: FDA-Approved Drugs | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=200166 | website=U.S. [[Food and Drug Administration]] (FDA) | access-date=11 August 2015}}</ref>
-=== Adderall ===
+====Adderall====
 [[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, or {{frac|3|4}} to {{frac|1|4}} ratio.<ref name="Adderall XR FDA label">{{cite web | title=Adderall XR- dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate and amphetamine aspartate capsule, extended release | website=DailyMed | date=17 July 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aff45863-ffe1-4d4f-8acf-c7081512a6c0 | access-date=7 April 2020}}</ref><ref name="Adderall FDA label">{{cite web | title=Adderall- dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate tablet | website=DailyMed | date=8 November 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f22635fe-821d-4cde-aa12-419f8b53db81 | access-date=7 April 2020}}</ref>
-=== Evekeo ===
+====Evekeo====
 [[Evekeo]] is an [[Food and Drug Administration|FDA]]-approved medication that contains racemic amphetamine sulfate (i.e., 50% levoamphetamine sulfate and 50% dextroamphetamine sulfate).<ref name="Evekeo FDA label">{{cite web | title=Evekeo- amphetamine sulfate tablet | website=DailyMed | date=14 August 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f469fb38-0380-4621-9db3-a4f429126156 | access-date=7 April 2020}}</ref> It is approved for the treatment of [[narcolepsy]], ADHD, and exogenous obesity.<ref name="Evekeo FDA label" /> 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.<ref name="Evekeo ODT FDA label">{{cite web | title=Evekeo ODT- amphetamine sulfate tablet, orally disintegrating | website=DailyMed | date=20 February 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e25f905-6c0b-4b19-a3b6-b2a386afa1c3 | access-date=7 April 2020}}</ref>
-=== Others ===
+====Other forms====
 Products using amphetamine base are now marketed. ''Dyanavel XR'', a liquid suspension form became available in 2015, and contains about 24% levoamphetamine.<ref name="Dyanavel">{{cite web|title=Dyanavel XR Prescribing Information |url=https://www.drugs.com/pro/dyanavel-xr.html|access-date=14 May 2017|date=January 2017}}</ref> ''Adzenys XR'', an orally dissolving tablet came to market in 2016 and contains 25% levoamphetamine.<ref name="Adzenys">{{cite web | title=Adzenys XR-ODT- amphetamine tablet, orally disintegrating | website=DailyMed | date=22 January 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c1179269-00b5-48ea-972d-31e614e99b7e | access-date=7 April 2020 | quote = Adzenys XR-ODT (amphetamine extended-release orally disintegrating tablet) contains a 3 to 1 ratio of d- to l-amphetamine, a central nervous system stimulant.}}</ref><ref>{{cite web | title=Adzenys ER- amphetamine suspension, extended release | website=DailyMed | date=21 January 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=eb1cc8d0-4231-41ea-8535-4fd872129713 | access-date=7 April 2020}}</ref>
-== See also ==
+==Pharmacology==
-* [[Levomethamphetamine]]
+===Pharmacodynamics===
-== Notes ==
+Levoamphetamine, similarly to [[dextroamphetamine]], acts as a [[reuptake inhibitor]] and [[releasing agent]] of [[norepinephrine]] and [[dopamine]] ''[[in vitro]]''.<ref name="HealSmithGosden2013" /><ref name="BielBopp1978" /> However, there are differences in [[potency (pharmacology)|potency]] between the two compounds.<ref name="HealSmithGosden2013" /><ref name="BielBopp1978" /> 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.<ref name="HealSmithGosden2013" /> 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.<ref name="HealSmithGosden2013" /> Dextroamphetamine is very weak as a reuptake inhibitor of [[serotonin]], whereas levoamphetamine is essentially inactive in this regard.<ref name="HealSmithGosden2013" /> Levoamphetamine and dextroamphetamine are both also relatively weak [[reversible inhibitor|reversible]] [[enzyme inhibitor|inhibitor]]s of [[monoamine oxidase]] (MAO).<ref name="HealSmithGosden2013" /><ref name="Clarke1980">{{cite journal | last=Clarke | first=D | title=Amphetamine and monoamine oxidase inhibition: an old idea gains new acceptance | journal=Trends in Pharmacological Sciences | volume=1 | issue=2 | date=1980 | doi=10.1016/0165-6147(80)90032-2 | pages=312–313}}</ref><ref name="MillerClarke1978">{{cite journal | vauthors = Miller HH, Clarke DE | title = In vitro inhibition of monoamine oxidase types A and B by d- and l-amphetamine | journal = Commun Psychopharmacol | volume = 2 | issue = 4 | pages = 319–325 | date = 1978 | pmid = 729356 | doi = | url = }}</ref>
+In rodent studies, both dextroamphetamine and levoamphetamine [[dose dependence|dose-dependently]] induce the release of dopamine in the [[striatum]] and norepinephrine in the [[prefrontal cortex]].<ref name="HealSmithGosden2013" /> 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.<ref name="HealSmithGosden2013" /> Dextroamphetamine has greater effects on dopamine levels than on norepinephrine levels, whereas levoamphetamine has relatively more balanced effects on dopamine and norepinephrine levels.<ref name="HealSmithGosden2013" /> As with rodent studies, levoamphetamine and dextroamphetamine have been found to be similarly potent in elevating norepinephrine levels in [[cerebrospinal fluid]] in monkeys.<ref name="Ziegler1989">{{cite book | last=Ziegler | first=Michael G. | title=Handbook of Research Methods in Cardiovascular Behavioral Medicine | chapter=Catecholamine Measurement in Behavioral Research | publisher=Springer US | publication-place=Boston, MA | date=1989 | isbn=978-1-4899-0908-4 | doi=10.1007/978-1-4899-0906-0_11 | page=167–183}}</ref><ref name="ZieglerRaymondLakeEbert1979">{{cite journal | last=Ziegler | first=Michael G. | last2=Raymond Lake | first2=C. | last3=Ebert | first3=Michael H. | title=Norepinephrine elevations in cerebrospinal fluid after d- and l-amphetamine | journal=European Journal of Pharmacology | volume=57 | issue=2-3 | date=1979 | doi=10.1016/0014-2999(79)90358-3 | pages=127–133}}</ref> By an uncertain [[mechanism of action|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).<ref name="HealSmithGosden2013" />
+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 45{{nbsp}}minutes, 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.<ref name="HealSmithGosden2013" /> The magnitudes of the effects of amphetamines are greater than those of classical reuptake inhibitors like [[atomoxetine]] and [[bupropion]].<ref name="HealSmithGosden2013" /> In addition, unlike with reuptake inhibitors, there is no [[dose–response relationship|dose–effect]] [[ceiling effect (pharmacology)|ceiling]] in the case of amphetamines.<ref name="HealSmithGosden2013" /> Although dextroamphetamine is more potent than levoamphetamine, both enantiomers can maximally increase striatal dopamine release by more than 5,000% of baseline.<ref name="HealSmithGosden2013" /><ref name="CeethamKulkarniRowley2007">Cheetham, S. C., Kulkarni, R. S., Rowley, H. L., & Heal, D. J. (2007). The SH rat model of ADHD has profoundly different catecholaminergic responses to amphetamine’s enantiomers compared with Sprague-Dawleys. Society for Neurosciences. https://scholar.google.com/scholar?cluster=850792164327952775</ref> 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|euphoric]].<ref name="HealSmithGosden2013" />
+Dextroamphetamine has greater potency in producing stimulant-like effects in rodents and non-human primates than levoamphetamine.<ref name="HealSmithGosden2013" /> Some rodent studies have found it to be 5- to 10-fold more potent in its stimulant-like effects than levoamphetamine.<ref name="BielBopp1978">{{cite book | last=Biel | first=J. H. | last2=Bopp | first2=B. A. | title=Stimulants | chapter=Amphetamines: Structure-Activity Relationships | publisher=Springer US | publication-place=Boston, MA | date=1978 | isbn=978-1-4757-0512-6 | doi=10.1007/978-1-4757-0510-2_1 | page=1–39 | quote = Snyder and his colleagues (1970b; Taylor and Snyder, 1970; Coyle and Snyder, 1969) have compared the effects of the two amphetamine isomers on norepinephrine and dopamine uptake by synaptosomes from the rat hypothalamus and corpus striatum, respectively. The dextro isomer was ten times more potent than the levo isomer in inhibiting norepinephrine uptake but the two isomers were equipotent in inhibiting dopamine uptake. The marked difference in the potency (tenfold) of the two isomers in increasing locomotor activity contrasted with a relatively small (twofold) difference in potency in eliciting stereotyped behavior. [...] The dextro isomers of both amphetamine and methamphetamine are considerably more potent as stimulants than the levo isomers. Depending on the parameter measured, the potency difference may range from two- to tenfold (Taylor and Snyder, 1970; Snyder et at., 1970b; Svensson, 1971; Roth et at., 1954; Van Rossum, 1970; Moore, 1963). The anorexic activity of the dextro isomers also exceeds that of the levo isomers (Lawlor et at., 1969). However, the two isomers are approximately equipotent in eliciting certain peripheral effects, such as the vasoconstriction, vasopressor, and other cardiovascular effects (Roth et at., 1954; Swanson et at., 1943).The dextro isomers of both amphetamine and methamphetamine are considerably more potent as stimulants than the levo isomers. Depending on the parameter measured, the potency difference may range from two- to tenfold (Taylor and Snyder, 1970; Snyder et at., 1970b; Svensson, 1971; Roth et at., 1954; Van Rossum, 1970; Moore, 1963). The anorexic activity of the dextro isomers also exceeds that of the levo isomers (Lawlor et at., 1969). However, the two isomers are approximately equipotent in eliciting certain peripheral effects, such as the vasoconstriction, vasopressor, and other cardiovascular effects (Roth et at., 1954; Swanson et at., 1943).}}</ref><ref name="Segal1975">{{cite journal | vauthors = Segal DS | title = Behavioral characterization of d- and l-amphetamine: neurochemical implications | journal = Science | volume = 190 | issue = 4213 | pages = 475–477 | date = October 1975 | pmid = 1166317 | doi = 10.1126/science.1166317 | url = }}</ref><ref name="TaylorSnyder1970">{{cite journal | vauthors = Taylor KM, Snyder SH | title = Amphetamine: differentiation by d and l isomers of behavior involving brain norepinephrine or dopamine | journal = Science | volume = 168 | issue = 3938 | pages = 1487–1489 | date = June 1970 | pmid = 5463064 | doi = 10.1126/science.168.3938.1487 | url = }}</ref> Levoamphetamine is also less potent than dextroamphetamine in its [[anorectic]] effects in rodents.<ref name="BielBopp1978" /><ref name="LawlorTrivediYelnosky1969">{{cite journal | vauthors = Lawlor RB, Trivedi MC, Yelnosky J | title = A determination of the anorexigenic potential of dl-amphetamine, d-amphetamine, l-amphetamine and phentermine | journal = Arch Int Pharmacodyn Ther | volume = 179 | issue = 2 | pages = 401–407 | date = June 1969 | pmid = 5367311 | doi = | url = }}</ref> 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 reinforcement|positive reinforcing]] effects in humans.<ref name="HealSmithGosden2013" /><ref name="HeinonenLammintausta1991" /><ref name="BalsterSchuster1973">{{cite journal | vauthors = Balster RL, Schuster CR | title = A comparison of d-amphetamine, l-amphetamine, and methamphetamine self-administration in rhesus monkeys | journal = Pharmacol Biochem Behav | volume = 1 | issue = 1 | pages = 67–71 | date = 1973 | pmid = 4204513 | doi = 10.1016/0091-3057(73)90057-9 | url = }}</ref> Potency ratios of dextroamphetamine versus levoamphetamine with single doses of 5 to 80{{nbsp}}mg in terms of psychological effects in humans including [[stimulant|stimulation]], [[wakefulness]], activation, euphoria, [[management of attention deficit hyperactivity disorder|reduction of hyperactivity]], and exacerbation of [[psychosis]] have ranged from 1:1 to 4:1 in a variety of older clinical studies.<ref name="SmithDavis1977">{{cite journal | vauthors = Smith RC, Davis JM | title = Comparative effects of d-amphetamine, l-amphetamine, and methylphenidate on mood in man | journal = Psychopharmacology (Berl) | volume = 53 | issue = 1 | pages = 1–12 | date = June 1977 | pmid = 407607 | doi = 10.1007/BF00426687 | url = | quote = The comparative effects of d-amphetamine, l-amphetamine, and methylphenidate were assessed in 16 normal subjects, using a double-blind, crossover placebo-controlled design. Within the dose range tested, the efficacy ratio of d-amphetamine:l-amphetamine was about 2:1, and graphic presentation of dose response scores indicated a relatively small difference in potency between the amphetamine isomers. [...] The efficacy ratios for d-amphetamine:l-amphetamine on increasing euphoric mood in man were similar to the previously reported ratios of these two isomers in inducing or exacerbating psychosis in humans. [...] The results of this study indicate that d-AMP is about 2 times as effective as l-AMP [...] in increasing euphoric and activating moods in man. [...] the relatively small efficacy ratios of about 2:1 that we report here for the euphoric effects of d- vs. l-AMP in our normal subjects are similar to those recently reported by other studies using different groups of subjects—Van Kamen et al. (1976) in depressed patients and Janowsky and Davis (1976) in acute psychotics. [...] Moreover, the 2:1 ratio of d- and l-AMP effects on euphoric mood is very similar to the ratios (1.3:1 to 2.1:1) which have been reported for the efficacy of amphetamine isomers on other classes of behavior in man—for example, the activation of psychosis and the treatment of hyperkinetic children (see Table 1). [...] Table 1. Some previous studies comparing effects of d-amphetamine, l-amphetamine, and methylphenidate in man. [...]}}</ref>{{#tag:ref|Smith & Davis (1977) reviewed 11{{nbsp}}clinical studies of dextroamphetamine and levoamphetamine including potency ratios in terms of a variety of psychological and behavioral effects.<ref name="SmithDavis1977" /> The summaries of these studies are in Table 1 of the paper.<ref name="SmithDavis1977" />|name=smith-davis-1977-review|group=note}}<ref name="VanKammenMurphy1975">{{cite journal | vauthors = Van Kammen DP, Murphy DL | title = Attenuation of the euphoriant and activating effects of d- and l-amphetamine by lithium carbonate treatment | journal = Psychopharmacologia | volume = 44 | issue = 3 | pages = 215–224 | date = November 1975 | pmid = 1824 | doi = 10.1007/BF00428897 | url = | quote = Seven of nine depressed patients experienced a 4.3-fold increase in rated euphoria and activation following 30 mg d-amphetamine in a replicated dose, double blind study. d-Amphetamine was 2 to 2.3-fold more effective in producing activation, euphoria, and antidepressant effects than the same dose of l-amphetamine.}}</ref> With very large doses, ranging from 270 to 640{{nbsp}}mg, 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.<ref name="SmithDavis1977" /> 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.<ref name="HealSmithGosden2013" />
+In addition to inducing norepinephrine release in the brain, levoamphetamine and dextroamphetamine induce the release of [[epinephrine]] (adrenaline) in the [[peripheral nervous system|peripheral]] [[sympathetic nervous system]] and this is related to their [[cardiovascular]] effects.<ref name="HealSmithGosden2013" /> Although levoamphetamine is less potent than dextroamphetamine as a stimulant, it is approximately [[equipotent]] with dextroamphetamine in producing various peripheral effects, including [[vasoconstriction]], [[vasopressor|vasopression]], and other cardiovascular effects.<ref name="BielBopp1978" />
+Similarly to dextroamphetamine, levoamphetamine has been found to improve symptoms in a [[animal model]] of ADHD, the [[spontaneously hypertensive rat]] (SHR), including improving [[sustained attention]] and reducing [[hyperactivity|overactivity]] and [[impulsivity]].<ref name="Kantak2022">{{cite journal | vauthors = Kantak KM | title = Rodent models of attention-deficit hyperactivity disorder: An updated framework for model validation and therapeutic drug discovery | journal = Pharmacol Biochem Behav | volume = 216 | issue = | pages = 173378 | date = May 2022 | pmid = 35367465 | doi = 10.1016/j.pbb.2022.173378 | url = }}</ref><ref name="TealIngramBubser2023">{{cite book | last=Teal | first=Laura B. | last2=Ingram | first2=Shalonda M. | last3=Bubser | first3=Michael | last4=McClure | first4=Elliott | last5=Jones | first5=Carrie K. | title=Drug Development in Psychiatry | chapter=The Evolving Role of Animal Models in the Discovery and Development of Novel Treatments for Psychiatric Disorders | publisher=Springer International Publishing | publication-place=Cham | volume=30 | date=2023 | isbn=978-3-031-21053-2 | doi=10.1007/978-3-031-21054-9_3 | page=37–99}}</ref><ref name="Sagvolden2011">{{cite journal | vauthors = Sagvolden T | title = Impulsiveness, overactivity, and poorer sustained attention improve by chronic treatment with low doses of l-amphetamine in an animal model of Attention-Deficit/Hyperactivity Disorder (ADHD) | journal = Behav Brain Funct | volume = 7 | issue = | pages = 6 | date = March 2011 | pmid = 21450079 | pmc = 3086861 | doi = 10.1186/1744-9081-7-6 | url = }}</ref><ref name="SagvoldenXu2008">{{cite journal | vauthors = Sagvolden T, Xu T | title = l-Amphetamine improves poor sustained attention while d-amphetamine reduces overactivity and impulsiveness as well as improves sustained attention in an animal model of Attention-Deficit/Hyperactivity Disorder (ADHD) | journal = Behav Brain Funct | volume = 4 | issue = | pages = 3 | date = January 2008 | pmid = 18215285 | pmc = 2265273 | doi = 10.1186/1744-9081-4-3 | url = }}</ref> 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.<ref name="HealSmithGosden2013" /><ref name="SmithDavis1977" />
+===Pharmacokinetics===
+The [[pharmacokinetics]] of levoamphetamine have been studied.<ref name="MarkowitzPatrick2017" /> Usually this has been [[oral administration|orally]] in [[combination drug|combination]] with [[dextroamphetamine]] at different ratios.<ref name="MarkowitzPatrick2017" /> The pharmacokinetics of levoamphetamine have also been studied as a [[metabolite]] of [[selegiline]].<ref name="HeinonenLammintausta1991" /><ref name="KraemerMaurer2002" />
+====Absorption====
+The [[Tmax (pharmacology)|time to peak]] levels of levoamphetamine with [[immediate-release]] (IR) formulations of [[amphetamine]] ranges from 2.5 to 3.5{{nbsp}}hours and with [[extended-release]] (ER) formulations ranges from 5.3 to 8.2{{nbsp}}hours depending on the formulation and the study.<ref name="MarkowitzPatrick2017" /> For comparison, the time to peak levels of [[dextroamphetamine]] with IR formulations ranges from 2.4 to 3.3{{nbsp}}hours and with ER formulations ranges from 4.0 to 8.0{{nbsp}}hours.<ref name="MarkowitzPatrick2017" /> The [[Cmax (pharmacology)|peak]] levels of levoamphetamine are proportionally similar to those of dextroamphetamine with administration of amphetamine at different ratios.<ref name="MarkowitzPatrick2017" /> With a single oral dose of 10{{nbsp}}mg racemic amphetamine (a 1:1 ratio of enantiomers, or 5{{nbsp}}mg dextroamphetamine and 5{{nbsp}}mg levoamphetamine), peak levels of dextroamphetamine were 14.7{{nbsp}}ng/mL and peak levels of levoamphetamine were 12.0{{nbsp}}ng/mL in one study.<ref name="MarkowitzPatrick2017" />
+During oral [[selegiline]] therapy at a dosage of 10{{nbsp}}mg/day, circulating levels of levoamphetamine have been found to be 6 to 8{{nbsp}}ng/mL and levels of [[levomethamphetamine]] have been reported to be 9 to 14{{nbsp}}ng/mL.<ref name="HeinonenLammintausta1991" /> 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 [[side effect]]s of selegiline.<ref name="HeinonenLammintausta1991" />
+====Distribution====
+The [[plasma protein binding]] of levoamphetamine is 31.7%, whereas that of dextroamphetamine was 29.0% in the same study.<ref name="LosackerRoehrich2021">{{cite journal | vauthors = Losacker M, Roehrich J, Hess C | title = Enantioselective determination of plasma protein binding of common amphetamine-type stimulants | journal = J Pharm Biomed Anal | volume = 205 | issue = | pages = 114317 | date = October 2021 | pmid = 34419812 | doi = 10.1016/j.jpba.2021.114317 | url = | quote = Amphetamine-type stimulants (ATS) like amphetamine ('speed'), methamphetamine ('crystal meth') and 3,4-methylenedioxy-N-methylamphetamine (MDMA, 'ecstasy') represent some of the most frequently abused drugs worldwide. [...] The enantiomers of these four compounds exhibit different pharmacokinetic and pharmacodynamic properties. According to the free drug theory, the pharmacological properties of a substance are dependent on its plasma protein binding (PPB). However, data on PPB of stimulant enantiomers in humans are rare or non-existent. [...] For (R)-amphetamine a slightly but significantly higher PPB was found compared to the (S)-enantiomer (31.7 % vs 29.0 %).}}</ref>
+====Metabolism====
+The pharmacokinetics of levoamphetamine generated as a [[metabolite]] from [[selegiline]] have been found not to significantly vary in [[CYP2D6]] [[poor metabolizer]]s versus [[extensive metabolizer]]s, suggesting that CYP2D6 is minimally involved in the [[metabolism]] of levoamphetamine.<ref name="KraemerMaurer2002">{{cite journal | vauthors = Kraemer T, Maurer HH | title = Toxicokinetics of amphetamines: metabolism and toxicokinetic data of designer drugs, amphetamine, methamphetamine, and their N-alkyl derivatives | journal = Ther Drug Monit | volume = 24 | issue = 2 | pages = 277–89 | date = April 2002 | pmid = 11897973 | doi = 10.1097/00007691-200204000-00009 | url = | quote = [...] in vivo studies with five poor and eight extensive metabolizers by Scheinin et al (61) showed that CYP2D6 polymorphism was not crucial for the disposition of selegiline. These authors did not find significant differences in the pharmacokinetic parameters of selegiline, desmethylselegiline, and R(−)- amphetamine between poor metabolizers and extensive metabolizers. However, the area under the serum concentration-time curve values of R(−)-methamphetamine were, on average, 46% higher in poor metabolizers than in extensive metabolizers.}}</ref><ref name="ScheininAnttilaDahl1998">{{cite journal | vauthors = Scheinin H, Anttila M, Dahl ML, Karnani H, Nyman L, Taavitsainen P, Pelkonen O, Bertilsson L | title = CYP2D6 polymorphism is not crucial for the disposition of selegiline | journal = Clin Pharmacol Ther | volume = 64 | issue = 4 | pages = 402–411 | date = October 1998 | pmid = 9797797 | doi = 10.1016/S0009-9236(98)90071-6 | url = }}</ref>
+====Elimination====
+The mean [[elimination half-life]] of levoamphetamine ranges from 12.0 to 15.2{{nbsp}}hours in different studies.<ref name="MarkowitzPatrick2017" /> For comparison, the mean elimination half-life of dextroamphetamine ranges from 10.1 to 12.4{{nbsp}}hours in different studies.<ref name="MarkowitzPatrick2017" />
+With [[selegiline]] at a oral dose of 10{{nbsp}}mg, levoamphetamine and levomethamphetamine are [[elimination (pharmacology)|eliminated]] in [[urine]] and recovery of levoamphetamine is 9 to 30% (or about 1–3{{nbsp}}mg) while that of levomethamphetamine is 20 to 60% (or about 2–6{{nbsp}}mg).<ref name="HeinonenLammintausta1991" />
+==Chemistry==
+Levoamphetamine is a [[substituted phenethylamine]] and [[substituted amphetamine|amphetamine]]. It is also known as <small>L</small>-α-methyl-β-phenylethylamine or as (2''R'')-1-phenylpropan-2-amine.<ref name="PubChem" /> Levoamphetamine is the [[levorotatory]] [[stereoisomer]] of the amphetamine molecule. [[Racemic]] amphetamine contains two [[enantiomer|optical isomer]]s in equal amounts, [[dextroamphetamine]] (the [[dextrorotatory]] enantiomer) and levoamphetamine.<ref name="Adderall XR FDA label" /><ref name="Adderall FDA label" />
+==History==
+[[Amphetamine]], a [[racemate|racemic mixture]] of [[dextroamphetamine]] and levoamphetamine, was first discovered in 1910.<ref name="HealSmithGosden2013" /> However, it was not until 1927 that amphetamine was [[chemical synthesis|synthesized]] by [[Gordon Alles]] and was studied by him in animals and humans.<ref name="HealSmithGosden2013" /> This eventually led to the discovery of the stimulating effects of amphetamine in humans.<ref name="HealSmithGosden2013" /> 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.<ref name="HealSmithGosden2013" /> It was indicated for the treatment of [[narcolepsy]], mild [[depression (mood)|depression]], [[parkinsonism]], and a variety of other conditions.<ref name="HealSmithGosden2013" /> Dextroamphetamine was found to be the more [[potency (pharmacology)|potent]] of the two [[enantiomer]]s of amphetamine and was introduced as an enantiopure drug under the brand name Dexedrine in 1937.<ref name="HealSmithGosden2013" /> Consequent to its lower potency, levoamphetamine has received far less attention than racemic amphetamine or dextroamphetamine.<ref name="HealSmithGosden2013" />
+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.<ref name="HealSmithGosden2013" /> As a result, it was marketed as an [[enantiopure]] drug under the brand name Cydril for the treatment of ADHD in the 1970s.<ref name="HealSmithGosden2013" /><ref name="ArnoldWenderMcCloskey1972">{{cite journal | vauthors = Arnold LE, Wender PH, McCloskey K, Snyder SH | title = Levoamphetamine and dextroamphetamine: comparative efficacy in the hyperkinetic syndrome. Assessment by target symptoms | journal = Arch Gen Psychiatry | volume = 27 | issue = 6 | pages = 816–22 | date = December 1972 | pmid = 4564954 | doi = 10.1001/archpsyc.1972.01750300078015 | url = }}</ref> However, it was reported in 1976 that racemic amphetamine was less effective than dextroamphetamine in treating ADHD.<ref name="HealSmithGosden2013" /> As a result of this study, use of racemic amphetamine in the treatment of ADHD dramatically declined in favor of dextroamphetamine.<ref name="HealSmithGosden2013" /> Enantiopure levoamphetamine was eventually discontinued and is no longer available today.<ref name="HealSmithGosden2013" />
+==Research==
+Levoamphetamine as an [[enantiopure]] drug has been studied in the past in a variety of contexts.<ref name="SilverstoneWells1980">{{cite book | vauthors = Silverstone T, Wells B | title=Amphetamines and Related Stimulants: Chemical, Biological, Clinical, and Sociological Aspects | chapter=Clinical Psychopharmacology of Amphetamine and Related Compounds | publisher=CRC Press | date=1980 | isbn=978-0-429-27984-3 | doi=10.1201/9780429279843-10 | pages=147–160 | quote = A comparison of dextroamphetamine and levoamphetamine revealed that the dextrorotatory isomer was the more potent in elevating mood in normal subjects, being at least twice as potent as the levo form.35 [...] Narcolepsy was one of the first conditions to be treated successfully with amphetamine3 and remains one of the few (some would say the only) clinical indications for its use. While the required oral dose of dextroamphetamine (Dexedrine®) ranges from 5 to 120 mg/day, most patients respond to 10 mg two to four times daily. [...] The closely related compound methylphenidate (Ritalin®), 20 mg two to four times daily, has been shown to be as effective as dextroamphetamine but with less likelihood of causing side effects.61 The same is true of levoamphetamine.62 [...] Nevertheless, as amphetamine has an action on dopaminergic pathways it was considered worthwhile to examine the effects of amphetamine under controlled conditions.95 Twenty patients, all on other anti-Parkinsonian drugs, were studied. There was some subjective improvement in a proportion (less than half) of the patients when they received either dextroamphetamine or levoamphetamine, but there was little objective improvement. The authors remarked that amphetamine was unlikely to have worked anyway in Parkinson's disease as it acts mainly by releasing dopamine and noradrenaline from presynaptic neurons; as the underlying pathology involves a reduction of presynaptic dopamine, there would be insufficient dopamine for amphetamine to release.}}</ref> These include its effects in and/or treatment of [[mood (psychology)|mood]],<ref name="SilverstoneWells1980" /> "[[minimal brain dysfunction]]",<ref name="ArnoldHuestisSmeltzer1976">{{cite journal | vauthors = Arnold LE, Huestis RD, Smeltzer DJ, Scheib J, Wemmer D, Colner G | title = Levoamphetamine vs dextroamphetamine in minimal brain dysfunction. Replication, time response, and differential effect by diagnostic group and family rating | journal = Arch Gen Psychiatry | volume = 33 | issue = 3 | pages = 292–301 | date = March 1976 | pmid = 769721 | doi = 10.1001/archpsyc.1976.01770030012002 | url = }}</ref> [[narcolepsy]],<ref name="SilverstoneWells1980" /><ref name="ParkesFenton1973">{{cite journal | vauthors = Parkes JD, Fenton GW | title = Levo(-) amphetamine and dextro(+) amphetamine in the treatment of narcolepsy | journal = J Neurol Neurosurg Psychiatry | volume = 36 | issue = 6 | pages = 1076–81 | date = December 1973 | pmid = 4359162 | pmc = 1083612 | doi = 10.1136/jnnp.36.6.1076 | url = }}</ref> "[[hyperkinetic disorder|hyperkinetic syndrome]]" and [[aggression]],<ref name="ArnoldKirilcukCorson1973">{{cite journal | vauthors = Arnold LE, Kirilcuk V, Corson SA, Corson EO | title = Levoamphetamine and dextroamphetamine: differential effect on aggression and hyperkinesis in children and dogs | journal = Am J Psychiatry | volume = 130 | issue = 2 | pages = 165–70 | date = February 1973 | pmid = 4568123 | doi = 10.1176/ajp.130.2.165 | url = }}</ref><ref name="ArnoldWenderMcCloskey1972">{{cite journal | vauthors = Arnold LE, Wender PH, McCloskey K, Snyder SH | title = Levoamphetamine and dextroamphetamine: comparative efficacy in the hyperkinetic syndrome. Assessment by target symptoms | journal = Arch Gen Psychiatry | volume = 27 | issue = 6 | pages = 816–22 | date = December 1972 | pmid = 4564954 | doi = 10.1001/archpsyc.1972.01750300078015 | url = }}</ref> [[sleep]],<ref name="GillinvanKammenGraves1975">{{cite journal | vauthors = Gillin JC, van Kammen DP, Graves J, Murphy D | title = Differential effects of D- and L-amphetamine on the sleep of depressed patients | journal = Life Sci | volume = 17 | issue = 8 | pages = 1223–1240 | date = October 1975 | pmid = 172755 | doi = 10.1016/0024-3205(75)90132-0 | url = }}</ref><ref name="HartmannCravens1976">{{cite journal | vauthors = Hartmann E, Cravens J | title = Sleep: effects of d- and l-amphetamine in man and in rat | journal = Psychopharmacology (Berl) | volume = 50 | issue = 2 | pages = 171–175 | date = November 1976 | pmid = 826958 | doi = 10.1007/BF00430488 | url = }}</ref> [[schizophrenia]],<ref name="JanowskyDavis1976">{{cite journal | vauthors = Janowsky DS, Davis JM | title = Methylphenidate, dextroamphetamine, and levamfetamine. Effects on schizophrenic symptoms | journal = Arch Gen Psychiatry | volume = 33 | issue = 3 | pages = 304–308 | date = March 1976 | pmid = 769722 | doi = 10.1001/archpsyc.1976.01770030024003 | url = }}</ref> [[wakefulness]],<ref name="HartmannOrzackBranconnier1977">{{cite journal | vauthors = Hartmann E, Orzack MH, Branconnier R | title = Sleep deprivation deficits and their reversal by d- and l-amphetamine | journal = Psychopharmacology (Berl) | volume = 53 | issue = 2 | pages = 185–189 | date = July 1977 | pmid = 408844 | doi = 10.1007/BF00426490 | url = }}</ref> [[Tourette's syndrome]],<ref name="CaineLudlowPolinsky1984">{{cite journal | vauthors = Caine ED, Ludlow CL, Polinsky RJ, Ebert MH | title = Provocative drug testing in Tourette's syndrome: d- and l-amphetamine and haloperidol | journal = J Am Acad Child Psychiatry | volume = 23 | issue = 2 | pages = 147–152 | date = March 1984 | pmid = 6585416 | doi = 10.1097/00004583-198403000-00005 | url = }}</ref> and [[Parkinson's disease]], among others.<ref name="SilverstoneWells1980" /><ref name="ParkesTarsyMarsden1975">{{cite journal | vauthors = Parkes JD, Tarsy D, Marsden CD, Bovill KT, Phipps JA, Rose P, Asselman P | title = Amphetamines in the treatment of Parkinson's disease | journal = J Neurol Neurosurg Psychiatry | volume = 38 | issue = 3 | pages = 232–7 | date = March 1975 | pmid = 1097600 | pmc = 491901 | doi = 10.1136/jnnp.38.3.232 | url = }}</ref> Levoamphetamine has been studied in the treatment of [[multiple sclerosis]] in more modern studies and has been reported to improve [[cognition]] and [[memory]] as well.<ref name="Patti2012">{{cite journal | vauthors = Patti F | title = Treatment of cognitive impairment in patients with multiple sclerosis | journal = Expert Opin Investig Drugs | volume = 21 | issue = 11 | pages = 1679–1699 | date = November 2012 | pmid = 22876911 | doi = 10.1517/13543784.2012.716036 | url = }}</ref><ref name="LoveraKovner2012">{{cite journal | vauthors = Lovera J, Kovner B | title = Cognitive impairment in multiple sclerosis | journal = Curr Neurol Neurosci Rep | volume = 12 | issue = 5 | pages = 618–627 | date = October 2012 | pmid = 22791241 | pmc = 4581520 | doi = 10.1007/s11910-012-0294-3 | url = }}</ref><ref name="RoyBenedictDrake2016">{{cite journal | vauthors = Roy S, Benedict RH, Drake AS, Weinstock-Guttman B | title = Impact of Pharmacotherapy on Cognitive Dysfunction in Patients with Multiple Sclerosis | journal = CNS Drugs | volume = 30 | issue = 3 | pages = 209–225 | date = March 2016 | pmid = 26884145 | doi = 10.1007/s40263-016-0319-6 | url = }}</ref><ref name="MorrowKaushikVarevics2009">{{cite journal | vauthors = Morrow SA, Kaushik T, Zarevics P, Erlanger D, Bear MF, Munschauer FE, Benedict RH | title = The effects of L-amphetamine sulfate on cognition in MS patients: results of a randomized controlled trial | journal = J Neurol | volume = 256 | issue = 7 | pages = 1095–102 | date = July 2009 | pmid = 19263186 | doi = 10.1007/s00415-009-5074-x | url = }}</ref><ref name="BenedictMunschauerZarevics2008">{{cite journal | vauthors = Benedict RH, Munschauer F, Zarevics P, Erlanger D, Rowe V, Feaster T, Carpenter RL | title = Effects of l-amphetamine sulfate on cognitive function in multiple sclerosis patients | journal = J Neurol | volume = 255 | issue = 6 | pages = 848–852 | date = June 2008 | pmid = 18481035 | doi = 10.1007/s00415-008-0760-7 | url = }}</ref><ref name="SumowskiChiaravallotiErlanger2011">{{cite journal | vauthors = Sumowski JF, Chiaravalloti N, Erlanger D, Kaushik T, Benedict RH, DeLuca J | title = L-amphetamine improves memory in MS patients with objective memory impairment | journal = Mult Scler | volume = 17 | issue = 9 | pages = 1141–1145 | date = September 2011 | pmid = 21561956 | doi = 10.1177/1352458511404585 | url = }}</ref>
+==Notes==
 {{Reflist|group=note}}
-== References ==
+==References==
 {{Reflist}}
@@ Line 85: / Line 147: @@
 {{Monoamine releasing agents}}
 {{Phenethylamines}}
 {{Portal bar|Medicine|Chemistry|Biology}}
@@ Line 92: / Line 153: @@
 [[Category:Drugs acting on the nervous system]]
 [[Category:Enantiopure drugs]]
+[[Category:Euphoriants]]
+[[Category:Human drug metabolites]]
 [[Category:Norepinephrine-dopamine releasing agents]]
+[[Category:Phenethylamines]]
 [[Category:Stimulants]]
 [[Category:Substituted amphetamines]]
+[[Category:Sympathomimetics]]
 [[Category:TAAR1 agonists]]
 [[Category:VMAT inhibitors]]

v t e Stimulants
Adamantanes	Adapromine Amantadine Bromantane Memantine Rimantadine
Adenosine antagonists	8-Chlorotheophylline 8-Cyclopentyltheophylline 8-Phenyltheophylline Aminophylline Caffeine CGS-15943 Dimethazan Istradefylline Paraxanthine SCH-58261 Theobromine Theophylline
Alkylamines	Cyclopentamine Cypenamine Cyprodenate Heptaminol Isometheptene Methylhexaneamine Octodrine Propylhexedrine Tuaminoheptane
Ampakines	CX-516 CX-546 CX-614 CX-691 CX-717 IDRA-21 LY-404,187 LY-503,430 Nooglutyl Org 26576 PEPA S-18986 Sunifiram Unifiram
Arylcyclohexylamines	Benocyclidine Dieticyclidine Esketamine Eticyclidine Gacyclidine Ketamine Phencyclamine Phencyclidine Rolicyclidine Tenocyclidine Tiletamine
Benzazepines	6-Br-APB SKF-77434 SKF-81297 SKF-82958
Cathinones	3-FMC 3-MMC 3,4-DMMC 4-BMC 4-CMC 4-Methylbuphedrone 4-Methylcathinone 4-MEAP 4-Methylpentedrone Amfepramone Benzedrone Buphedrone Bupropion Butylone Cathinone Dimethylcathinone Ethcathinone Ethylone Flephedrone Hexedrone Isoethcathinone Mephedrone Methcathinone Methedrone Methylenedioxycathinone Methylone Mexedrone N-Ethylbuphedrone N-Ethylhexedrone Pentedrone Pentylone Phthalimidopropiophenone
Cholinergics	A-84,543 A-366,833 ABT-202 ABT-418 AR-R17779 Altinicline Anabasine Arecoline Bradanicline Cotinine Cytisine Dianicline Epibatidine Epiboxidine GTS-21 Ispronicline Nicotine PHA-543,613 PNU-120,596 PNU-282,987 Pozanicline Rivanicline Sazetidine A SIB-1553A SSR-180,711 TC-1698 TC-1827 TC-2216 Tebanicline UB-165 Varenicline WAY-317,538
Convulsants	Anatoxin-a Bicuculline DMCM Flurothyl Gabazine Pentetrazol Picrotoxin Strychnine Thujone
Eugeroics	Adrafinil Armodafinil CRL-40,940 CRL-40,941 Fluorenol Modafinil
Oxazolines	4-Methylaminorex Aminorex Clominorex Cyclazodone Fenozolone Fluminorex Pemoline Thozalinone
Phenethylamines	1-(4-Methylphenyl)-2-aminobutane 1-Methylamino-1-(3,4-methylenedioxyphenyl)propane 2-Fluoroamphetamine 2-Fluoromethamphetamine 2-OH-PEA 2-Phenyl-3-aminobutane 2,3-MDA 3-Fluoroamphetamine 3-Fluoroethamphetamine 3-Methoxyamphetamine 3-Methylamphetamine 4-Fluoroamphetamine 4-Fluoromethamphetamine 4-MA 4-MMA 4-MTA 6-FNE AL-1095 Alfetamine a-Ethylphenethylamine Amfecloral Amfepentorex Amidephrine 2-Amino-1,2-dihydronaphthalene 2-Aminoindane 5-(2-Aminopropyl)indole 2-Aminotetralin Acridorex Amphetamine (Dextroamphetamine, Levoamphetamine) Amphetaminil Arbutamine β-Methylphenethylamine β-Phenylmethamphetamine Benfluorex Benzphetamine BDB BOH 3-Benzhydrylmorpholine BPAP Camfetamine Cathine Chlorphentermine Cilobamine Cinnamedrine Clenbuterol Clobenzorex Cloforex Clortermine Cypenamine D-Deprenyl Denopamine Dimethoxyamphetamine Dimethylamphetamine Dobutamine DOPA (Dextrodopa, Levodopa) Dopamine Dopexamine Droxidopa EBDB Ephedrine Epinephrine Epinine Etafedrine Ethylnorepinephrine Etilamfetamine Etilefrine Famprofazone Fencamfamin Fencamine Fenethylline Fenfluramine (Dexfenfluramine, Levofenfluramine) Fenproporex Feprosidnine Fludorex Formetorex Furfenorex Gepefrine Hexapradol HMMA Hordenine 4-Hydroxyamphetamine 5-Iodo-2-aminoindane Ibopamine Indanylamphetamine Iofetamine Isoetarine Isoprenaline L-Deprenyl (Selegiline) Lefetamine Lisdexamfetamine Lophophine MBDB MDA (tenamfetamine) MDBU MDEA MDMA (midomafetamine) MDMPEA MDOH MDPR MDPEA Mefenorex Mephentermine Metanephrine Metaraminol Mesocarb Methamphetamine (Dextromethamphetamine, Levomethamphetamine) Methoxamine Methoxyphenamine MMA Methoxyphenamine MMDA MMDMA MMMA Morforex N,alpha-Diethylphenylethylamine N,N-Dimethylphenethylamine Naphthylamphetamine Nisoxetine Norepinephrine Norfenefrine Norfenfluramine Normetanephrine L-Norpseudoephedrine Octopamine Orciprenaline Ortetamine Oxifentorex Oxilofrine PBA PCA PCMA PHA Pentorex Phenatine Phenpromethamine Phentermine Phenylalanine Phenylephrine Phenylpropanolamine Pholedrine PIA PMA PMEA PMMA PPAP Prenylamine Propylamphetamine Pseudoephedrine Ropinirole Salbutamol (Levosalbutamol) Sibutramine Solriamfetol Synephrine Theodrenaline Tiflorex Tranylcypromine Tyramine Tyrosine Xylopropamine Zylofuramine
Phenylmorpholines	3-Fluorophenmetrazine Fenbutrazate Fenmetramide G-130 Manifaxine Morazone Morforex Oxaflozane PD-128,907 Phendimetrazine Phenmetrazine 2-Phenyl-3,6-dimethylmorpholine Pseudophenmetrazine Radafaxine
Piperazines	2C-B-BZP 3C-PEP BZP CM156 DBL-583 GBR-12783 GBR-12935 GBR-13069 GBR-13098 GBR-13119 JJC8-088 MeOPP MBZP oMPP Vanoxerine
Piperidines	1-Benzyl-4-(2-(diphenylmethoxy)ethyl)piperidine 2-Benzylpiperidine 2-Methyl-3-phenylpiperidine 3,4-Dichloromethylphenidate 4-Benzylpiperidine 4-Fluoromethylphenidate 4-Methylmethylphenidate Desoxypipradrol Difemetorex Diphenylpyraline Ethylnaphthidate Ethylphenidate Methylnaphthidate Isopropylphenidate JZ-IV-10 Methylphenidate (Dexmethylphenidate) Nocaine Phacetoperane Pipradrol Propylphenidate Serdexmethylphenidate SCH-5472
Pyrrolidines	2-Diphenylmethylpyrrolidine 4-Cl-PVP 5-DBFPV α-PPP α-PBP α-PCYP α-PHiP α-PHP α-PHPP α-PVP α-PVT Diphenylprolinol DMPVP FPOP FPVP MDPPP MDPBP MPBP MPHP MPPP MOPVP MOPPP Indapyrophenidone MDPV Naphyrone PEP Picilorex Prolintane Pyrovalerone
Racetams	Oxiracetam Phenylpiracetam Phenylpiracetam hydrazide
Tropanes	4-fluorotropacocaine 4'-Fluorococaine Altropane (IACFT) Brasofensine CFT (WIN 35,428) β-CIT (RTI-55) Cocaethylene Cocaine Dichloropane (RTI-111) Difluoropine FE-β-CPPIT FP-β-CPPIT Ioflupane (¹²³I) Norcocaine PIT PTT RTI-31 RTI-32 RTI-51 RTI-112 RTI-113 RTI-120 RTI-121 (IPCIT) RTI-126 RTI-150 RTI-177 RTI-229 RTI-336 RTI-354 RTI-371 RTI-386 Salicylmethylecgonine Tesofensine Troparil (β-CPT, WIN 35,065-2) Tropoxane WF-23 WF-33
Tryptamines	4-HO-αMT 4-Methyl-αET 4-Methyl-αMT 5-Chloro-αMT 5-Fluoro-αMT 5-MeO-αET 5-MeO-αMT 5-MeO-DIPT 6-Fluoro-αMT 7-Methyl-αET αET αMT
Others	2-MDP 3,3-Diphenylcyclobutanamine Amfonelic acid Amineptine Amiphenazole Atipamezole Atomoxetine Bemegride Benzydamine BTQ BTS 74,398 Centanafadine Ciclazindol Clofenciclan Cropropamide Crotetamide D-161 Desipramine Diclofensine Dimethocaine Efaroxan Etamivan Fenisorex Fenpentadiol Gamfexine Gilutensin GSK1360707F GYKI-52895 Hexacyclonate Idazoxan Indanorex Indatraline JNJ-7925476 Lazabemide Leptacline Lomevactone LR-5182 Mazindol Meclofenoxate Medifoxamine Mefexamide Methamnetamine Methastyridone Methiopropamine Naphthylaminopropane Nefopam Nikethamide Nomifensine O-2172 Oxaprotiline PNU-99,194 PRC200-SS Rasagiline Rauwolscine Rubidium chloride Setazindol Tametraline Tandamine Thiopropamine Thiothinone Trazium UH-232 Yohimbine
ATC code: N06B

v t e ADHD pharmacotherapies
CNSTooltip central nervous system stimulants	Amphetamine (Mixed amphetamine salts, Levoamphetamine, Dextroamphetamine, Lisdexamfetamine) Methamphetamine Methylphenidate Dexmethylphenidate Serdexmethylphenidate (+dexmethylphenidate)
Non-classical CNS stimulants	Armodafinil Atomoxetine Modafinil Viloxazine
α₂-adrenoceptor agonists	Clonidine Guanfacine
Antidepressants	Amitriptyline Bupropion Buspirone Desipramine Duloxetine Imipramine Milnacipran Moclobemide Nortriptyline Reboxetine Venlafaxine
Miscellaneous/others	Amantadine Carbamazepine
Related articles	Attention deficit hyperactivity disorder (ADHD) Attention deficit hyperactivity disorder management Hypokalemic sensory overstimulation Monoamine releasing agent Dopamine (DA) Dopamine transporter (DAT) Dopamine reuptake inhibitor (DRI) Norepinephrine (NE) Norepinephrine transporter (NET) Norepinephrine reuptake inhibitor (NRI) Serotonin (5-HT) Serotonin transporter (SERT) Selective serotonin reuptake inhibitor (SSRI) Serotonin-norepinephrine reuptake inhibitor (SNRI) Norepinephrine-dopamine reuptake inhibitor (NDRI) Serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI)

v t e Phenethylamines
Phenethylamines	Psychedelics: 25B-NBOMe 25C-NBOMe 25D-NBOMe 25I-NBOMe 25N-NBOMe 2C-B 2C-B-AN 2C-Bn 2C-Bu 2C-C 2C-CN 2C-CP 2C-D 2C-E 2C-EF 2C-F 2C-G 2C-G-1 2C-G-2 2C-G-3 2C-G-4 2C-G-5 2C-G-6 2C-G-N 2C-H 2C-I 2C-iP 2C-N 2C-NH2 2C-O 2C-O-4 2C-P 2C-Ph 2C-SE 2C-T 2C-T-2 2C-T-3 2C-T-4 2C-T-5 2C-T-6 2C-T-7 2C-T-8 2C-T-9 2C-T-10 2C-T-11 2C-T-12 2C-T-13 2C-T-14 2C-T-15 2C-T-16 2C-T-17 2C-T-18 2C-T-19 2C-T-20 2C-T-21 2C-T-22 2C-T-22.5 2C-T-23 2C-T-24 2C-T-25 2C-T-27 2C-T-28 2C-T-30 2C-T-31 2C-T-32 2C-T-33 2C-TFE 2C-TFM 2C-YN 2C-V Allylescaline DESOXY Escaline Isoproscaline Jimscaline Macromerine MEPEA Mescaline Metaescaline Methallylescaline Proscaline Psi-2C-T-4 TCB-2 Stimulants: Phenylethanolamine Hordenine Phenethylamine Phenpromethamine α-Methylphenethylamine (amphetamine) β-Methylphenethylamine m-Methylphenethylamine N-Methylphenethylamine o-Methylphenethylamine p-Methylphenethylamine Methylphenidate Entactogens: Lophophine MDPEA MDMPEA Others: BOH DMPEA
Amphetamines	Psychedelics: 3C-AL 3C-BZ 3C-E 3C-MAL 3C-P Aleph Beatrice Bromo-DragonFLY D-Deprenyl DMA DMCPA DMMDA DOB DOC DOEF DOET DOI DOM DON DOPR DOTFM Ganesha MMDA MMDA-2 Psi-DOM TMA TeMA ZDCM-04 Stimulants: 2-FA 2-FMA 3-FA 3-FMA Acridorex Alfetamine Amfecloral Amfepentorex Amphetamine (Dextroamphetamine, Levoamphetamine) Amphetaminil Benfluorex Benzphetamine Cathine Clobenzorex Dimethylamphetamine Ephedrine Etilamfetamine Fencamfamin Fencamine Fenethylline Fenfluramine (Dexfenfluramine, Levofenfluramine) Fenproporex Flucetorex Fludorex Formetorex Furfenorex Gepefrine 4-Hydroxyamphetamine Iofetamine Isopropylamphetamine Lefetamine Lisdexamfetamine Mefenorex Metaraminol Methamphetamine (Dextromethamphetamine, Levomethamphetamine) Methoxyphenamine MMA Morforex Norfenfluramine L-Norpseudoephedrine N,alpha-Diethylphenylethylamine Oxifentorex Oxilofrine Ortetamine PBA PCA PFA PFMA PIA PMA PMEA PMMA Phenylpropanolamine Pholedrine Prenylamine Propylamphetamine Pseudoephedrine Sibutramine Tiflorex Tranylcypromine Xylopropamine Zylofuramine Entactogens: 4-FA 4-FMA 4-MA 4-MMA 4-MTA 5-APB 5-APDB 5-EAPB 5-IT 5-MAPB 5-MAPDB 6-APB 6-APDB 6-Chloro-MDMA 6-EAPB 6-IT 6-MAPB 6-MAPDB EDA IAP 2,3-MDA 3,4-MDA (tenamfetamine) MDEA MDHMA MDMA (midomafetamine) MDOH Methamnetamine MMDMA Naphthylaminopropane TAP Others: 3,4-DCA Amiflamine DiFMDA Selegiline (also D-Deprenyl)
Phentermines	Stimulants: Chlorphentermine Cloforex Clortermine Etolorex Mephentermine Pentorex Phentermine Entactogens: MDPH MDMPH Others: Cericlamine
Cathinones	Stimulants: 3-FMC 4-MC 4-BMC 4-CMC 4-EMC 4-FMC 4-MEC 4-MeMABP 4-MPD Amfepramone Benzedrone Brephedrone Buphedrone Bupropion Cathinone Dimethylcathinone Ethcathinone Eutylone Hydroxybupropion Methcathinone Methedrone NEB N-Ethylhexedrone N-Ethylpentedrone Pentedrone Pentylone Radafaxine Entactogens: 3,4-DMMC 3-MMC Butylone Ethylone Methylone Methylenedioxycathinone Mephedrone
Phenylisobutylamines	Entactogens: 4-CAB 4-MAB Ariadne BDB Butylone EBDB Eutylone MBDB Stimulants: Phenylisobutylamine
Phenylalkylpyrrolidines	Stimulants: α-PBP α-PHP α-PPP α-PVP MDPBP MDPPP MDPV 4-MePBP 4-MePHP 4-MePPP MOPPP MOPVP MPBP MPHP MPPP Naphyrone PEP Prolintane Pyrovalerone
Catecholamines (and close relatives)	6-FNE 6-OHDA a-Me-DA a-Me-TRA Adrenochrome Ciladopa D-DOPA (Dextrodopa) Dimetofrine Dopamine Epinephrine Epinine Etilefrine Ethylnorepinephrine Fenclonine Ibopamine Isoprenaline Isoetarine L-DOPA (Levodopa) L-DOPS (Droxidopa) L-Phenylalanine L-Tyrosine m-Tyramine Metanephrine Metaraminol Metaterol Metirosine Methyldopa N,N-Dimethyldopamine Nordefrin (Levonordefrin) Norepinephrine Norfenefrine (m-Octopamine) Normetanephrine Orciprenaline p-Octopamine p-Tyramine Phenylephrine Synephrine
Miscellaneous	AL-LAD Amidephrine Arbutamine Cafedrine Denopamine Desvenlafaxine Diphenidine Dizocilpine Dobutamine Dopexamine Ephenidine Etafedrine ETH-LAD Famprofazone Fluorolintane Hexapradol IP-LAD Lysergic acid amide Lysergic acid 2-butyl amide Lysergic acid 2,4-dimethylazetidide Lysergic acid diethylamide Methoxamine Methoxphenidine MT-45 PARGY-LAD Phenibut PRO-LAD Pronethalol Salbutamol (Levosalbutamol) Solriamfetol Theodrenaline Thiamphenicol UWA-101 Venlafaxine