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Levmetamfetamine

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Levmetamfetamine
Clinical data
Trade namesVicks VapoInhaler, Everclear Inhaler, others
Other namesLevomethamphetamine; Levodesoxyephedrine
Routes of
administration		Medical: Intranasal
Recreational: By mouth, intravenous, insufflation, inhalation, suppository
Drug classNorepinephrine releasing agent; Sympathomimetic; Decongestant
Legal status
Legal status
Pharmacokinetic data
BioavailabilityOral: ~100%[2][3]
MetabolismLiver (CYP2D6)[5][6]
MetabolitesLevoamphetamine[2][4][3]
Elimination half-life10–15 hours[2][4][3]
ExcretionUrine (41–49% unchanged, 2–3% as levoamphetamine)[2][4][3]
Identifiers
  • (R)-N-methyl-1-phenylpropan-2-amine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard100.046.974 Edit this at Wikidata
Chemical and physical data
FormulaC10H15N
Molar mass149.237 g·mol−1
3D model (JSmol)
ChiralityLevorotatory enantiomer
  • N([C@@H](Cc1ccccc1)C)C
  • InChI=1S/C10H15N/c1-9(11-2)8-10-6-4-3-5-7-10/h3-7,9,11H,8H2,1-2H3/t9-/m1/s1 checkY
  • Key:MYWUZJCMWCOHBA-SECBINFHSA-N checkY
  (verify)

Levmetamfetamine, also known as l-desoxyephedrine or levomethamphetamine, and commonly sold under the brand name Vicks VapoInhaler among others, is an optical isomer of methamphetamine primarily used as a topical nasal decongestant.[2] It is used to treat nasal congestion from allergies and the common cold.[7] It was first used medically as decongestant beginning in 1958 and has been used for such purposes, primarily in the United States, since then.[8]

Medical uses

[edit]

Levmetamfetamine is used to treat nasal congestion related to the common cold and allergic rhinitis. It is available in the form of an inhaler containing 50 mg total per inhaler and delivering between 0.04 and 0.15 mg of the drug per inhalation.[2] Inhalers with a total of 113 mg levmetamfetamine were previously marketed in the United States, but the total amount was eventually reduced to 50 mg.[2]

Side effects

[edit]

When the nasal decongestant is taken in excess, levmetamfetamine has potential side effects. These would be similar to those of other decongestants.

Pharmacology

[edit]

Pharmacodynamics

[edit]
Monoamine release of levmetamfetamine and related agents (EC50Tooltip Half maximal effective concentration, nM)
Compound NETooltip Norepinephrine DATooltip Dopamine 5-HTTooltip Serotonin Ref
Phenethylamine 10.9 39.5 >10000 [9][10][11]
Amphetamine ND ND ND ND
  D-Amphetamine 6.6–7.2 5.8–24.8 698–1765 [12][13]
  L-Amphetamine 9.5 27.7 ND [10][11]
Racephedrine ND ND ND ND
  Ephedrine (D-) 43.1–72.4 236–1350 >10000 [12]
  L-Ephedrine 218 2104 >10000 [12][14]
Methamphetamine ND ND ND ND
  D-Methamphetamine 12.3–13.8 8.5–24.5 736–1291.7 [12][15]
  L-Methamphetamine 28.5 416 4640 [12]
Racemic pseudoephedrine ND ND ND ND
  D-Pseudoephedrine 4092 9125 >10000 [14]
  Pseudoephedrine (L-) 224 1988 >10000 [14]
Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs: [16][17]

Levmetamfetamine acts as a selective norepinephrine releasing agent.[12][16][18][4] The potencies of levmetamfetamine, levoamphetamine, dextromethamphetamine, and dextroamphetamine in terms of norepinephrine release in vitro and in vivo in rats are all similar.[19][20][21][22][16]

Conversely, whereas dextromethamphetamine and dextroamphetamine are relatively balanced releasers of dopamine and norepinephrine in vitro, levmetamfetamine is about 15- to 20-fold less potent in inducing dopamine release relative to norepinephrine release.[16][18][4][12][21] Moreover, whereas levoamphetamine is about 3- to 5-fold less potent in terms of dopamine release than dextroamphetamine in vivo, levmetamfetamine is dramatically less potent than dextromethamphetamine and substantially less potent than levoamphetamine in this regard.[20][19][22]

In accordance with the findings of catecholamine release studies, levmetamfetamine is 2- to 10-fold or more less potent than dextromethamphetamine in terms of psychostimulant-like effects in rodents.[23][24][25] For comparison, levoamphetamine is only 1- to 4-fold less potent than dextroamphetamine in its stimulating and reinforcing effects in monkeys and humans.[19][26]

The effects of levmetamfetamine are qualitatively distinct relative to those of racemic methamphetamine and dextromethamphetamine and it does not possess the same potential for euphoria or addiction that these drugs possesses.[2][25][27][4][22] In clinical studies, levmetamfetamine at oral doses of 1 to 10 mg has been found not to affect subjective drug responses, heart rate, blood pressure, core temperature, electrocardiography, respiration rate, oxygen saturation, or other clinical parameters.[2][3] As such, doses of levmetamfetamine of less than or equal to 10 mg have no significant physiological or subjective effects.[2][3] However, higher doses of levmetamfetamine, for instance 0.25 to 0.5 mg/kg (mean doses of ~18–37 mg) intravenously, have been reported to produce significant pharmacological effects, including increased heart rate and blood pressure, increased respiration rate, and subjective effects like intoxication and drug liking.[2][4] On the other hand, in contrast to dextromethamphetamine, levmetamfetamine also produces subjective "bad" or aversive drug effects.[18][4] Among the physiological effects of levmetamfetamine is vasoconstriction, which makes it useful for nasal decongestion.[28]

For comparison to levmetamfetamine, 5 to 60 mg oral doses of the related drug levoamphetamine have been used clinically and have been reported to produce significant pharmacological effects, for instance on wakefulness and mood.[29][30][31][26][note 1]

In addition to its norepinephrine-releasing activity, levmetamfetamine is also an agonist of the trace amine-associated receptor 1 (TAAR1).[32][33][34] Levmetamfetamine has also been found to act as a catecholaminergic activity enhancer (CAE), notably at much lower concentrations than its catecholamine releasing activity.[35][36][37][38][39] It is 1- to 10-fold less potent than selegiline but is 3- to 5-fold more potent than dextromethamphetamine in this action.[36][37][38] The CAE effects of such agents may be mediated by TAAR1 agonism.[40][39]

Pharmacokinetics

[edit]

Absorption

[edit]

The bioavailability of levmetamfetamine is approximately 100%.[2][3] The peak levels of levmetamfetamine range from 3.3 to 31.4 ng/mL with single oral doses of 1 to 10 mg and from 65.4 to 125.9 ng/mL with single intravenous doses of 0.25 to 0.5 mg/kg.[2][4][41] The area-under-the-curve (AUC) levels of levmetamfetamine range from 73.0 to 694.7 ng⋅h/mL with single oral doses of 1 to 10 mg and from 1,190.7 to 2,368.1 mg/kg with single intravenous doses of 0.25 to 0.5 mg/kg.[2][4][41]

Distribution

[edit]

The volume of distribution of levmetamfetamine is 288.5 to 315.5 L or 4.15 to 4.17 L/kg.[2][4][3]

Metabolism

[edit]

The pharmacokinetics of levmetamfetamine generated as a metabolite from selegiline have been found to be significantly different in CYP2D6 poor metabolizers versus extensive metabolizers.[5][6] Area-under-the-curve (AUC) levels of levmetamfetamine were 46% higher and its elimination half-life was 33% longer in CYP2D6 poor metabolizers compared to extensive metabolizers.[5][6] These findings suggest that CYP2D6 may be significantly involved in the metabolism of levmetamfetamine.[5][6]

Levmetamfetamine is metabolized into levoamphetamine in small amounts.[2][4][3]

Elimination

[edit]

Levmetamfetamine is excreted in urine 40.8 to 49.0% as unchanged levmetamfetamine and 2.1 to 3.3% as levoamphetamine.[2][4][3]

The mean elimination half-life of levmetamfetamine ranges between 10.2 and 15.0 hours.[2][4] For comparison, the elimination half-life of dextromethamphetamine was around 10.2 to 10.7 hours in the same studies.[2][4] The clearance of levmetamfetamine is 15.5 to 19.1 L/h or 0.221 L/h⋅kg.[2][4][3]

With selegiline at an oral dose of 10 mg, levmetamfetamine and levoamphetamine are eliminated in urine and recovery of levmetamfetamine is 20 to 60% (or about 2–6 mg) while that of levoamphetamine is 9 to 30% (or about 1–3 mg).[42]

Chemistry

[edit]

Levmetamfetamine, also known as L-α,N-dimethyl-β-phenylethylamine or as L-N-methylamphetamine, is a substituted phenethylamine and amphetamine.[2][43] It is the levorotatory enantiomer of methamphetamine.[2] Racemic methamphetamine contains two optical isomers in equal amounts, dextromethamphetamine (the dextrorotatory enantiomer) and levmetamfetamine.[2]

Detection in body fluids

[edit]

Levmetamfetamine can register on urine drug tests as either methamphetamine, amphetamine, or both, depending on the subject's metabolism and dosage. Levmetamfetamine metabolizes completely into levoamphetamine after a period of time.[44]

History

[edit]

Methamphetamine, a racemic mixture of dextromethamphetamine and levmetamfetamine, was first discovered and synthesized in 1919.[45][46] Methamphetamine was first introduced for medical use in 1938 in oral form under the brand name Pervitin in Germany.[45][46] Over-the-counter nasal decongestant inhalers containing enantiopure levmetamfetamine, originally labeled with the chemical name l-desoxyephedrine, were first introduced in 1958 under the brand name Vicks Inhaler.[8][47][48] By 1995, the brand name was changed to Vicks Vapor Inhaler.[49][50] In 1998, the United States Food and Drug Administration (FDA) required that the chemical name on the labeling be changed from l-desoxyephedrine to levmetamfetamine.[51]

Society and culture

[edit]

Recreational use

[edit]

As of 2006, there were no studies demonstrating "drug liking" scores of oral levmetamfetamine that are similar to racemic methamphetamine or dextromethamphetamine in either recreational users or medicinal users.[4] In any case, misuse of levmetamfetamine at high doses has been reported.[52][53][54][55]

In recent years, tighter controls in Mexico on certain methamphetamine precursors like ephedrine and pseudoephedrine has led to a greater percentage of illicit methamphetamine from Mexican drug cartels consisting of a higher ratio of levmetamfetamine to dextromethamphetamine within batches of racemic methamphetamine.[56]

Manufacturing

[edit]

The manufacturing of levmetamfetamine products for therapeutic use is done according to government regulations and pharmacopeia monographs. The most recent change in Food and Drug Administration regulations for levmetamfetamine inhalers was in 1994, with the adoption of a final monograph.[57]

Notes

[edit]
  1. ^ Smith & Davis (1977) reviewed 11 clinical studies of dextroamphetamine and levoamphetamine including doses and potency ratios in terms of a variety of psychological and behavioral effects.[26] The summaries of these studies are in Table 1 of the paper.[26]

References

[edit]
  1. ^ Anvisa (28 May 2024). "RDC Nº 877 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 877 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União. Archived from the original on 25 September 2024. Retrieved 25 September 2024.
  2. ^ a b c d e f g h i j k l m n o p q r s t u v w 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.
  3. ^ a b c d e f g h i j k Li L, Lopez JC, Galloway GP, Baggott MJ, Everhart T, Mendelson J (August 2010). "Estimating the intake of abused methamphetamines using experimenter-administered deuterium labeled R-methamphetamine: selection of the R-methamphetamine dose". Ther Drug Monit. 32 (4): 504–7. doi:10.1097/FTD.0b013e3181db82f2. PMC 3040572. PMID 20592647.
  4. ^ a b c d e f g h i j k l m n o p q Mendelson J, Uemura N, Harris D, Nath RP, Fernandez E, Jacob P, et al. (October 2006). "Human pharmacology of the methamphetamine stereoisomers". Clin Pharmacol Ther. 80 (4): 403–420. doi:10.1016/j.clpt.2006.06.013. PMID 17015058. The stereoisomers of methamphetamine produce markedly different dopamine, norepinephrine, and serotonin responses in various brain regions in rats.41,42 d-Methamphetamine (2 mg/kg) is more potent in releasing caudate dopamine than l-methamphetamine (12 and 18 mg/kg). By use of in vitro uptake and release assays, d-methamphetamine (50% effective concentration [EC50], 24.5 ± 2.1 nmol/L) was 17 times more potent in releasing dopamine than l-methamphetamine (EC50, 416 ± 20 nmol/L) and significantly more potent in blocking dopamine uptake (inhibition constant [Ki ], 114 ± 11 nm versus 4840 ± 178 nm).12,13
  5. ^ a b c d 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.
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  18. ^ a b c Kohut SJ, Jacobs DS, Rothman RB, Partilla JS, Bergman J, Blough BE (December 2017). "Cocaine-like discriminative stimulus effects of "norepinephrine-preferring" monoamine releasers: time course and interaction studies in rhesus monkeys". Psychopharmacology (Berl). 234 (23–24): 3455–3465. doi:10.1007/s00213-017-4731-5. PMC 5747253. PMID 28889212. In the present experiments, two monoamine releasers, l-MA and PAL-329, were shown to produce cocaine-like discriminative-stimulus effects in monkeys, suggesting that they meet the above criteria. One of these compounds, l-MA, also has been shown to serve as a positive reinforcer in rodents (Yokel and Pickens 1973) and monkeys (Winger et al 1994), further confirming the overlap with behavioral effects of cocaine. Both compounds also exhibit an approximately 15-fold greater potency in releasing NE than DA, which may be therapeutically advantageous. For example, the subjective effects of l-MA in human studies are similar in some respects to those of d-MA. However, the subjective effects of the two isomers also differ in potentially important ways. While both l-MA and d-MA produce subjective ratings of "drug liking" and "good effects" in experienced stimulant users, only lMA produces concomitant ratings of bad or aversive drug effects (Mendelson et al 2006), a factor which may limit its abuse liability.
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  42. ^ 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.
  43. ^ "Levmetamfetamine". PubChem. Retrieved 31 July 2024.
  44. ^ DeGeorge M, Weber J (30 November 2012). "Methamphetamine Urine Toxicology: An In-depth Review". Practical Pain Management. Vertical Health LLC. Archived from the original on 13 February 2016. Retrieved 21 February 2016.
  45. ^ a b Vearrier D, Greenberg MI, Miller SN, Okaneku JT, Haggerty DA (February 2012). "Methamphetamine: history, pathophysiology, adverse health effects, current trends, and hazards associated with the clandestine manufacture of methamphetamine". Disease-a-Month. 58 (2): 38–89. doi:10.1016/j.disamonth.2011.09.004. PMID 22251899. Japanese chemist Akira Ogata first synthesized methamphetamine in 1919 using ephedrine as a precursor. [...] In 1959 the S. Pfeiffer Company began producing Valo inhalers that contained 150-200 mg of methamphetamine.4,5 [...] Temmler Pharmaceutical Company introduced Pervitin in 1938 to the European market. Pervitin was available as 3 mg tablets that physicians could provide for the German military units.
  46. ^ a b Ciccarone D (March 2011). "Stimulant abuse: pharmacology, cocaine, methamphetamine, treatment, attempts at pharmacotherapy". Prim Care. 38 (1): 41–58. doi:10.1016/j.pop.2010.11.004. PMC 3056348. PMID 21356420. In 1919, Japanese chemist Akira Ogata, as part of his effort to prove the structure of ephedrine, reported the synthesis of the closely related compound we now call methamphetamine, and this result was described in the Western literature (Amatsu & Kubota, 1913; Lee, 2011; Ogata, 1920). [...] As a result, when competitors began to consider emulating SKF's success in the late 1930s, they turned to methamphetamine, which had nearly indistinguishable effects but—because its synthesis together with its pharmacological characteristics was published before 1920—was free from patent encumbrance. [...] In any event, by 1940 Benzedrine Sulfate had achieved medical acclaim and quickly growing sales as an antidepressant effective for milder forms of the condition, both in the United States and the United Kingdom. In Germany, the Temmler drug firm quickly copied SKF, marketing methamphetamine (again, unprotected by patents) tablets under the Pervitin brand, with claims that it restored "joy in work" in cases of mild depression around 1938 (Rasmussen, 2006; Steinkamp, 2006).
  47. ^ Di Cyan E, Hessman L (1972). Without Prescription: A Guide to the Selection and Use of Medicines You Can Get Over-the-counter Without Prescription, for Safe Self-medication. A Fireside book. Simon and Schuster. p. 53. ISBN 978-0-671-21137-0. Retrieved 9 July 2024. Vicks Inhaler (Vick)—Contains l-desoxyephedrine, [menthol], camphor, methyl salicylate, and bromyl acetate.
  48. ^ Krantz JC, Carr CJ, Aviado DM (1972). Krantz and Carr's Pharmacologic Principles of Medical Practice: A Textbook on Pharmacology and Therapeutics for Students and Practitioners of Medicine, Pharmacy, and Dentistry. Williams & Wilkins. p. 389. ISBN 978-0-683-00292-8. Retrieved 9 July 2024. Methamphetamine, also known as desoxyephedrine, is available as an inhalant (VICKS INHALER). The volatile base of methamphetamine is mixed with menthol, camphor, methyl salicylate, oil of sassafras and bornylacetate, which add to the customer acceptibility of the inhalant. The nasal decongestant effect of methamphetamine has been demonstrated in the experimental animal (Aviado et al., 1959). The other pharmacologic features of methamphetamine are discussed under its use as a vasopressor drug (Section VIII) and an anorexigenic drug (Section XV).
  49. ^ American Pharmaceutical Association (1995). Handbook of Non-prescription Drugs. American Pharmaceutical Association. p. 109. ISBN 978-0-917330-70-4. Retrieved 9 July 2024. Product & Manufacturer or Supplier: Vicks Vapor Inhaler, Procter & Gamble. Dosage Form: nasal inhaler. Sympathomimetic Agent: levodesoxyephedrine, 50 mg/inhaler. Preservative: None. Other Ingredients: bornyl acetate • camphor • lavender oil • menthol.
  50. ^ Rapp R (1997). The Pill Book Guide. Bantam Books. p. 220. ISBN 978-0-553-57729-7. Retrieved 9 July 2024. Vicks Vapor Inhaler (VIKS): Generic Ingredient: l-Desoxyephedrine. Type of Drug: Topical decongestant. Used for: Temporary relief of nasal congestion due to colds and allergies. General Information: Vicks Vapor Inhaler contains l-desoxyephedrine, which acts as a topical decongestant by narrowing or constricting blood vessels in the nose. This action reduces the blood supplied to the nose and decreases the swelling of nasal mucous membranes. [...]
  51. ^ Bovett R (January 2006). "Meth Epidemic Solutions". North Dakota Law Review. 82 (4): 1195–1216. Rules & Regulations Dep't of Health & Human Services, 61 Fed. Reg. 9,570 (Mar. 8, 1996) (codified at 21 C.F.R pt. 321). Vicks® Vapor Inhaler uses this active ingredient. For a time, the active ingredient was labeled "l-desoxyephedrine," which is simply another name for lmeth. Id. The FDA later changed the labeling requirement to "levmetamfetamine." Rules & Regulations Dep't of Health & Human Services, 63 Fed. Reg. 40,647 (July 30, 1998) (codified at 21 C.F.R. pts. 310 and 321).
  52. ^ Mendelson JE, McGlothlin D, Harris DS, Foster E, Everhart T, Jacob P, et al. (July 2008). "The clinical pharmacology of intranasal l-methamphetamine". BMC Clin Pharmacol. 8: 4. doi:10.1186/1472-6904-8-4. PMC 2496900. PMID 18644153. The 64-inhalation condition produced a small (change score of ~6) increase in "Good Drug Effect" suggesting a low potential for abuse even though occurrences of inhaler abuse is reported in the literature [1,18,19]. Larger doses of intravenous lmethamphetamine are psychoactive and may have some abuse potential in methamphetamine users [16].
  53. ^ Gal J (1982). "Amphetamines in Nasal Inhalers". Journal of Toxicology: Clinical Toxicology. 19 (5): 517–518. doi:10.3109/15563658208992508. ISSN 0731-3810.
  54. ^ Halle AB, Kessler R, Alvarez M (June 1985). "Drug abuse with Vicks nasal inhaler". South Med J. 78 (6): 761–2. doi:10.1097/00007611-198506000-00043. PMID 4002016.
  55. ^ Ferrando RL, McCorvey E, Simon WA, Stewart DM (March 1988). "Bizarre behavior following the ingestion of levo-desoxyephedrine". Drug Intell Clin Pharm. 22 (3): 214–217. doi:10.1177/106002808802200308. PMID 3366062.
  56. ^ Cunningham JK, Maxwell JC, Campollo O, Liu LM, Lattyak WJ, Callaghan RC (April 2013). "Mexico's precursor chemical controls: emergence of less potent types of methamphetamine in the United States". Drug Alcohol Depend. 129 (1–2): 125–36. doi:10.1016/j.drugalcdep.2012.10.001. PMID 23127541.
  57. ^ Research Cf (28 February 2022). "Rulemaking History for OTC Nasal Decongestant Drug Products". FDA.
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