Levomethamphetamine

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Levomethamphetamine
INN: Levmetamfetamine
Clinical data
Trade namesVicks Inhaler; Vicks Vapor Inhaler; Pervitin
Other namesLevmetamfetamine; L-Methamphetamine; R-(-)-Methamphetamine; Levodesoxyephedrine; L-Desoxyephedrine
Routes of
administration		Medical: Inhalation (nasal)
Recreational: Oral, intravenous, insufflation, inhalation, suppository
Legal status
Legal status
Pharmacokinetic data
BioavailabilityOral: ~100%[2][3]
MetabolismLiver
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
 ☒NcheckY (what is this?)  (verify)

Levomethamphetamine, also known as l-desoxyephedrine[note 1] and sold under the brand name Vicks Vapor Inhaler among others, is a sympathomimetic, decongestant, and stimulant medication which is used to treat nasal congestion.[2] It is available over-the-counter at low doses as a decongestant in the United States and is taken by inhalation for this use.[2]

Levomethamphetamine act as a selective releasing agent of norepinephrine.[5][6][4] It also induces the release of dopamine to a far lesser extent.[5][7][4] Levomethamphetamine is an amphetamine and is the levorotatory enantiomer of the better-known methamphetamine.[2] The effects of levomethamphetamine are distinct from those of racemic methamphetamine and dextromethamphetamine and it does not have the same misuse potential as these substances.[2][8][9][4][10]

Methamphetamine was first discovered in 1919[11][12] and was introduced for medical use in oral form in 1938 under the brand name Pervitin.[13] Decongestant inhalers containing enantiopure levomethamphetamine were introduced in 1958 under the brand name Vicks Inhaler.[13]

Medical uses

Nasal decongestion

Levomethamphetamine is used as a nasal decongestant.[2]

Available forms

Levomethamphetamine is available in the form of decongestant inhalers containing 50 mg total levomethamphetamine per inhaler and delivering between 0.04 and 0.15 mg of the drug per inhalation.[2] Inhalers with a total of 113 mg levomethamphetamine were previously marketed in the United States, but the total amount was reduced to 50 mg starting in 2009.[2]

Side effects

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

Pharmacology

Pharmacodynamics

Levomethamphetamine acts as a selective norepinephrine releasing agent.[6][5][7][4] The potencies of levomethamphetamine, levoamphetamine, dextromethamphetamine, and dextroamphetamine in terms of norepinephrine release in vitro and in vivo in rats are all similar.[14][15][16][10][5]

Conversely, whereas dextromethamphetamine and dextroamphetamine are relatively balanced releasers of dopamine and norepinephrine in vitro, levomethamphetamine is about 15- to 20-fold less potent in inducing dopamine release relative to norepinephrine.[5][7][4][6][16] Moreover, whereas levoamphetamine is about 3- to 5-fold less potent in terms of dopamine release than dextroamphetamine in vivo, levomethamphetamine is dramatically less potent than dextromethamphetamine and substantially less potent than levoamphetamine in this regard.[15][14][10]

Monoamine release of levomethamphetamine and related substances (EC50Tooltip Half maximal effective concentration, nM)[5][17]
Compound 5-HTTooltip Serotonin NETooltip Norepinephrine DATooltip Dopamine Type Class Ref
Amphetamine ND ND ND NDRA Amphetamine ND
  D-Amphetamine 698–1765 6.6–7.2 5.8–24.8 NDRA Amphetamine [6][18]
  L-Amphetamine ND ND ND NRA Amphetamine ND
Ephedrine ND ND ND NDRA Cathinol ND
  D-Ephedrine >10000 43.1–72.4 236–1350 NDRA Cathinol [6]
  L-Ephedrine >10000 218 2104 NRA Cathinol [6][19]
Methamphetamine ND ND ND NDRA Amphetamine ND
  D-Methamphetamine 736–1291.7 12.3–13.8 8.5–24.5 NDRA Amphetamine [6][20]
  L-Methamphetamine 4640 28.5 416 NRA Amphetamine [6]
Pseudoephedrine ND ND ND NDRA Cathinol ND
  D-Pseudoephedrine >10000 4092 9125 NDRA Cathinol [19]
  L-Pseudoephedrine >10000 224 1988 NRA Cathinol [19]
Note: The smaller the value, the more strongly the substance releases the neurotransmitter.

In accordance with the findings of catecholamine release studies, levomethamphetamine is 2- to 10-fold or more less potent than dextromethamphetamine in terms of psychostimulant-like effects in rodents.[21][22][8] For comparison, levoamphetamine is only 1- to 4-fold less potent than dextroamphetamine in its stimulating and reinforcing effects in monkeys and humans.[14][23]

The effects of levomethamphetamine 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][8][9][4][10] In clinical studies, levomethamphetamine 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 levomethamphetamine of less than or equal to 10 mg have no significant physiological or subjective effects.[2][3] However, higher doses of levomethamphetamine, 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, levomethamphetamine also produces subjective "bad" or aversive drug effects.[7][4] Among the physiological effects of levomethamphetamine is vasoconstriction, which makes it useful for nasal decongestion.[24]

For comparison to levomethamphetamine, 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.[25][26][27][23][note 2]

In addition to its norepinephrine-releasing activity, levomethamphetamine is also an agonist of the trace amine-associated receptor 1 (TAAR1).[28][29][30]

Pharmacokinetics

The bioavailability of levomethamphetamine is approximately 100%.[2][3] The peak levels of levomethamphetamine 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][31] The area-under-the-curve (AUC) levels of levomethamphetamine range from 73.0 to 694.7 ng⋅h/mL with single oral doses of 1 to 10 mg and from 1190.7 to 2368.1 mg/kg with single intravenous doses of 0.25 to 0.5 mg/kg.[2][4][31]

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

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

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

Chemistry

Detection in body fluids

Levomethamphetamine can register on urine drug tests as either methamphetamine, amphetamine, or both, depending on the subject's metabolism and dosage. Levomethamphetamine metabolizes completely into levoamphetamine after a period of time.[32]

History

Methamphetamine, a racemic mixture of dextromethamphetamine and levomethamphetamine, was first discovered and synthesized in 1919.[11] [12] Methamphetamine was first introduced for medical use in 1938 in oral form under the brand name Pervitin in Germany.[11][12] Over-the-counter nasal decongestant inhalers containing enantiopure levomethamphetamine, originally labeled with the chemical name l-desoxyephedrine, were first introduced in 1958 under the brand name Vicks Inhaler.[13][33][34] By 1995, the brand name was changed to Vicks Vapor Inhaler.[35][36] 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.[37]

Society and culture

Recreational use

As of 2006, there were no studies demonstrating "drug liking" scores of oral levomethamphetamine that are similar to racemic methamphetamine or dextromethamphetamine in either recreational users or medicinal users.[4] In any case, misuse of levomethamphetamine at high doses has been reported.[38][39][40][41]

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 levomethamphetamine to dextromethamphetamine within batches of racemic methamphetamine.[42] However, in recent years, cartels have used chiral separation to produce relatively pure dextromethamphetamine from the racemic substance.

Other drugs

Selegiline

Main article: Selegiline

Levomethamphetamine is an active metabolite of the antiparkinsonian and antidepressant medication selegiline. Selegiline, a selective monoamine oxidase B (MAOB) inhibitor at low doses,[note 3] is also metabolized into levomethamphetamine and levoamphetamine.[43][44] This has caused users to test positive for amphetamines.[45][46] With a 10 mg oral dose of selegiline, about 2 to 6 mg levomethamphetamine and 1 to 3 mg levoamphetamine is excreted in urine.[47][48][49] Selegiline itself has neuroprotective and neurorestorative effects, but concern over the resulting levomethamphetamine's side effects and potential neurotoxicity led to development of alternative MAOB inhibitors, such as rasagiline, that do not produce toxic metabolites.[50][51]

Notes

  1. ^ Other names include levmetamfetamine (INNTooltip International Nonproprietary Name), L-methamphetamine, R-(-)-methamphetamine, levodesoxyephedrine, and L-desoxyephedrine.
  2. ^ Smith & Davis (1977) reviewed 11 clinical studies of dextroamphetamine and levoamphetamine including potency ratios in terms of a variety of psychological and behavioral effects.[23] The summaries of these studies are in Table 1 of the paper.[23]
  3. ^ It is a selective MAOB inhibitor at normal clinical doses. MAOB is an enzyme that metabolizes dopamine, the neurotransmitter deficient in Parkinson's disease.

References

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  33. ^ 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.
  34. ^ 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. 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).
  35. ^ 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.
  36. ^ 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. [...]
  37. ^ Bovett R. "Meth Epidemic Solutions". North Dakota Law Review. 82 (4): 5. 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).
  38. ^ 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].
  39. ^ Gal J (1982). "Amphetamines in Nasal Inhalers". Journal of Toxicology: Clinical Toxicology. 19 (5): 517–518. doi:10.3109/15563658208992508. ISSN 0731-3810.
  40. ^ 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.
  41. ^ 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.
  42. ^ 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.
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  45. ^ Cody JD (December 1993). "Metabolic Precursors to Amphetamine and Methamphetamine". Forensic Science Review. 5 (2): 109–127. PMID 26270078.
  46. ^ Cody JT (May 2002). "Precursor medications as a source of methamphetamine and/or amphetamine positive drug testing results". Journal of Occupational and Environmental Medicine. 44 (5): 435–450. doi:10.1097/00043764-200205000-00012. PMID 12024689. S2CID 44614179.
  47. ^ Poston KL, Waters C (October 2007). "Zydis selegiline in the management of Parkinson's disease". Expert Opin Pharmacother. 8 (15): 2615–24. doi:10.1517/14656566.8.15.2615. PMID 17931095.
  48. ^ Mahmood I (August 1997). "Clinical pharmacokinetics and pharmacodynamics of selegiline. An update". Clin Pharmacokinet. 33 (2): 91–102. doi:10.2165/00003088-199733020-00002. PMID 9260033.
  49. ^ Chrisp P, Mammen GJ, Sorkin EM (May 1991). "Selegiline: A Review of its Pharmacology, Symptomatic Benefits and Protective Potential in Parkinson's Disease". Drugs Aging. 1 (3): 228–48. doi:10.2165/00002512-199101030-00006. PMID 1794016.
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