Levomethamphetamine

Levomethamphetamine, also known as l-desoxyephedrine 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. It is available over-the-counter at low doses as a decongestant in the United States and is taken by inhalation for this use.

Levomethamphetamine act as a selective releasing agent of norepinephrine. It also induces the release of dopamine to a far lesser extent. Levomethamphetamine is an amphetamine and is the levorotatory enantiomer of the better-known methamphetamine. 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.

Methamphetamine was first discovered in 1919 and was introduced for medical use in oral form in 1938 under the brand name Pervitin. Decongestant inhalers containing enantiopure levomethamphetamine were introduced in 1958 under the brand name Vicks Inhaler. In addition to being used in pharmaceutical drugs itself, levomethamphetamine is a known active metabolite of certain other drugs, such as selegiline ( L -deprenyl).

Nasal decongestion
Levomethamphetamine is used as a nasal decongestant.

Available forms
Levomethamphetamine is available in the form of decongestant inhalers containing 50mg total levomethamphetamine per inhaler and delivering between 0.04 and 0.15mg of the drug per inhalation. Inhalers with a total of 113mg levomethamphetamine were previously marketed in the United States, but the total amount was eventually reduced to 50mg. These inhalers have been sold under brand names like Vicks Inhaler and Vicks Vapor Inhaler.

Levomethamphetamine was previously available in the form of racemic methamphetamine, a 1:1 combination of dextromethamphetamine and levomethamphetamine, in the form of oral tablets under brand names like Pervitin. However, these formulations were eventually discontinued. Dextromethamphetamine is still marketed under the brand name Desoxyn, but this medication is enantiopure and does not contain any levomethamphetamine.

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

Pharmacodynamics
Levomethamphetamine acts as a selective norepinephrine releasing agent. The potencies of levomethamphetamine, levoamphetamine, dextromethamphetamine, and dextroamphetamine in terms of norepinephrine release in vitro and in vivo in rats are all similar.

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 release. 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.

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. For comparison, levoamphetamine is only 1- to 4-fold less potent than dextroamphetamine in its stimulating and reinforcing effects in monkeys and humans.

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. In clinical studies, levomethamphetamine at oral doses of 1 to 10mg has been found not to affect subjective drug responses, heart rate, blood pressure, core temperature, electrocardiography, respiration rate, oxygen saturation, or other clinical parameters. As such, doses of levomethamphetamine of less than or equal to 10mg have no significant physiological or subjective effects. However, higher doses of levomethamphetamine, for instance 0.25 to 0.5mg/kg (mean doses of ~18–37mg) 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. On the other hand, in contrast to dextromethamphetamine, levomethamphetamine also produces subjective "bad" or aversive drug effects. Among the physiological effects of levomethamphetamine is vasoconstriction, which makes it useful for nasal decongestion.

For comparison to levomethamphetamine, 5 to 60mg 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.

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

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

Distribution
The volume of distribution of levomethamphetamine is 288.5 to 315.5L or 4.15 to 4.17L/kg.

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

Levomethamphetamine is metabolized into levoamphetamine in small amounts.

Elimination
Levomethamphetamine is excreted in urine 40.8 to 49.0% as unchanged levomethamphetamine and 2.1 to 3.3% as levoamphetamine.

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

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

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.

History
Methamphetamine, a racemic mixture of dextromethamphetamine and levomethamphetamine, was first discovered and synthesized in 1919. Methamphetamine was first introduced for medical use in 1938 in oral form under the brand name Pervitin in Germany. 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. By 1995, the brand name was changed to Vicks Vapor Inhaler. 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.

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. In any case, misuse of levomethamphetamine at high doses has been reported.

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. However, in recent years, cartels have used chiral separation to produce relatively pure dextromethamphetamine from the racemic substance.

Selegiline
Levomethamphetamine is a major active metabolite of selegiline ( L -deprenyl; N-propargyl- L -methamphetamine). Selegiline is a monoamine oxidase inhibitor (MAOI), specifically a selective inhibitor of monoamine oxidase B (MAO-B) at lower doses and a dual inhibitor of both monoamine oxidase A (MAO-A) and MAO-B at higher doses. It also has additional activities, such as acting as a catecholaminergic activity enhancer (CAE), possibly via agonism of the TAAR1, and having potential neuroprotective effects. Selegiline is clinically used as an antiparkinsonian agent in the treatment of Parkinson's disease and as an antidepressant in the treatment of major depressive disorder.

In addition to levomethamphetamine, selegiline also metabolizes into levoamphetamine. With a 10mg oral dose of selegiline, about 2 to 6mg levomethamphetamine and 1 to 3mg levoamphetamine is excreted in urine. As levomethamphetamine and levoamphetamine are norepinephrine and/or dopamine releasing agents, they may contribute to the effects and side effects of selegiline. This may particularly include cardiovascular and sympathomimetic effects of selegiline. Other selective MAO-B inhibitors that do not metabolize into amphetamine metabolites or have associated cardiovascular effects, such as rasagiline, have also been developed and introduced.

Because selegiline metabolizes into levomethamphetamine and levoamphetamine, people taking selegiline can erroneously test positive for amphetamines on drug tests.