Pharmacology of R-(−)-Methamphetamine in Humans: A Systematic Review of the Literature

Abstract

Methamphetamine exists as two stereoisomers: S-(+)-methamphetamine ((+)-MAMP) and R-(−)-methamphetamine ((−)-MAMP). The (+)-MAMP stereoisomer is a well-known central nervous system stimulant, available as a pharmaceutical and clandestine drug of abuse. However, the (−)-MAMP stereoisomer is less well understood despite commercial availability for over 30 years as an over-the-counter (OTC) nasal decongestant in the Vicks Vapor Inhaler (a product of Procter & Gamble). Recently, several generic versions have become available, decreasing the cost and increasing the availability of (−)-MAMP-containing nasal sprays to consumers. Despite widespread commercial availability and use in the United States, a paucity of literature exists on the pharmacology of (−)-MAMP in humans. This knowledge gap is problematic, given the difficulty in separating (−)-MAMP and (+)-MAMP isomers in laboratory assays for workplace drug testing, suspected impaired drivers, post-mortem investigations, and assessment of drug involvement in crimes. In response, this systematic review of the literature coalesces and summarizes available knowledge of (−)-MAMP pharmacology in humans. It was found that available knowledge relies heavily on urine drug and metabolite concentrations, systematic pharmacokinetics studies are lacking, and existing knowledge has been derived from a total of 99 unique participants. The impacts of highlighted gaps in the literature are discussed, focusing on forensic toxicology and law enforcement, and future research directions are suggested.

Methamphetamine exists as two stereoisomers: S-(+)-methamphetamine ((+)-MAMP) and R-(−)-methamphetamine ((−)-MAMP). The (+)-MAMP stereoisomer is a well-known central nervous system stimulant and drug of abuse,¹ available in both pharmaceutical and clandestine preparations across the globe. However, the (−)-MAMP stereoisomer is less well understood, despite the long-term availability (prior to 1994)²⁻⁴ of the over-the-counter (OTC) nasal decongestant in the Vicks Vapor Inhaler (marketed by Procter & Gamble).⁵ Vicks Vapor Inhalers originally contained 113 mg (reduced to 50 mg in 2009)⁶ of levmetamfetamine ((−)-MAMP) per inhaler, as well as “soothing Vicks vapors” consisting of camphor, menthol, and other similar scents.⁵ Preparation instructions declared that each inhalation (in the 50 mg preparation) delivered between 0.04 and 0.15 mg of (−)-MAMP.⁵ Recommended administration for adults and children 12 years of age and older consisted of two inhalations in each nostril, no more than once every 2 h. Children 6 to under 12 years were to receive only one inhalation per nostril, with adult supervision, no more than once every 2 h. Vapor Inhaler use was not recommended for children under 6 years, unless otherwise instructed by a doctor. Vapor Inhalers were marketed as providing fast relief from nasal congestion due to colds, hay fever, and other upper respiratory allergies.

Through 2013, the Vicks Vapor Inhaler (rebranded as the VapoInhaler in 2009) was the only OTC (−)-MAMP product available to consumers in the United States. Beginning in 2014, Vicks switched to a homeopathic formulation, removing the levmetamfetamine and leaving the “soothing Vicks vapors” consisting of camphor, menthol, methyl salicylate (wintergreen scent), and Siberian Fir oil. Around the same time, several generic versions of levmetamfetamine-containing nasal spray decongestants became commercially available from both brick and mortar and online retailers. All available generic versions contain 50 mg (−)-MAMP per inhaler and include the same recommended administration instructions as described above for Vicks Vapor Inhalers. Despite widespread commercial availability and use in the U.S., a paucity of literature exists on the pharmacology of (−)-MAMP in humans. The lack of knowledge of (−)-MAMP pharmacokinetics is particularly problematic given the difficulty in separating (−)-MAMP and (+)-MAMP isomers in clinical and forensic testing. The stereoselectivity of methamphetamine metabolic pathways remains undefined, giving those who must interpret toxicological assay results little to go on. Inadequate enantiomer separation impacts interpretation of results from workplace drug testing, suspected impaired driver testing, and assessment of drug-involvement in crimes.

One might consider the long-term OTC availability of a substance as evidence of its relative safety. However, in 2021 the U.S. Food and Drug Administration (FDA) issued a Drug Safety Communication about another intranasal decongestant, propylhexedrine (marketed under the brand name Benzedrex since 1949), which is also a psychostimulant and similar in structure to (−)-MAMP.⁷ The Drug Safety Communication warns that the OTC nasal decongestant propylhexedrine can cause significant cardiovascular and mental health harms if misused or abused.⁷ This warning exemplifies the danger of lacking research data and publications on OTC pharmaceuticals such as (−)-MAMP. Just because a substance has been available OTC for a long time (nearly 75 years) does not mean it is safe or lacks abuse potential.

This review aimed to coalesce and examine existing knowledge on the pharmacology of (−)-MAMP in humans. This included both pharmacokinetic and pharmacodynamic measures of (−)-MAMP in humans and any reported adverse events. A systematic review of available literature was performed, adopting the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA).^8,9 Identified peer-reviewed literature was coalesced and summarized, with careful consideration of the routes of administration and biological matrix chosen to assess pharmacokinetics. Available pharmacodynamic information was also coalesced and summarized. Gaps in the knowledge are highlighted from the perspective of workplace drug testing, suspected impaired drivers, and assessment of drug-involved crimes. High-priority future directions are proposed to fill these gaps.

Methodology

Design and Registration

This systematic review was registered with the international prospective register for systematic reviews (PROSPERO). The registration number is 367503.¹⁰

Search Strategy

A systematic search of the literature was performed adopting the 2020 preferred reporting items for systematic reviews and meta-analysis (PRISMA).^8,9 Eligibility criteria included peer-reviewed literature concerning the administration of R-(−)-methamphetamine to humans. Studies were grouped for synthesis by the route of administration: oral, intravenous, and intranasal. One author (H.M.B.) searched PubMed and Web of Science databases on October 11, 2022. Search terms included methamphetamine isomer, methamphetamine enantiomer, methamphetamine stereoisomer, l-methamphetamine, methamphetamine, R-(−)-methamphetamine, R-methamphetamine, levomethamphetamine, levodesoxyephedrine, l-desoxyephedrine, and levmetamfetamine. In PubMed, studies were limited to clinical trials and randomized controlled clinical trials. In Web of Science, the search terms were queried using the AND function with the search term human. Additional searches were performed by two authors (H.M.B. and A.M.) using Google and Google Scholar on October 12 and 13, 2022. No restrictions by publication date of the literature were applied. Studies were limited to the English language. The references included in identified studies were also scrutinized for applicable literature. Resulting references were uploaded into Covidence (2022, version 3030) for title and abstract screening, full-text eligibility analysis, quality and bias assessment, and data extraction.

Study Selection

Two authors (H.M.B. and R.H.) independently performed the title and abstract review. Studies were included if they assessed the pharmacokinetics and/or the pharmacodynamics of (−)-MAMP in humans. Studies were excluded if (−)-MAMP was a metabolite of another drug (e.g., selegiline), if the work only considered racemic methamphetamine, if the methamphetamine isomer was never disclosed (referred to as simply “methamphetamine”), or data was generated from animal models. Reviews and meta-analyses were also excluded unless new data was simultaneously presented. Both authors (H.M.B. and R.H.) independently performed full text review and agreed upon the included works.

Risk of Bias and Confidence Assessment

Risk of bias was independently assessed by two authors (H.M.B. and R.H.) in Covidence using the standard quality assessment form. The risk of bias assessment included blinding of participants, blinding of the study team, allocation concealment, incomplete outcome data, and selective outcome reporting. Bias was assessed as either high risk, low risk, or uncertain risk according to Cochrane collaboration tools for assessing the risk of bias.¹¹ Study confidence was assessed by considering the study participant pool size and demographics.

Outcomes Analyzed

The main outcomes analyzed were qualitative and quantitative descriptions of analyte concentrations in biological specimens and pharmacodynamics measures of drug effects collected at various time points post study drug administration. Analytes included R-(−)-methamphetamine, S-(+)-methamphetamine ((+)-MAMP), R-(−)-amphetamine ((−)-AMP), and S-(+)-amphetamine ((+)-AMP). and biological matrices considered were urine, blood, plasma, and oral fluid. Pharmacodynamic measures included heart rate, blood pressure, and body temperature. Other pharmacodynamics measures such as subjective drug effects were also included as secondary outcomes when available. Reporting on adverse events including withdrawal or discontinuation due to drug-related adverse events were recorded as a secondary outcome.

Data Extraction

Data were independently extracted by two authors (H.M.B. and R.H.) in Covidence using a slightly modified data extraction standard form. The following data were extracted from each study: title, lead author, country, aim of study, study design (e.g., randomized controlled trial, non-randomized experimental study, qualitative research, diagnostic test accuracy, or other), publication date, funding source, conflicts of interest, population description, inclusion criteria, exclusion criteria, method of recruitment, total number of participants, demographic details (i.e., age, sex, race), intervention and comparisons, route of administration, pharmacokinetic outcomes, pharmacodynamic outcomes, and adverse events. Due to the paucity of available literature encompassing a wide range of doses and different routes of administration, only a qualitative synthesis of extracted data was performed.

Results

A total of 153 references were identified from PubMed, Web of Science, Google, Google Scholar, and a review of references of included studies. Of these, 22 were duplicates and 114 were deemed ineligible during the title and abstract screen. Of the 17 remaining studies, 4 were excluded during the full text review as 3 considered pre-existing clinical specimens and 1 assessed animal models. Therefore, 13 studies¹²⁻²⁴ were included for qualitative synthesis, see Figure 1. Of the included studies, (−)-MAMP was administered orally,²²⁻²⁴ intravenously,^12,13,24 and intranasally,¹⁴⁻²¹ see Table 1. However, 2 of the intravenous administration papers^12,13 considered data derived from a single participant pool as did 3 of the intranasal administration papers.¹⁵⁻¹⁷ Therefore, only 10 distinct studies were considered. These works administered a wide range of doses, from 0.0168 mg¹⁸ to 45.4 mg.^12,13 To minimize dosing variability while comparing results, summaries and data extracted from studies were grouped by route of administration: oral, intravenous, and intranasal.

Figure 1.

PRISMA diagram detailing selection of studies included in this work.

Table 1. Summary of Studies Included in This Review^a.

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^aAbbreviations: PK, pharmacokinetics; PD, pharmacodynamics; HR, heart rate; BP, blood pressure; T, body temperature; and resp, respirations.

These works included a total of 99 participants and a summary of participant demographics, as available, is displayed in Table 2 and Figure 2. Most studies did not provide demographic details about participants. Participant sex was reported for 66 (66.6%) of participants, and those studies were 81.8% male and 18.2% female. Participant age was only reported for 22 (22.2%) participants. Of those, 54.5% were 10–19, 18.2% were 20–29, 9.1% were 30–39, and 18.2% were 40–49 years old. Participant race was reported for 57 (57.6%) participants, and of those 40.3% were White, 49.1% were Black, 1.8% were Native American, and 8.8% were more than one race. While summarizing relevant findings from studies included in this review, participant demographics are not discussed unless a unique subpopulation (e.g., high school students¹²) was considered.

Table 2. Summary of Included Participants and Available Demographic Details.

Figure 2.

Participant gender, age, and race reported in included works. The number of participants whose details were not reported in each category is also included as “unreported”. In the graphic illustrating participant race, 1 identified as Native American.

Oral Administration

The first report of (−)-MAMP pharmacology in humans was published in 1973 by Beckett et al.²³ In this work, the urinary pharmacokinetics of unchanged and metabolized (+)-MAMP and (−)-MAMP were considered alongside those of ethyl-, n-propyl-, and n-butyl-amphetamine. After oral administration of the study drug (12.45 mg of methamphetamine HCl), urine specimens were collected from participants (N = 6) every half hour for the first 4 h, hourly up to 12 h, with intervals increasing in duration up to 24 and 48 h. Study endpoints included the concentration of (+)-MAMP (−)-MAMP and their (+)-AMP and (−)-AMP metabolites in collected urine specimens. Authors used an in-house gas–liquid chromatography approach²⁵ and thin layer chromatography (TLC) to measure analytes. It was found that (+)-MAMP was metabolized to amphetamine more than (−)-MAMP. Also, peak excretion rates of methamphetamine occurred 1–3 h after study drug administration, and (−)-MAMP was excreted more rapidly than (+)-MAMP. The calculated half-life and rate constants were reported for four participants: two for (+)-MAMP and two for (−)-MAMP. Authors calculated the rate constant from the half-life and recovery in urine unchanged, assuming there was no change in half-life beyond 24 h. The average amount of methamphetamine and amphetamine excreted unchanged in the urine and the calculated half-life can be found in Table 3. Results from this study indicate that methamphetamine stereochemistry impacts human metabolism, although only urine specimens were considered.

Table 3. Summary of Observed Pharmacokinetic Parameters^a.

^aAbbreviations: MAMP (%), amount of methamphetamine excreted unchanged in the urine; AMP (%), amount of amphetamine excreted in the urine; AUC_0-24, area under the concentration–time curve spanning 0 to 24 h; AUC_0-∞, area under the concentration–time curve extrapolated from time 0 to an infinite time; C_max, peak concentration; CL, clearance; V_d, volume of distribution; and t_1/2, half-life. ^b = Administered as oral 2.5 mg dose followed 1.5 h later by intravenous 2.5 mg infusion over 30 min.

Another example of (−)-MAMP pharmacology from oral study drug administration was published in 2001 by Jirovský et al.²² Here, 20 mg doses of (+)-MAMP, (−)-MAMP, and racemic methamphetamine were administered separately (N = 1). Urine specimens were collected at 6, 12, 24, and 48 h post study drug administration. Authors used a capillary zone electrophoresis method²⁶ with a chiral selector to quantify (+)-MAMP, (−)-MAMP, (+)-AMP, and (−)-AMP in urine specimens. Measured concentrations of all analytes were presented as a figure, but no pharmacokinetic parameters were calculated. This work focused on describing a novel enantiomer separation and quantification method. Although a human was dosed with methamphetamine, the authors missed the opportunity to assess (−)-MAMP pharmacology.

In 2010, Li et al. reported findings of a randomized, double-blind, placebo-controlled, balanced crossover study (N = 8) administering oral (−)-MAMP and intravenous deuterium-labeled (−)-MAMP ((−)-MAMP-d₃) to humans.²⁴ Authors hypothesized that (−)-MAMP-d₃ could be administered during methamphetamine treatment clinical trials to semi-quantitatively assess illicit methamphetamine exposure. That is, assessing biological concentrations from a known dose of deuterated (−)-MAMP enables researchers to estimate methamphetamine intake from non-controlled sources. To that end, authors constructed a study with five sessions: (1) oral 1 mg (−)-MAMP followed 1.5 h later by intravenous placebo (0.9% NaCl), (2) oral 2.5 mg (−)-MAMP followed 1.5 h later by intravenous 2.5 mg of (−)-MAMP-d₃ (infused over 30 min), (3) oral 5 mg (−)-MAMP followed 1.5 h later by intravenous placebo, (4) oral 10 mg (−)-MAMP followed 1.5 h later by intravenous placebo, and (5) oral placebo followed 1.5 h later by intravenous placebo. Plasma samples were collected prior to dosing and 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 24, and 48 h after dosing. All urine was collected as aliquots from each void and pooled in 24-h intervals. Authors quantified analytes using a gas chromatography–mass spectrometry (GC-MS) method with derivatization.²⁷ The authors used a non-compartmental trapezoid method to calculate pharmacokinetic parameters, displayed in Table 3. Generally, the authors found that all (−)-MAMP doses were well tolerated, and no serious adverse events occurred. This dose range also lacked physiological activity as study drug administration did not result in relevant heart rate, blood pressure, core temperature, respiration rate, or oxygen saturation changes compared to the placebo, as detailed in Table 4. Furthermore, no differences were detected in participant-reported subjective effects of study drug administration compared to the placebo. From this work, we learn that orally administered doses of (−)-MAMP at or below 10 mg do not result in significant physiological or subjective effects. Affiliated (−)-MAMP pharmacokinetic parameters were also reported. However, the study lacked a (+)-MAMP comparator which limits application of this pharmacokinetic data to forensic and clinical toxicology results where (+)-MAMP or racemic methamphetamine consumption is suspected.

Table 4. Summary of Pharmacodynamic Observations.

Intravenous Administration

As stated above, Li et al. administered an intravenous dose of (−)-MAMP-d₃ (2.5 mg over 30 min) 1.5 h after an oral dose of (−)-MAMP (2.5 mg).²⁴ This approach enabled the authors to estimate the absolute bioavailability of (−)-MAMP. Resulting calculated pharmacokinetic parameters (see Table 3) revealed a bioavailability close to 1, indicating complete absorption of the oral dose. Administration of a deuterated intravenous dose to estimate uncontrolled methamphetamine consumption is a novel and effective tool to corroborate self-reported methamphetamine use. However, future studies should include other biological matrices such as urine, whole blood, dried capillary blood spots, and oral fluid. Assessing a suite of biological matrices of various levels of invasiveness increases translatability of results.

Similarly, Mendelson et al.¹⁹ administered participants (N = 12) a single intravenous (−)-MAMP (5 mg, 15 min infusion) dose to determine absolute bioavailability. Plasma samples were collected before and 0.5, 1, 2, 4, 8, 18, 24, and 30 h after study drug administration. All urine was collected and pooled according to 0–12, 12–24, and 24–36 h increments. A GC/MS method²⁷ was used to quantify analyte concentrations, and total urinary methamphetamine excretion was found from the intravenous dose. Authors assumed similar distribution and elimination of intranasal and intravenous (−)-MAMP administration and used the total urinary methamphetamine excretion to estimate how much (−)-MAMP was administered during intranasal dosing, which is described in the Intranasal Administration section, below.

Prior to this work, Mendelson et al.¹³ carried out a six-session, double-blind placebo-controlled, Latin-square, balanced crossover study (N = 12) assessing the pharmacokinetics and pharmacodynamics of (−)-MAMP, (+)-MAMP, and a 1:1 racemic mixture. Dosages included 0.25 mg/kg and 0.5 mg/kg for both (−)-MAMP and (+)-MAMP. The racemic dose was 0.5 mg/kg, and the placebo was 0.9% NaCl. Blood was collected from volunteers prior to study drug administration and 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 30, 36, and 48 h after dosing. Pharmacokinetic parameters were calculated using the linear trapezoidal rule. Available pharmacokinetic parameters are included in Table 3. Of note, the authors found that the apparent exposure of (+)-MAMP and (−)-MAMP (0.25 and 0.5 mg/kg doses) were bioequivalent when considering the area under the concentration–time curve (AUC) whereas the racemate dose did not meet the criteria for bioequivalence. They hypothesize that the presence of one enantiomer is inhibiting or inducing metabolism of the other. Authors also assessed the pharmacodynamics of (−)-MAMP through physiologic and subjective measures. Physiologic measures included heart rate, blood pressure, respiration rate, skin temperature, and core temperature collected before dosing and at 0.08, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 36, and 48 h after dosing. Subjective measures included verbal ratings of global intoxication and several other subjective drug effects such as “good drug effect”, “drug liking”, and “bad drug effect”, among others which were collected prior to dosing and 0.5, 1, 1.5, 3, 4, 5.5, 8, 12, and 24 h after dosing. A summary of all observed pharmacodynamic measures is available in Table 4. Cardiovascular and subjective effects from (+)-MAMP (0.5 mg/kg) were much longer-lasting than those from (−)-MAMP (0.5 mg/kg). Although both enantiomers (0.5 mg/kg) produced similar peak subjective effects, those from (−)-MAMP dissipated rapidly compared to (+)-MAMP. The 0.25 mg/kg (−)-MAMP dose did not produce significant physiologic or subjective effects when compared to the placebo. Unexpectedly, effects from the racemic dose (1:1, 0.5 mg/kg total) were like that of the 0.5 mg/kg (+)-MAMP dose. Authors found that racemic methamphetamine has more than an additive effect when comparing results to equivalent doses of (+)-MAMP and (−)-MAMP. Results from this work are heavily relied upon by clinical and forensic toxicologists. Use of both (+)-MAMP and placebo controls contextualized the robust data on (−)-MAMP pharmacokinetics and pharmacodynamics. Furthermore, racemic methamphetamine results are particularly interesting, and warrant further inquiry.

Using the same participant pool, Li et al.¹² re-analyzed the data with a new focus on urinary pharmacokinetics. In this work, the percent recovery of methamphetamine and amphetamine in urine was reported. Plasma pharmacokinetic parameters were also re-analyzed, and although the values vary slightly from their prior publication, all are within published confidence intervals. Therefore, the percent recovery values are added to Table 3 as a joint entry with their prior work. In agreement with their, and others prior work, the authors conclude that metabolism of methamphetamine is stereoselective. Through consideration of other metabolites, such as para-hydroxymethamphetamine in this work, researchers can begin to elucidate which metabolic pathways are stereoselective. That said, future works should include other methamphetamine metabolites to gain a better understanding of which metabolic pathways are stereoselective. This information may reveal new biomarkers distinguishing (+)-MAMP versus (−)-MAMP consumption, which would hold great value to clinical and forensic toxicologists.

Intranasal Administration

Researchers identified the need to quantify how use of OTC nasal decongestants containing (−)-MAMP (at the time, each inhaler contained 113 mg levmetamfetamine⁶) impacted workplace and other drug testing results beginning in 1988. Fitzgerald et al.¹⁴ reported results from a human subjects study (N = 3) where volunteers were instructed to take several deep inhalations from an inhaler containing (−)-MAMP every 20 min for 6 h. This dosing is significantly greater than the manufacturer recommended maximum of two inhalations in each nostril once every 2 h. Authors went on to collect urine specimens in intervals of 0–1, 1–3, 3–5, 5–7, and 7–24 h. Several commercially available immunoassays developed to detect (+)-MAMP were then used to assess for cross-reactivity to (−)-MAMP. Immunoassays considered included the EMIT (Syva), Toxilab (Analytical Systems), TDx (Abbot), and Abuscreen RIA (Roche). Authors also analyzed urine specimens by GC-MS with a chiral derivatizing reagent to quantify methamphetamine enantiomers also described in this work. Authors discovered that immunoassays with low limits of detection for (+)-MAMP (EMIT, Toxilab, and TDx) were cross reactive to (−)-MAMP and gave “methamphetamine positive” results. As clinical and forensic toxicology laboratories retire immunoassays in favor of high-resolution mass spectrometry screening techniques, results from this early work are less informative. That said, it is still important that laboratories understand the strengths and limitation of any screening tool, including selectivity and sensitivity to relevant isomers.

Similarly, Poklis et al. published three manuscripts¹⁵⁻¹⁷ describing cross-reactivity results of the EMIT II amphetamine/methamphetamine assay (Syva),¹⁷ TDxADx/FLx amphetamine/methamphetamine II fluorescence polarization immunoassay (Abbot),¹⁶ and the EMIT-d.a.u. class (EC) and EMIT-d.a.u. monoclonal amphetamine/methamphetamine (ME) assays (Syva).¹⁵ When an immunoassay gave a positive result, an aliquot of that urine specimen was analyzed by chiral GC/MS.¹⁴ All these works resulted from one participant pool (N = 7) which was divided into two arms. One arm (N = 4) received the manufacturer suggested dosing of 2 inhalations (from the 113 mg inhaler formulation) in each nostril once every 2 h for 5 days. The other arm (N = 3) received double the manufacturer suggested dose of 2 inhalations in each nostril every hour for 3 days. All voided urine was collected over the 5-day study period. When following the manufacturer suggested dosing regimen, the greatest (−)-MAMP urine concentration was 872 ng/mL and at double the manufacturer suggested dose the maximum was 1,560 ng/mL. The TDxADx/FLx and EMIT-d.a.u. immunoassays gave positive results for some urine specimens from some participants. The EMIT II assay did not give any positive results, even at double the manufacturer suggested (−)-MAMP dose. It is worth noting that participants in the double-dose arm reported significant discomfort from frequent and prolonged inhaler use. Authors report adverse events including excessively dry nose and mouth, significant lingering menthol and camphor taste and smell, and rebound congestion upon cessation of the study drug. A major strength of these works was the separation and quantification of (−)-MAMP in urine specimens that yielded a methamphetamine positive immunoassay result. From this work, we learn the theoretical maximum urine concentration of (−)-MAMP following heavy use of OTC intranasal products. However, the lack of corresponding concentrations in whole blood and plasma limits the translatability of results.

Along the same line, Smith et al.²⁰ sought to probe the enantiomeric selectivity of commercially available immunoassays following controlled intranasal administration of (−)-MAMP (N = 22). Doses were administered in accordance with manufacturer recommendations of 2 inhalations (from the 113 mg inhaler formulation) per nostril every 2 h. Participants received six intranasal doses on day one and a single intranasal dose on day two. Urine was collected for 32 h after administration of the first dose. Authors assessed three commercially available immunoassays; the EMIT II Plus Amphetamines assay (Siemens AG), KIMS Amphetamines II (Roche Diagnostics), and DRI Amphetamines assay (Microgenics Corporation) as well as analyte quantification via a GC/MS method.²⁸ Authors found that all three immunoassays had efficiencies of >97%, but the EMIT II Plus assay was cross-reactive to (−)-MAMP and gave several “methamphetamine positive” results. No (+)-MAMP or (+)-AMP was detected by GC/MS in any biological specimen. Authors also commented that significant intersubject variability existed, hindering calculation of any pharmacokinetic parameters. Combining immunoassay results and analyte concentration data yields a robust understanding of the strengths and limitations of available immunoassays. Furthermore, this study confirms that (−)-MAMP is not converted to (+)-MAMP in the body, which is valuable information for clinical and forensic toxicologists.

The pharmacodynamics of intranasal (−)-MAMP was first reported by Mendelson et al.¹⁹ wherein healthy volunteers (N = 12) participated in an open-label, ascending dose, multi-session study design. This was the first work to report results using the updated Vicks Vapo Inhaler formulation containing only 50 mg levmetamfetamine per inhaler.⁵ Doses started at those suggested by the manufacturer (2 inhalations per nostril every 2 h) and increased to 2 and 4 times the recommended dose. Several intranasal doses (4 dosing events) were administered over an 8-h period and volunteers remained at the research clinic for about 36 h. As discussed above, bioavailability of (−)-MAMP was also assessed via intravenous (−)-MAMP (5 mg) administration during a fourth study session. Total urinary methamphetamine excretion from the intravenous administration was used to estimate intranasal doses. Authors calculated intranasal doses as [mean (SD)] 74.0 (56.1) μg, 124.7 (106.6) μg, and 268.1 (220.5) μg at 1, 2, and 4 times the recommended dose. Plasma samples were collected 15 min after each dosing event and 5 min prior to the following dosing event. Plasma samples were also collected 4, 8, 18, 24, and 30 h after the fourth dosing event. All urine was collected and pooled according to 0–12, 12–24, and 24–36 h increments. A GC/MS method²⁷ was used to quantify analyte concentrations. However, most plasma specimens did not contain a detectable (>5 ng/mL) level of methamphetamine or amphetamine, so no pharmacokinetic parameters were calculated. Urine specimens did contain detectable levels, with concentrations increasing commiserate with dose escalation. Pharmacodynamics were assessed through blood pressure, heart rate, skin and core body temperature, respiratory rate, stress echocardiographic, and impedance cardiograph measurements. Subjective effects were captured through Visual Analog Scale ratings of “any drug effect”, “good drug effect”, “bad drug effect”, “nasal stuffiness”, “nasal dryness”, “headache”, and “dizziness”. Minimal cardiovascular and subjective effects were observed. Authors went on to conclude that (−)-MAMP, even at 4 times the recommended intranasal dose, is well tolerated and elicits minimal pharmacodynamic effects. Of importance to clinical and forensic toxicologists, plasma methamphetamine concentrations remained below 5 ng/mL, even at 4 times the recommended dose. For laboratories that consider plasma, and by extrapolation whole blood, this means even excessive use of intranasal (−)-MAMP decongestants are unlikely to be detected. However, repeated intranasal (−)-MAMP dosing does result in urine concentrations high enough to be detected by clinical and forensic toxicology laboratories. Conclusions drawn from this study are made translatable to other works and routes of administration through the authors’ efforts to estimate intranasal doses. Prior to this, readers were unable to infer total amounts of (−)-MAMP administered from different intranasal dosing conditions. This hindered translatability of all results to oral or intravenous administration studies where total dose is tightly controlled and reported.

As described above, intranasal administration of (−)-MAMP can result in detectable urine (−)-MAMP concentrations. This became world news in 2002 when Alain Baxter, a British Olympian, lost their Bronze Olympic metal after testing positive for (−)-MAMP.²⁹ They admitted to Vicks Vapor Inhaler use, but the International Olympic Committee forbids the presence of methamphetamine without distinguishing between isomers.^30,31 As a result, Dufka et al.¹⁸ sought to identify if intranasal (−)-MAMP (from the 50 mg inhaler formulation) provided any athletic performance enhancement as measured by distance traveled during a 20 min bike ride. Authors designed a two-session ascending-dose, double-blind, placebo-controlled study using high school student volunteers (N = 12). The first session administered 4 inhalations (∼16 μg) and the second session 12 inhalations (∼48 μg) of (−)-MAMP. The placebo was a similar inhaler that lacked the (−)-MAMP active ingredient. Pharmacodynamic effects were assessed by measuring volunteer heart rate, blood pressure, and distance traveled on the bike. Authors also probed subjective effects including “ability to breathe”, “energy”, “performance”, and “endurance”. The presence of (−)-MAMP did not significantly impact physiologic or subjective pharmacodynamic measures. This study confirmed that low dose (−)-MAMP consumption does not result in meaningful physiological effects nor does it enhance physical performance.

Most recently, Newmeyer et al.²¹ identified that no data existed on (−)-MAMP oral fluid concentration post controlled exposure. To fill the gap, they dosed participants (N = 16) intranasally (from the 50 mg inhaler formulation) per manufacturer recommendations a total of 6 times during day 1 and one more time in the morning of day 2. Biological specimens were collected prior to and 0.5, 1, 2, 2.5, 3, 4, 4.5, 5, 6, 6.5, 7, 8, 8.5, 9, 10, 10.5, 11, 12, 13, 15, 21, 24, 26, 28, 30, and 32 h after the first dosing event. Oral fluid was collected using 2 commercially available oral fluid collection devices, Quantisal and Oral-Eze, and screened with the DrugTest 5000. Analytes in plasma and oral fluid (both Quantisal and Oral-Eze) samples were quantified using a GC/MS method.³² Authors observed (−)-MAMP accumulation in oral fluid after several doses, with all participants achieving detectable levels of (−)-MAMP in their oral fluid at some point over the course of the study. The Quantisal and Oral-Eze collection devices yielded comparable results, and no oral fluid specimen screened on the DrugTest 5000 gave a positive methamphetamine result. Authors note that oral fluid/plasma ratios varied significantly across and within subjects. Furthermore, no (+)-MAMP was detected in any biological specimen. This was the first work to assess the pharmacokinetics of (−)-MAMP in oral fluid and used three modern and relevant oral fluid collection and screening tools. As the DrugTest 5000 is used in roadside drug impaired driving enforcement, the lack of cross-reactivity to (−)-MAMP from these intranasal dosing conditions is encouraging. However, future studies should build upon this work and assess other biological matrices such as whole blood and dried capillary blood spots.

Discussion

A total of 13 references including 10 unique studies (see Table 1) and 99 participants (see Table 2) were identified assessing the pharmacology of (−)-MAMP in humans. It is important to note that these works administered a wide range of doses, from 0.0168 mg¹⁸ to 45.4 mg.^12,13 Therefore, works were grouped by route of administration (i.e., oral, intravenous, and intranasal) and resulting pharmacokinetics (see Table 3), pharmacodynamics (see Table 4), and any reported adverse events were summarized. Across all pharmacokinetic assessments of (−)-MAMP, urine was the most popular matrix, considered in 9 studies and including 87 participants. Of those, urine was the only matrix considered in 8 studies including 51 participants, yielding a rudimentary understanding of (−)-MAMP pharmacokinetics. Plasma concentrations were only considered in 3 studies with 32 participants and oral fluid was considered once with 16 participants. No works quantified (−)-MAMP concentrations in whole blood, which is problematic given how prevalent whole blood testing is in forensic applications. This limits our ability to apply results from these works to current clinical and forensic toxicology workflows. Therefore, future works are required to determine the blood-to-plasma ratio for (−)-MAMP, which will aid in interpretation and interoperability of biological specimen test results.

Many urine-focused studies sought to understand the cross-reactivity of methamphetamine detection assays available at the time. In these works, the highest (−)-MAMP urine concentrations (via intranasal administration) reported was 6000 ng/mL.¹⁴ Recent toxicological investigation cutoff recommendations for methamphetamine were 200 ng/mL and 50 ng/mL for screening and confirmation urine assays, respectively.³³ Therefore, use of OTC intranasal decongestants containing (−)-MAMP may result in a positive methamphetamine result when considering urine specimens.^14−16,20 Increased awareness of this cross-reactivity is critical, with the need for future works to assess cross-reactivity of modern assays. No cross-reactivity works considered plasma or whole blood matrices, and none considered ELISA assays.

Of the available pharmacokinetic assessments (see Table 3), significant intra- and inter-subject variability was noted.^20,21 Despite variability, comparisons of metabolism of (+)-MAMP versus (−)-MAMP indicated that the presence of one enantiomer was impacting the metabolism of the other.¹³ To that end, Li et al. considered concentrations of para-hydroxymethamphetamine to begin understanding which metabolic pathways are stereoselective.¹² Given this limited information, much more remains to be learned about differences in (+)-MAMP and (−)-MAMP pharmacokinetics, including knowledge on the stereoselectivity of metabolic pathways. Understanding the stereoselectivity of metabolic pathways has implications beyond methamphetamine, as this information could be applied to other pharmaceuticals including improving drug design. Furthermore, understanding stereoselectivity may also improve prediction of potential side effects, drug toxicities, and drug interactions.

Pharmacodynamic measures were only assessed in 4 studies including 44 participants (see Table 4) and included doses across the entire range of 0.0168 mg¹⁸ to 45.4 mg.¹³ Generally, doses at or below 0.25 mg/kg (or 17.0–22.7 mg) lacked significant physiologic or subjective activity. Interestingly, Mendelson et al. identified that racemic methamphetamine (0.50 mg/kg 1:1 (+)-MAMP and (−)-MAMP) displayed more than an additive effect when compared to equivalent doses of (+)-MAMP and (−)-MAMP.¹³ This adds to the body of evidence that the presence of one isomer impacts metabolism of the other. As described above, more work is required to identify stereoselective metabolic effects of (−)-MAMP and (+)-MAMP. Additionally, a natural extension of observed synergistic effects from co-administration of (+)-MAMP and (−)-MAMP is potential impacts on other substances. Future works should consider interactions of both methamphetamine isomers with other OTC and prescribed pharmaceuticals, assessing for clinically relevant drug interactions and potential for increased adverse events. Furthermore, interactions between methamphetamine isomers and ethanol or opioids should also be studied, as polysubstance use, particularly methamphetamine and opioid co-use, continues to increase.³⁴⁻³⁶

Only one study group (Poklis et al.), including three publications and 7 participants,¹⁵⁻¹⁷ specifically mentioned observed adverse events. They reported that intranasal (−)-MAMP administration using the Vicks VapoInhaler resulted in excessive dry nose and mouth, significant and lingering taste and smell of menthol and camphor, and rebound congestion once study drug administration stopped. Only one other work, Li et al., including 8 participants and doses ranging from 1 to 10 mg mentioned adverse events, but only to state that no serious adverse events occurred.²⁴

Conclusion

Several generic OTC decongestant nasal sprays contain (−)-MAMP (or levmetamfetamine) as the active ingredient. Despite widespread availability to purchase (−)-MAMP nasal sprays both online and in physical retailers, a paucity of literature exists on (−)-MAMP pharmacology in humans. We identified only 10 unique studies including 99 participants with doses ranging from 0.0168 mg¹⁸ to 45.4 mg^12,13 across oral, intravenous, and intranasal administration. Alongside a summary of available pharmacokinetic and pharmacodynamic information, we identified the following areas in need of future research:

• (1)increased data on (−)-MAMP pharmacokinetics, including identification of the blood-to-plasma ratio
• (2)survey of modern methamphetamine screening assays for cross reactivity to (−)-MAMP across various biological matrices
• (3)increased awareness and understanding of stereoselective metabolic pathways as it relates to (+)-MAMP and (−)-MAMP
• (4)consideration of potential interactions from co-use of (−)-MAMP and therapeutic or recreational substances

Increasing knowledge around the pharmacology of (−)-MAMP in humans can provide important information about the drug’s safety, efficacy, and potential adverse events and inform interpretation of biological specimen methamphetamine concentration results. For example, when subjected to drug testing (e.g., for workplace testing, impaired driving, or drug-facilitated crimes investigations), methamphetamine results are often not isomer specific, even if methamphetamine concentration is quantified. Furthermore, the presence of (−)-MAMP does not, by itself, rule out illicit use, as methamphetamine synthesized in clandestine laboratories may be a racemic mixture of (+)-MAMP and (−)-MAMP. This creates a complicated interpretational landscape for physicians, toxicologists, and court officials.

Data Availability Statement

All data used in this work were derived from publications. Summaries of extracted data are included in this work.

The authors declare no competing financial interest.