Keywords: Methamphetamine,R-(−)-methamphetamine,l-methamphetamine, pharmacokinetics, pharmacodynamics, systematic review

Design and Registration

This systematic review wasregistered with the international prospective register for systematicreviews (PROSPERO). The registration number is 367503.¹⁰

Search Strategy

A systematic search of the literaturewas performed adopting the 2020 preferred reporting items for systematicreviews and meta-analysis (PRISMA).^8,9 Eligibilitycriteria included peer-reviewed literature concerning the administrationofR-(−)-methamphetamine to humans. Studieswere grouped for synthesis by the route of administration: oral, intravenous,and intranasal. One author (H.M.B.) searched PubMed and Web of Sciencedatabases on October 11, 2022. Search terms included methamphetamineisomer, methamphetamine enantiomer, methamphetamine stereoisomer,l-methamphetamine, methamphetamine,R-(−)-methamphetamine,R-methamphetamine, levomethamphetamine, levodesoxyephedrine,l-desoxyephedrine, and levmetamfetamine. In PubMed, studies were limitedto clinical trials and randomized controlled clinical trials. In Webof Science, the search terms were queried using the AND function withthe search term human. Additional searches were performed by two authors(H.M.B. and A.M.) using Google and Google Scholar on October 12 and13, 2022. No restrictions by publication date of the literature wereapplied. Studies were limited to the English language. The referencesincluded in identified studies were also scrutinized for applicableliterature. Resulting references were uploaded into Covidence (2022,version 3030) for title and abstract screening, full-text eligibilityanalysis, quality and bias assessment, and data extraction.

Study Selection

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

Risk of Bias and Confidence Assessment

Risk of biaswas independently assessed by two authors (H.M.B. and R.H.) in Covidenceusing the standard quality assessment form. The risk of bias assessmentincluded blinding of participants, blinding of the study team, allocationconcealment, incomplete outcome data, and selective outcome reporting.Bias was assessed as either high risk, low risk, or uncertain riskaccording to Cochrane collaboration tools for assessing the risk ofbias.¹¹ Study confidence was assessed byconsidering the study participant pool size and demographics.

Outcomes Analyzed

The main outcomes analyzed were qualitativeand quantitative descriptions of analyte concentrations in biologicalspecimens and pharmacodynamics measures of drug effects collectedat various time points post study drug administration. Analytes includedR-(−)-methamphetamine,S-(+)-methamphetamine((+)-MAMP),R-(−)-amphetamine ((−)-AMP),andS-(+)-amphetamine ((+)-AMP). and biological matricesconsidered were urine, blood, plasma, and oral fluid. Pharmacodynamicmeasures included heart rate, blood pressure, and body temperature.Other pharmacodynamics measures such as subjective drug effects werealso included as secondary outcomes when available. Reporting on adverseevents including withdrawal or discontinuation due to drug-relatedadverse events were recorded as a secondary outcome.

Data Extraction

Data were independently extracted bytwo authors (H.M.B. and R.H.) in Covidence using a slightly modifieddata extraction standard form. The following data were extracted fromeach 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), publicationdate, funding source, conflicts of interest, population description,inclusion criteria, exclusion criteria, method of recruitment, totalnumber of participants, demographic details (i.e., age, sex, race),intervention and comparisons, route of administration, pharmacokineticoutcomes, pharmacodynamic outcomes, and adverse events. Due to thepaucity of available literature encompassing a wide range of dosesand different routes of administration, only a qualitative synthesisof extracted data was performed.

Table 1. Summary of Studies Included in ThisReview^a.

Table 2. Summary of Included Participants andAvailable Demographic Details.

Oral Administration

The first report of (−)-MAMPpharmacology in humans was published in 1973 by Beckett et al.²³ In this work, the urinary pharmacokinetics ofunchanged and metabolized (+)-MAMP and (−)-MAMP were consideredalongside those of ethyl-,n-propyl-, andn-butyl-amphetamine. After oral administration of the studydrug (12.45 mg of methamphetamine HCl), urine specimens were collectedfrom participants (N = 6) every half hour for thefirst 4 h, hourly up to 12 h, with intervals increasing in durationup to 24 and 48 h. Study endpoints included the concentration of (+)-MAMP(−)-MAMP and their (+)-AMP and (−)-AMP metabolites incollected urine specimens. Authors used an in-house gas–liquidchromatography approach²⁵ and thin layerchromatography (TLC) to measure analytes. It was found that (+)-MAMPwas metabolized to amphetamine more than (−)-MAMP. Also, peakexcretion rates of methamphetamine occurred 1–3 h after studydrug administration, and (−)-MAMP was excreted more rapidlythan (+)-MAMP. The calculated half-life and rate constants were reportedfor four participants: two for (+)-MAMP and two for (−)-MAMP.Authors calculated the rate constant from the half-life and recoveryin urine unchanged, assuming there was no change in half-life beyond24 h. The average amount of methamphetamine and amphetamine excretedunchanged in the urine and the calculated half-life can be found inTable3. Results from thisstudy indicate that methamphetamine stereochemistry impacts humanmetabolism, although only urine specimens were considered.

Another example of (−)-MAMP pharmacology fromoral studydrug 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, and48 h post study drug administration. Authors used a capillary zoneelectrophoresis method²⁶ with a chiralselector to quantify (+)-MAMP, (−)-MAMP, (+)-AMP, and (−)-AMPin urine specimens. Measured concentrations of all analytes were presentedas a figure, but no pharmacokinetic parameters were calculated. Thiswork focused on describing a novel enantiomer separation and quantificationmethod. Although a human was dosed with methamphetamine, the authorsmissed 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) tohumans.²⁴ Authors hypothesized that (−)-MAMP-d₃ could be administered during methamphetaminetreatment clinical trials to semi-quantitatively assess illicit methamphetamineexposure. That is, assessing biological concentrations from a knowndose of deuterated (−)-MAMP enables researchers to estimatemethamphetamine intake from non-controlled sources. To that end, authorsconstructed a study with five sessions: (1) oral 1 mg (−)-MAMPfollowed 1.5 h later by intravenous placebo (0.9% NaCl), (2) oral2.5 mg (−)-MAMP followed 1.5 h later by intravenous 2.5 mgof (−)-MAMP-d₃ (infused over 30min), (3) oral 5 mg (−)-MAMP followed 1.5 h later by intravenousplacebo, (4) oral 10 mg (−)-MAMP followed 1.5 h later by intravenousplacebo, and (5) oral placebo followed 1.5 h later by intravenousplacebo. 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 wascollected as aliquots from each void and pooled in 24-h intervals.Authors quantified analytes using a gas chromatography–massspectrometry (GC-MS) method with derivatization.²⁷ The authors used a non-compartmental trapezoid method tocalculate pharmacokinetic parameters, displayed inTable3. Generally, the authors foundthat all (−)-MAMP doses were well tolerated, and no seriousadverse events occurred. This dose range also lacked physiologicalactivity as study drug administration did not result in relevant heartrate, blood pressure, core temperature, respiration rate, or oxygensaturation changes compared to the placebo, as detailed inTable4. Furthermore, nodifferences were detected in participant-reported subjective effectsof study drug administration compared to the placebo. From this work,we learn that orally administered doses of (−)-MAMP at or below10 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 applicationof this pharmacokinetic data to forensic and clinical toxicology resultswhere (+)-MAMP or racemic methamphetamine consumption is suspected.

Intravenous Administration

As stated above, Li et al.administered an intravenous dose of (−)-MAMP-d₃ (2.5mg over 30 min) 1.5 h after an oral dose of (−)-MAMP (2.5 mg).²⁴ This approach enabled the authors to estimatethe absolute bioavailability of (−)-MAMP. Resulting calculatedpharmacokinetic parameters (seeTable3) revealed a bioavailability close to 1, indicatingcomplete absorption of the oral dose. Administration of a deuteratedintravenous dose to estimate uncontrolled methamphetamine consumptionis a novel and effective tool to corroborate self-reported methamphetamineuse. However, future studies should include other biological matricessuch as urine, whole blood, dried capillary blood spots, and oralfluid. Assessing a suite of biological matrices of various levelsof invasiveness increases translatability of results.

Similarly,Mendelson et al.¹⁹ administered participants(N = 12) a single intravenous (−)-MAMP (5mg, 15 min infusion) dose to determine absolute bioavailability. Plasmasamples were collected before and 0.5, 1, 2, 4, 8, 18, 24, and 30h after study drug administration. All urine was collected and pooledaccording to 0–12, 12–24, and 24–36 h increments.A GC/MS method²⁷ was used to quantify analyteconcentrations, and total urinary methamphetamine excretion was foundfrom the intravenous dose. Authors assumed similar distribution andelimination of intranasal and intravenous (−)-MAMP administrationand used the total urinary methamphetamine excretion to estimate howmuch (−)-MAMP was administered during intranasal dosing, whichis described in theIntranasal 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 pharmacokineticsand pharmacodynamics of (−)-MAMP, (+)-MAMP, and a 1:1 racemicmixture. Dosages included 0.25 mg/kg and 0.5 mg/kg for both (−)-MAMPand (+)-MAMP. The racemic dose was 0.5 mg/kg, and the placebo was0.9% NaCl. Blood was collected from volunteers prior to study drugadministration and 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 30, 36, and48 h after dosing. Pharmacokinetic parameters were calculated usingthe linear trapezoidal rule. Available pharmacokinetic parametersare included inTable3. Of note, the authors found that the apparent exposure of (+)-MAMPand (−)-MAMP (0.25 and 0.5 mg/kg doses) were bioequivalentwhen 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 inhibitingor inducing metabolism of the other. Authors also assessed the pharmacodynamicsof (−)-MAMP through physiologic and subjective measures. Physiologicmeasures included heart rate, blood pressure, respiration rate, skintemperature, 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 intoxicationand several other subjective drug effects such as “good drugeffect”, “drug liking”, and “bad drugeffect”, among others which were collected prior to dosingand 0.5, 1, 1.5, 3, 4, 5.5, 8, 12, and 24 h after dosing. A summaryof all observed pharmacodynamic measures is available inTable4. Cardiovascular andsubjective effects from (+)-MAMP (0.5 mg/kg) were much longer-lastingthan those from (−)-MAMP (0.5 mg/kg). Although both enantiomers(0.5 mg/kg) produced similar peak subjective effects, those from (−)-MAMPdissipated rapidly compared to (+)-MAMP. The 0.25 mg/kg (−)-MAMPdose did not produce significant physiologic or subjective effectswhen compared to the placebo. Unexpectedly, effects from the racemicdose (1:1, 0.5 mg/kg total) were like that of the 0.5 mg/kg (+)-MAMPdose. Authors found that racemic methamphetamine has more than anadditive effect when comparing results to equivalent doses of (+)-MAMPand (−)-MAMP. Results from this work are heavily relied uponby clinical and forensic toxicologists. Use of both (+)-MAMP and placebocontrols contextualized the robust data on (−)-MAMP pharmacokineticsand pharmacodynamics. Furthermore, racemic methamphetamine resultsare particularly interesting, and warrant further inquiry.

Usingthe same participant pool, Li et al.¹² re-analyzedthe data with a new focus on urinary pharmacokinetics.In this work, the percent recovery of methamphetamine and amphetaminein urine was reported. Plasma pharmacokinetic parameters were alsore-analyzed, and although the values vary slightly from their priorpublication, all are within published confidence intervals. Therefore,the percent recovery values are added toTable3 as a joint entry with their prior work.In agreement with their, and others prior work, the authors concludethat metabolism of methamphetamine is stereoselective. Through considerationof other metabolites, such aspara-hydroxymethamphetaminein this work, researchers can begin to elucidate which metabolic pathwaysare stereoselective. That said, future works should include othermethamphetamine metabolites to gain a better understanding of whichmetabolic pathways are stereoselective. This information may revealnew biomarkers distinguishing (+)-MAMP versus (−)-MAMP consumption,which would hold great value to clinical and forensic toxicologists.

Intranasal Administration

Researchers identified theneed 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 resultsbeginning in 1988. Fitzgerald et al.¹⁴ reportedresults from a human subjects study (N = 3) wherevolunteers were instructed to take several deep inhalations from aninhaler containing (−)-MAMP every 20 min for 6 h. This dosingis significantly greater than the manufacturer recommended maximumof two inhalations in each nostril once every 2 h. Authors went onto collect urine specimens in intervals of 0–1, 1–3,3–5, 5–7, and 7–24 h. Several commercially availableimmunoassays developed to detect (+)-MAMP were then used to assessfor cross-reactivity to (−)-MAMP. Immunoassays considered includedthe EMIT (Syva), Toxilab (Analytical Systems), TDx (Abbot), and AbuscreenRIA (Roche). Authors also analyzed urine specimens by GC-MS with achiral derivatizing reagent to quantify methamphetamine enantiomersalso described in this work. Authors discovered that immunoassayswith low limits of detection for (+)-MAMP (EMIT, Toxilab, and TDx)were cross reactive to (−)-MAMP and gave “methamphetaminepositive” results. As clinical and forensic toxicology laboratoriesretire immunoassays in favor of high-resolution mass spectrometryscreening techniques, results from this early work are less informative.That said, it is still important that laboratories understand thestrengths and limitation of any screening tool, including selectivityand sensitivity to relevant isomers.

Similarly, Poklis et al.published three manuscripts¹⁵⁻¹⁷ describing cross-reactivity resultsof the EMIT II amphetamine/methamphetamine assay (Syva),¹⁷ TDxADx/FLx amphetamine/methamphetamine II fluorescencepolarization immunoassay (Abbot),¹⁶ andthe EMIT-d.a.u. class (EC) and EMIT-d.a.u. monoclonal amphetamine/methamphetamine(ME) assays (Syva).¹⁵ When an immunoassaygave a positive result, an aliquot of that urine specimen was analyzedby chiral GC/MS.¹⁴ All these works resultedfrom one participant pool (N = 7) which was dividedinto two arms. One arm (N = 4) received the manufacturersuggested 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 of2 inhalations in each nostril every hour for 3 days. All voided urinewas collected over the 5-day study period. When following the manufacturersuggested dosing regimen, the greatest (−)-MAMP urine concentrationwas 872 ng/mL and at double the manufacturer suggested dose the maximumwas 1,560 ng/mL. The TDxADx/FLx and EMIT-d.a.u. immunoassays gavepositive results for some urine specimens from some participants.The EMIT II assay did not give any positive results, even at doublethe manufacturer suggested (−)-MAMP dose. It is worth notingthat participants in the double-dose arm reported significant discomfortfrom frequent and prolonged inhaler use. Authors report adverse eventsincluding excessively dry nose and mouth, significant lingering mentholand camphor taste and smell, and rebound congestion upon cessationof the study drug. A major strength of these works was the separationand quantification of (−)-MAMP in urine specimens that yieldeda methamphetamine positive immunoassay result. From this work, welearn the theoretical maximum urine concentration of (−)-MAMPfollowing heavy use of OTC intranasal products. However, the lackof corresponding concentrations in whole blood and plasma limits thetranslatability of results.

Along the same line, Smith et al.²⁰ soughtto probe the enantiomeric selectivity of commercially available immunoassaysfollowing controlled intranasal administration of (−)-MAMP(N = 22). Doses were administered in accordance withmanufacturer recommendations of 2 inhalations (from the 113 mg inhalerformulation) per nostril every 2 h. Participants received six intranasaldoses on day one and a single intranasal dose on day two. Urine wascollected for 32 h after administration of the first dose. Authorsassessed three commercially available immunoassays; the EMIT II PlusAmphetamines assay (Siemens AG), KIMS Amphetamines II (Roche Diagnostics),and DRI Amphetamines assay (Microgenics Corporation) as well as analytequantification via a GC/MS method.²⁸ Authorsfound that all three immunoassays had efficiencies of >97%, buttheEMIT II Plus assay was cross-reactive to (−)-MAMP and gaveseveral “methamphetamine positive” results. No (+)-MAMPor (+)-AMP was detected by GC/MS in any biological specimen. Authorsalso commented that significant intersubject variability existed,hindering calculation of any pharmacokinetic parameters. Combiningimmunoassay results and analyte concentration data yields a robustunderstanding of the strengths and limitations of available immunoassays.Furthermore, this study confirms that (−)-MAMP is not convertedto (+)-MAMP in the body, which is valuable information for clinicaland forensic toxicologists.

The pharmacodynamics of intranasal(−)-MAMP was first reportedby Mendelson et al.¹⁹ wherein healthy volunteers(N = 12) participated in an open-label, ascendingdose, multi-session study design. This was the first work to reportresults using the updated Vicks Vapo Inhaler formulation containingonly 50 mg levmetamfetamine per inhaler.⁵ Doses started at those suggested by the manufacturer (2 inhalationsper nostril every 2 h) and increased to 2 and 4 times the recommendeddose. Several intranasal doses (4 dosing events) were administeredover an 8-h period and volunteers remained at the research clinicfor about 36 h. As discussed above, bioavailability of (−)-MAMPwas also assessed via intravenous (−)-MAMP (5 mg) administrationduring a fourth study session. Total urinary methamphetamine excretionfrom the intravenous administration was used to estimate intranasaldoses. 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 collected15 min after each dosing event and 5 min prior to the following dosingevent. Plasma samples were also collected 4, 8, 18, 24, and 30 h afterthe fourth dosing event. All urine was collected and pooled accordingto 0–12, 12–24, and 24–36 h increments. A GC/MSmethod²⁷ was used to quantify analyte concentrations.However, most plasma specimens did not contain a detectable (>5ng/mL)level of methamphetamine or amphetamine, so no pharmacokinetic parameterswere calculated. Urine specimens did contain detectable levels, withconcentrations increasing commiserate with dose escalation. Pharmacodynamicswere assessed through blood pressure, heart rate, skin and core bodytemperature, respiratory rate, stress echocardiographic, and impedancecardiograph measurements. Subjective effects were captured throughVisual Analog Scale ratings of “any drug effect”, “gooddrug effect”, “bad drug effect”, “nasalstuffiness”, “nasal dryness”, “headache”,and “dizziness”. Minimal cardiovascular and subjectiveeffects were observed. Authors went on to conclude that (−)-MAMP,even at 4 times the recommended intranasal dose, is well toleratedand elicits minimal pharmacodynamic effects. Of importance to clinicaland forensic toxicologists, plasma methamphetamine concentrationsremained below 5 ng/mL, even at 4 times the recommended dose. Forlaboratories that consider plasma, and by extrapolation whole blood,this means even excessive use of intranasal (−)-MAMP decongestantsare unlikely to be detected. However, repeated intranasal (−)-MAMPdosing does result in urine concentrations high enough to be detectedby clinical and forensic toxicology laboratories. Conclusions drawnfrom this study are made translatable to other works and routes ofadministration through the authors’ efforts to estimate intranasaldoses. 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 intravenousadministration studies where total dose is tightly controlled andreported.

As described above, intranasal administration of (−)-MAMPcan result in detectable urine (−)-MAMP concentrations. Thisbecame world news in 2002 when Alain Baxter, a British Olympian, losttheir Bronze Olympic metal after testing positive for (−)-MAMP.²⁹ They admitted to Vicks Vapor Inhaler use, butthe International Olympic Committee forbids the presence of methamphetaminewithout 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 anyathletic performance enhancement as measured by distance traveledduring 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 (∼48μg) of (−)-MAMP. The placebo was a similar inhaler thatlacked the (−)-MAMP active ingredient. Pharmacodynamic effectswere assessed by measuring volunteer heart rate, blood pressure, anddistance traveled on the bike. Authors also probed subjective effectsincluding “ability to breathe”, “energy”,“performance”, and “endurance”. The presenceof (−)-MAMP did not significantly impact physiologic or subjectivepharmacodynamic measures. This study confirmed that low dose (−)-MAMPconsumption does not result in meaningful physiological effects nordoes it enhance physical performance.

Most recently, Newmeyeret al.²¹ identifiedthat no data existed on (−)-MAMP oral fluid concentration postcontrolled 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 andone more time in the morning of day 2. Biological specimens were collectedprior 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 firstdosing event. Oral fluid was collected using 2 commercially availableoral fluid collection devices, Quantisal and Oral-Eze, and screenedwith the DrugTest 5000. Analytes in plasma and oral fluid (both Quantisaland Oral-Eze) samples were quantified using a GC/MS method.³² Authors observed (−)-MAMP accumulationin oral fluid after several doses, with all participants achievingdetectable levels of (−)-MAMP in their oral fluid at some pointover the course of the study. The Quantisal and Oral-Eze collectiondevices yielded comparable results, and no oral fluid specimen screenedon the DrugTest 5000 gave a positive methamphetamine result. Authorsnote that oral fluid/plasma ratios varied significantly across andwithin subjects. Furthermore, no (+)-MAMP was detected in any biologicalspecimen. This was the first work to assess the pharmacokinetics of(−)-MAMP in oral fluid and used three modern and relevant oralfluid collection and screening tools. As the DrugTest 5000 is usedin roadside drug impaired driving enforcement, the lack of cross-reactivityto (−)-MAMP from these intranasal dosing conditions is encouraging.However, future studies should build upon this work and assess otherbiological matrices such as whole blood and dried capillary bloodspots.

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Data Availability Statement

All data usedin this work were derived from publications. Summaries of extracteddata are included in this work.