Methamphetamine Urine Toxicology: An In-depth Review

When a patient’s urine drug screen tests positive for methamphetamine by mass spectrometry, the result has serious implications for the patient and the provider. Determining the source of the methamphetamine is an important next step and is not always as straightforward as it appears.

Background
Methamphetamine increases synaptic dopamine, primarily by stimulating presynaptic release rather than by blocking reuptake. Small doses have central stimulant effects without significant peripheral actions. Methamphetamine produces subjective effects that are similar to those of cocaine, and it is for this reason that it is often a medication of abuse.1 In 2011, 133,000 persons aged 12 years or older abused methamphetamine for the first time and the overall number of past-month methamphetamine abusers was 439,000.2 Methamphetamine abuse carries significant morbidity. According to the Drug Abuse Warning Network, 6.6% of emergency department visits involving illicit drugs in 2009 were due to methamphetamine.3

In the United States, methamphetamine is a schedule II drug and is approved for treating both attention deficit hyperactivity disorder and obesity under the brand name Desoxyn. In addition, benzphetamine (Didrex) is a schedule III medication approved for treatment of obesity. Didrex is metabolized to methamphetamine. Besides prescription sources, methamphetamine (ie, “crystal meth”) can also be produced in small, clandestine laboratories using ephedrine or pseudoephedrine as a key ingredient. This has prompted restrictions on the distribution of these over-the-counter (OTC) medications.

Toxicology
Methamphetamine has 2 isomers, d-methamphetamine and l-methamphetamine. Prescription methamphetamine (Desoxyn)4 is composed entirely of the d isomer. D-methamphetamine increases alertness, concentration, energy, and in high doses, can induce euphoria, enhance self-esteem, and increase libido.1 These traits make d-methamphetamine very attractive to a potential abuser.

On the other hand, l-methamphetamine affects the sympathetic nervous system but has little activity in the central nervous system, so it is not thought to possess an addiction potential anywhere near that of the d-methamphetamine isomer. Among its few physiological effects is vasoconstriction, which makes it useful for nasal decongestion.1

Figure 1. OTC and Prescription Drugs Containing or Metabolized to Methamphetamine

The challenge for the laboratory is to differentiate between the d and the l isomer forms of methamphetamine. The clinician needs this critical information because without the d:l-isomer ratio, the clinician is unable to narrow down the potential sources of the methamphetamine. A positive methamphetamine test could be caused by use of an OTC product, a prescription drug, or illicit use (Table 1).5-8 The laboratory may run up to 3 distinct tests to produce a complete amphetamine profile. The first test is an immunoassay (IA) screening test for the amphetamine class of medications, which includes both amphetamines and methamphetamines. If the screening test is positive (a reaction greater than the cutoff), then a mass spectrometry (MS) confirmation test is performed to determine which specific compounds, amphetamine and/or methamphetamine, are present. Once methamphetamine is confirmed positive by MS, a third test may be performed to ascertain the ratio between the 2 isomers of methamphetamine. The d,l-isomer test also is performed by MS. Understanding each of the 3 testing steps is essential to clinical decision making related to patient care.

As noted, the first test is the IA screening test. This step is nonspecific in that the reaction can be caused not only by amphetamines but also by other compounds with a similar molecular structure, phentermine being a classic example. If the IA test is negative, no further testing is required and the amphetamines are considered negative. If the IA test is positive, the sample is analyzed by MS to determine whether it was an amphetamine that caused the reaction.

The MS confirmation test can come back with 4 possible results: 1) no amphetamines detected; 2) amphetamine only detected; 3) methamphetamine only detected; and 4) both amphetamine and methamphetamine detected (Figure 1). If no amphetamines are detected, then the amphetamine result is negative and no further testing is needed. If only amphetamine is detected, once again no further testing is needed. A finding of amphetamine-only positive by MS can be caused by prescription drugs (Adderall and various amphetamine salts) or as a result of methamphetamine metabolism, where the methamphetamine (whatever the source) has been converted to amphetamine. When methamphetamine is detected or both amphetamine and methamphetamine are detected, then the lab can run a d,l-isomer test to try and narrow the source of the positive methamphetamine finding (Figure 1).

The third and final test is the methamphetamine d,l-isomer test by MS (Figure 2). Based on a 1991 Department of Health and Human Services Technical Advisory, a d-methamphetamine level that is >20% of the total is considered indicative of a source other than an OTC product or a metabolite of selegiline.9 These sources could include a prescription medication or illegally manufactured methamphetamine. If the patient does not have a prescription for a drug that would result in >20% d-methamphetamine, illicit use of a diverted prescription product or street methamphetamine should be considered as a source.

A recent study by Esposito et al published in the Journal of Analytical Toxicology showed that d-methamphetamine percentages often were a few percentage points above or below the expected value based on the standard solutions they were testing.9 This was due to impurities in some of the derivatizing agents used. When interpreting test results, a clinician should consider that the result might never be 100% d or l isomer due to these impurities. Esposito concluded that the >20% d-methamphetamine guideline is still relevant and appropriate based on their findings.9

Summary
Illicit methamphetamine availability and use poses a serious health risk in the United States today. If abuse is suspected, urine drug tests are available to help clinicians detect its presence and intervene in order to optimize patient outcomes. There are a few distinct sources of methamphetamine. Using current methodology for urine toxicology testing will allow clinicians to narrow down the possible source of a positive result and assist them in managing their patients accordingly.

First published on: October 31, 2012