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CLINICAL ISSUES :: TOXICOLOGY


Cannabis testing in the era of legalization C


By Min Yu, MD, PhD, DABCC and Pratistha Ranjitkar, PhD, DABCC


It is a flowering plant that contains over 500 known compounds, including more than 100 dis- tinct cannabinoids and other non-cannabinoids.2


annabis is one of the most commonly used illicit drugs worldwide.1


Of the


known cannabinoids, tetrahydrocannabinol (THC) and can- nabidiol (CBD) are the predominant and most well defined compounds for medicinal and recreational purposes. Acting as a partial agonist, THC exerts its pharmacological effects by activating the human cannabinoid receptors CB1 and CB2.3


In contrast, CBD has proved to counteract psychoac- tive effects from THC and even possess multiple therapeu- tic properties, including antiepileptic, anti-anxiety, anti- inflammatory, and neuroprotective effects.4-6 The potency of cannabis—defined by the ratio of THC/ CBD—varies across different cannabis strains in which higher ratio correlates to a higher risk of psychotic effects of the drug.7


drop in levels in blood, albeit with continuing drug effects.11 After consumption by a variety of routes, THC is further metabolized to the psychoactive compound 11-OH-THC, inactivated to THC-COOH, and excreted in feces and urine. As a result of tissue deposition and slow redistribution back to systemic circulation, the half-life of THC and its major metabolites varies from days to months. While occasional users have THC/metabolites detectable for a few days, the detection window in chronic users who usually have large tissue burden, can last for months, confounding the question pertaining to recent use.


The ratio of THC/CBD is also the most obvious differ- ence between recreational and medicinal cannabis use. Typi- cal THC concentration is never above 10 percent in medical cannabis. However, recreational marijuana may contain THC in the range of 15-30 percent, with the highest concentration being 37 percent.8


In addition to the heterogeneity of the cannabis com- position, the current landscape of legalization status of cannabis also adds to its complexity. In the U.S., federal and state laws regarding medical use of cannabis and can- nabinoids are in conflict and have led to confusion among patients, caregivers, and healthcare providers. According to Control Act of 1970, the Federal Drug Enforcement Agency lists cannabis as a Schedule 1 substance.9


Under this provi-


sion marijuana is considered unacceptable for medical use, has a high potential for abuse, and is believed to be unsafe for use even under medical supervision. Despite the prohibi- tion of medical cannabis use under federal law, some states stand on the side of favoring marijuana use for its medicinal effects. Since California passed the first state law allowing medical marijuana in 1996, today 33 states and the District of Columbia have followed suit, among which 10 allow recreational marijuana consumption as well.10 With the advent of medical or legalized marijuana, pat- terns of cannabis use have changed dramatically. The ques- tions physicians and legal professionals are often interested in knowing include estimating the time the drug was used last and the concentration in a biological sample that correlates to impairment. These questions are challenging to answer given the non-linear pharmacokinetics (PK) of THC, various routes of consumption (smoking, vaporization, dabbing, oral, dermal), development of tolerance in chronic users, and titra- tion of dose to achieve desired affects by users.11


Thus, a clear


limit for impairment has not been established in any biologi- cal matrix. Furthermore, due to the complex PK of THC, the presence of THC and/or its metabolites in biological fluids is not sufficient to determine recent use. But it is an acceptable surrogate as evidence for impairment. THC is detectable in blood within seconds after inhalation, and peaks in about three to 10 minutes.11,12


In contrast, orally ingested cannabis


peaks at one to two hours after ingestion, demonstrating the PK variability with different modes of consumption. Being highly lipophilic, THC in circulation will quickly distribute to adipose tissue, liver, lung, and spleen, resulting in a rapid


16 MAY 2019 MLO-ONLINE.COM


Nevertheless, a number of controlled trials have aided in our understanding of THC PK in various biologi- cal fluids and identified cannabinoids that could predict recent use. The most common matrices include urine, blood, and oral fluid (OF). Most laboratories offer either an immunoassay-based screening test or a more specific and sensitive test by liquid chromatography (LC) or gas chromatography mass spectrometry (GC-MS), which has the ability to detect individual metabolites. Testing in each of these matrices, although imperfect, elucidates some history of marijuana use and it is important to understand these inadequacies to accurately interpret laboratory results.


Testing in urine


In medical settings, clinicians often test for THC in urine to monitor abstinence in patients enrolled in a transplant pro- gram, drug abuse treatment program, or pain management program.11


The most commonly detected marker in urine is THC-COOH. Other THC metabolites are either absent, present at very low concentrations in urine, or commercial standards are unavailable precluding their identification.13 Presence of these metabolites in urine is only indicative of cannabis exposure and cannot be used to predict when it was used last or to glean impairment.


In occasional smokers, the detection window in urine can be several days. In contrast, chronic users can have detect- able THC-COOH for months following abstinence.11


As such,


mathematical models have been developed to identify new cannabis use from residual excretion in both groups. The premise of the models comprises of comparing creatinine- normalized THC-COOH ratios from two different urine col- lections.14


prediction for the time interval between urine collections is indicative of new use.14


In occasional users, a ratio greater than the model’s In frequent users, rules that account


for residual excretion are incorporated in ratio comparison for a more accurate prediction of residual excretion vs. new use.15 In this model, based on the amount of creatinine normal- ized THC-COOH excreted in the first urine sample, the algo- rithm prescribes obtaining a second sample either 48 hours later or on the fifth day. Subsequent comparison of the ratio either predicts residual use, new use, or recommends addi- tional sample collection for further comparison. Thus, urine testing is generally informative in determining continued abstinence or detecting renewed use.


Testing in blood Testing cannabis metabolites in blood/plasma is indicated for evaluation of possible impairment in cognitive or psycho- motor functioning. Although cannabis-impairing effects are


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