crossposting from tlneuro.wordpress.com
Drug “tolerance” is a fairly simple concept (Wikipedia). It means that with successive exposure to a given drug, in many cases the same dose produces a reduced effect. This can be for any number of mechanistic reasons including a change in the metabolism and/or excretion of that drug, a change in the number or sensitivity of the receptor sites through which the drug interacts with the body or a change in the neuronal circuitry, or physiological processes, that are affected. Of course, things are complicated since tolerance may or may not be produced depending on the behavioral or physiological measure in question, on the drug in question, on the circumstances (dose, freqency, etc) of drug exposure and a whole host of other factors. Drugs can even produce sensitization, which is a progressive increase in the effect with successive exposure.
Legalization of marijuana for medical use purposes in many US states and the recent decriminalization of purely recreational marijuana use in Colorado and Washington states has been associated with an effort to determine legal impairment. This is most typically in the context of the limit for operating an automobile. In WA, the decriminalization initiative set 5 ng THC per mL of blood is the “per se” limit for presumed impairment of the ability to operate an automobile. In Colorado, the State Senate passed a similar limit.
Leaving aside the question of what the limit should be, today I want to discuss a paper that makes some of the issues involved clearer and shows why there are not any straightforward answers.
Ginsburg BC, Hruba L, Zaki A, Javors MA, McMahon LR. Blood levels do not predict behavioral or physiological effects of Δ⁹-tetrahydrocannabinol in rhesus monkeys with different patterns of exposure.Drug Alcohol Depend. 2014 Jun 1;139:1-8.
[PubMed, Journal Site]
Ginsburg and colleagues report the relationship between blood levels of THC and effects on behavior and thermoregulation in rhesus monkeys. The key part of the paper is the comparison between a group of animals who had received twice-daily THC (1 mg/kg, s.c.) or animals who had received lower doses of THC (0.1 mg/kg, i.v.) only every 3 o4 4 days. These are referred to as the Intermittent and Chronic exposure regimens/groups.
The study examined the effect of a 3.2 mg/kg, s.c. dose of THC in each group. The primary outcome measures were rectal temperature (hypothermia is a classical effect of cannabinoids in laboratory models), response rate on stimulus-termination operant procedure and blood levels of THC. Response rate may not be the most complex behavior going but it does tend to be sensitive to general intoxication level. As you can see in Figure 1, reproduced here, the groups differ in the effect of an identical THC dose on both temperature and behavior. The Chronic treatment group had minimal to no response to THC whereas the Intermittent group had a significant drop in body temperature and a slowing of response rate. The key consideration was that there was no difference in the blood levels of THC between the groups. Thus, the tolerance that was observed cannot be due to metabolic tolerance, i.e., a change in the rate of drug metabolism and excretion. Importantly, this means that chronic and occasional users of marijuana being tested for possible DUI will not differ due to metabolism of the drug.
As I noted, this study does not really speak to what blood level would be associated with impaired human driving after THC. The behavioral measure is simply too distantly related for good inference-particularly since driving crashes are more about failures of attention and judgment then about physical control over the car. What it does show, however, is that a given THC blood level is fairly meaningless as a predictor of the impairment of a given individual without any knowledge of that person’s history of exposure to THC.