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Pregnenolone: A hormone that can pump the brakes on intoxication from cannabis

Sources: Vallée et al, Science 343, 94 (2014); Blum et al, Journal of Reward Deficiency Syndrome 1(1), 20 (2015)

Although the scientific literature indicates that patients using cannabis to treat their ailments cannot overdose from ingesting too much Δ9-THC, anyone who has ingested more than they wanted to has likely experienced THC-induced anxiety. Recently, however, a hormonal steroid called pregnenolone has been implicated as playing a key role in diminishing the effects of too much THC. Steroids are known to play several roles within our bodies. Some steroids help regulate physiological processes such as eating, waking up, and sexual behavior. They can also regulate mood, our memories, and the ability to cope with stress.

Some hormones, called neurosteroids, are made in our brains by pregnenolone. Thus, it’s been thought that pregnenolone was just an inactive building-block chemical in our bodies that creates other molecules. The reduction of these neurosteroids in our bodies is thought to be associated with different impairments related to aging.

Researchers, predominantly from the French National Institute of Health and Medical Research (INSERM), injected THC into Wistar rats (rats developed specifically for biological and medical research in 1906) at doses corresponding to the median effective dose of about 3 mg/kg of body weight. The introduction of THC into the bloodstream had the concomitant effect of increasing pregnenolone via activation of the CB1 receptors in the rodents’ brains. Studies evaluating whether CB2 receptors were involved in these processes revealed no significant effects.

A 1500% increase in pregnenolone concentration was measured when induced by THC, and the duration of this increase lasted longer than ones induced by other drugs such as cocaine, morphine, nicotine, and alcohol. These other drugs increased pregnenolone, too, by approximately 300%. The largest increase in THC-induced pregnenolone levels was a whopping 3000% higher than the control in Wistar rats and in C57BL/6N mice, the most commonly used strain of lab mouse.

The highest THC-induced increase in pregnenolone in rats was observed in the frontal regions of the brain, including the prefrontal cortex, thalamus, striatum, and nucleus accumbens. These regions are known to be involved in motor and rewards systems, the latter of which involve things like motivation, wanting, desire, craving, positive rewards which involve pleasure (euphoria and ecstasy), planning, personality expression, decision-making, consciousness, and sensation.

Pregnenolone then acts as an inhibitor of the CB1 receptor, meaning the hormone can lessen the effects of THC. This occurs by a negative feedback activity on the CB1 receptor, which in turn interferes with most of the known behavioral and bodily effects of THC. Negative feedback helps regulate biological processes. Biologically, cannabis is known to introduce the “cannabinoid tetrad”: hypolocomotion, hypothermia, catalepsy, and analgesia. In layman’s terms, these refer to inhibitions in locomotion, reduced body temperatures, loss of motor control and the slowing down of bodily functions, and pain relief, respectively.

The researchers also studied the effects that injections of pregnenolone had on the animals. No effects were measured from subjectswhodid not receive THC, whereas the injection of pregnenolone in animals also having been given THC resulted in blocked THC-induced food intake (reduced “munchies”) in rats and mice, and diminishedTHC-induced memory impairment. Pregnenolone increase, therefore, does not delete the effects of THC; it just pumps the brakes, and lessens the effects.

Some have hypothesized that use of pregnenolone could help patients use cannabis without the head trip, similar to CBD–based medicines. For some diseases, like cancer, however, where patients may need the appetite-stimulating effects of THC, this would not be advantageous. While the authors of the pregnenolone study advocate use of the hormone as having potential for treating cannabis intoxication, another study cautioned the scientific community about blocking CB1 receptors, since other CB1 receptor blockers brought to market, like Rimonabant, have been pulled from the market in Europe, or rejected by the Food and Drug Administration due to dangerous mood changes including thoughts of suicide. Blocking these receptors, the authors state, would lead to a reduced release of dopamine, and long-term blockage of CB1 receptors could introduce a hypodopaminergic state, potentially leading to abnormalsubstance and behavioral addictions.

There is no universal agreement, however, as to the additive capabilities of cannabis, or whether discussions of a substance to aid on combating cannabis dependence is even warranted. The lack of an apparent lethal dose for THC, or even strong evidence that long-term cannabis use will have deleterious effects on productivity, motivation, creativity, etc., doesn’t sound the herald that a new agent is needed to block CB1 receptors. This notion was also discussed by Mitch Earleywine, Professor of Psychology at the University of Albany, State University of New York, and author of the book Understanding MarijuanaEarleywine told reporters that, “although the authors pitch this as a novel way to treat cannabis abuse, it’s actually a superb — if partial — explanation for why cannabis appears to have no potential lethal dose and why its capacity for creating addiction is more like caffeine’s than that of any illicit drug.”

Thus, the saga continues as does the argument for understanding all sides of an equation. THC-induced anxiety might be much more palatable for patients than developing other behavioral problems from an advanced hypodopaminergic state.

About the author

Jason S. Lupoi, Ph.D.

Jason S. Lupoi, Ph.D.

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