Is Cannabis Safe? How Safe is "Safe"?

The discussion of the overall safety of cannabis often starts with the notion that no fatal overdose of cannabis alone has ever been reported. While this is reassuring, it is difficult to prove that something has never happened, anywhere at any time. The scientific approach to assessing the safety of a drug, dietary supplement, botanical compound - whatever - is to test the substance in toxicology studies, typically involving animals.

In these studies, the LD50 is often used as a measure of toxicity. LD50 is an abbreviation for "Lethal Dose, 50%". This is the median amount of a substance (per body weight) required to kill 50% of the population being tested.1 The LD50 for Aspirin (acetylsalicylic acid), for example, is 200 mg/kg, when given orally. This means that 50% of rodents would be expected to die when given 200 mg of aspirin for every kilogram of their body weight. An over-the-counter dose of “Regular Strength” aspirin contains 325 mg. If the LD50, determined in rodents, was applied to humans, a 150-pound human (68.18 kilograms) consuming 42 aspirin at one time would face a 50% risk of death. Aspirin is considered very safe.

By comparison, the LD50 for IV heroin is 21.8 mg/kg.2 This is roughly 10% of the LD50 for aspirin, suggesting that heroin is 10 times more toxic than aspirin. Heroin is considered very dangerous.

What is the LD50 for Cannabis?

Cannabis is a plant. It’s hard to give a whole plant to a rodent. Besides, our pharmacology and pharmacognosy methods are designed to evaluate single molecules (i.e. “The active ingredient”). As a result, there is no LD50 for “cannabis”.

However, the LD50 for THC, the most psychoactive compound in cannabis, is 1,270 mg/kg, when administered orally in rodents.3 This is 6.4 times “safer” than aspirin, and 58.3 times safer than IV heroin.

I weigh 170 pounds, or 77 kilograms. If it required 1,270 mg of THC per kilogram of body weight to kill 50% of rodents, and we extrapolate to humans, consuming 100,000 mg of THC would increase my risk of death to 50%. It is not uncommon to find a cannabis brownie at a medical cannabis dispensary containing 100 mg of THC.

I would have to eat 1,000 of such brownies in one sitting to face a 50% risk of death. That’s a lot of brownies.

I should point out that I am directly extrapolating the LD50 for rodents to humans. It’s not that simple. And, the example uses ingested THC, not inhaled cannabis, or inhaled THC.

Beyond LD50

The safety of cannabis has always been one of its hallmark characteristics. In 1971, Lester Grinspoon MD, a Harvard professor, published a book entitled Marihuana Reconsidered, where he wrote, “One of the many exceptional features of cannabis is its remarkably limited toxicity.”4

In 1988, in an effort to reschedule cannabis from a Schedule I Controlled Substance (i.e. No medical value w/ high potential for abuse) to a Schedule II Controlled Substance (i.e. Accepted medical value w/ high potential for abuse), US Drug Enforcement Administration (DEA) Chief Administrative Law Judge Francis Young ruled "In the Matter of Marijuana Rescheduling" that, “Marijuana, in its natural form, is one of the safest therapeutically active substances known to man.”5 Despite this, then-DEA Administrator, John Lawn, ultimately rejected Young's ruling.6 Cannabis remained a Schedule I drug, as it is today.

The Physiology Behind Its Safety

One of the primary reasons why cannabis is so safe is because it does not suppress respiratory function, like opioids. Opioid-induced respiratory depression can be a cause of death, even in individuals taking the correctly prescribed amount of their opioid medication.

Cannabinoids exert their physiologic effects by binding to cannabinoid receptors in various tissues throughout the body. This is independent of whether these cannabinoids are produced internally (i.e. Endogenous cannabionids) or introduced to the body through the use of cannabis (i.e. Exogenous cannabionids). The specific effects are determined by the location, density and activity of these receptors. There are relatively few cannabinoid receptors in the cardio-pulmonary centers of the brain stem. As a result, the risk of death due to cannabis-induced respiratory depression is low.7

The Bottom Line

Cannabis is extremely safe. There is solid evidence to support this claim. That doesn’t mean that risks are not associated with its use however. Individuals who are inexperienced, suffer from significant psychiatric conditions, are pregnant or breast feeding, and/or taking multiple prescription medications should exercise caution and seek the counsel of a qualified medical practitioner.

References:

1. Median Lethal Dose. From Wikipedia, Free Encycl. https://en.wikipedia.org/wiki/Median_lethal_dose. Accessed September 4, 2017.

2. Diamorphine (PIM 261F, French). http://www.inchem.org/documents/pims/pharm/pim261f.htm. Accessed April 9, 2017.

3. Rosenkrantz H, Heyman IA, Braude MC. Inhalation, parenteral and oral LD50 values of Δ9-tetrahydrocannabinol in Fischer rats. Toxicol Appl Pharmacol. 1974;28(1):18-27. doi:10.1016/0041-008X(74)90126-4.

4. Grinspoon L. Marihuana Reconsidered. Quick American Archives; 1994.

5. Marijuana Rescheduling Petition, DEA Docket No. 86-22. http://www.iowamedicalmarijuana.org/Home/Young_1988. Accessed April 9, 2017.

6. 25 Years Ago: DEA’s Own Administrative Law Judge Ruled Cannabis Should Be Reclassified Under Federal Law - NORML.org - Working to Reform Marijuana Laws. http://norml.org/news/2013/09/05/25-years-ago-dea-s-own-administrative-law-judge-ruled-cannabis-should-be-reclassified-under-federal-law. Accessed April 9, 2017.

7. Herkenham M, Lynn AB, Little MD, et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A. 1990;87(5):1932-1936. http://www.ncbi.nlm.nih.gov/pubmed/2308954. Accessed April 9, 2017.