Busting the Overdose Myth

CANNABIS CULTURE – There’s been a lot of talk in the media about cannabis “overdoses” at public events like 420. This language, particularly as we face a continent wide opioid crisis, is entirely irresponsible. An overdose, is serious and tragic. People die from overdoses. And while, “greening out” can be a very unpleasant consequence of over-consumption, nobody dies from cannabis use. In fact, to quote Judge Francis L. Young’s 1988 report:

“At present it is estimated that marijuana’s LD-50 is around 1:20,000 or 1:40,000. In layman terms this means that in order to induce death a marijuana smoker would have to consume 20,000 to 40,000 times as much marijuana as is contained in one marijuana cigarette. NIDA-supplied marijuana cigarettes weigh approximately .9 grams. A smoker would theoretically have to consume nearly 1,500 pounds of marijuana within about fifteen minutes to induce a lethal response.”

Judge Young would go on to say:

“In strict medical terms marijuana is far safer than many foods we commonly consume. For example, eating 10 raw potatoes can result in a toxic response. By comparison, it is physically impossible to eat enough marijuana to induce death. Marijuana in its natural form is one of the safest therapeutically active substances known to man. By any measure of rational analysis marijuana can be safely used within the supervised routine of medical care.”

For a more updated look, this article by Professor Gaber looks at drug toxicity, with cannabis coming in near the bottom. The following graph illustrates this quite well:

From: https://commons.wikimedia.org/wiki/File:Drug_danger_and_dependence.svg

So, why is deadly cannabis “overdose” more theory than reality? We went over this last week when assessing Dr. Chris Wilkes’ claims, but to reiterate … Cannabinoids are allosteric modulators that act on the G-coupled protein receptors (GPCRs), cannabinoid receptors 1 and 2 (CB1 and CB2). These receptors have not faced the same evolutionary pressure to produce a specific endogenous ligand, meaning that the chances of deadly overdose from cannabinoids are less likely to occur. To quote ‘Drug Design Strategies for GPCR Allosteric Modulators’:

“Recently, a new “wave” of drug discovery research has emerged to fill this gap, purposely aiming to modulate target receptors by the use of allosteric ligands, which interact with the receptor at a binding site topographically distinct from the endogenous ligand. By binding at this new receptor region, challenging chemical space may be avoided. Moreover, enhanced subtype selectivity profiles may be obtained compared with that of an orthosteric agent binding to a highly conserved site, potentially leading to improved safety and pharmacology profiles. Furthermore, the lack of desensitization arising from receptor overstimulation under constant exposure to an agonist, and preservation of the temporal and local patterns of physiological activity of the endogenous ligand are additional appealing attributes of allosteric modulators.”

So, if people ask you why cannabis and the discovery of the endocannabinoid system (ECS) has changed the way we think about drugs and medications, point them to this sort of research. Cannabinoids, terpenoids and allosteric modulation could be the way forward with regards to developing relatively safe, effective, powerful drugs and medications that could help treat a whole range of conditions. The feedback systems of the ECS seems to ensure that THC and other cannabinoids never go into too high a concentration in the body to start having poisonous effects. For example, THC seems to inhibit the enzyme fatty acid amide hydrolase – FAAH – leading to an increase in anandamide. However, the body breaks down THC very quickly, meaning it does not necessarily lead to a level that reaches overdose.

Yet, if we are to say that the ECS plays an intimate role in homeostasis, then we can be assured that it is a very powerful system indeed. Endogenous cannabinoids are important for all sorts of physiological processes, from reward and hunger to immune regulation and the early stages of human pregnancy. Whilst natural cannabinoids seem to be well-tolerated by the human body, synthetic cannabinoids (SCBs) are a different kettle of fish, as the way in which they affect the ECS is unknown. Playing around with endogenous cannabinoids and desensitizing or “shutting off” the body’s endocannabinoid receptors could have some very detrimental effects, including psychosis and even death. So, with this in mind, a “cannabis overdose” is certainly possible – it just depends upon which cannabinoid we’re talking about, and it would involve inert plant materials sprayed with man-made cannabinoids of unknown effect, rather than the natural cannabis plant (which, like any biological organism, has “checks and balances” of its own, perhaps ensuring that an overabundance of any one particular cannabinoid is not produced).

There is also potentially another way that cannabis can be involved in an “overdose”, but in an indirect way. Cannabidiol (CBD) desensitizes the liver enzyme cytochrome P450 (CYP450) – an enzyme involved in the processing of many drugs, e.g. benzodiazepines. Should a person be using CBD as well as benzodiazepines, their liver may not be able process the benzodiazepines, leading to a buildup of dangerous levels of benzodiazepines in the body. CBD also affects the immune system, so may interfere with some types of immunosuppressants and antiretrovirals. Other cannabinoids may also affect the body in different ways, and different combinations and profiles may also interfere with different kinds of drugs – more research is needed in this area. Some even theorize that cannabinoids may make the body more “sensitive”, “insensitive” and/or potentiate the effects of other drugs and medications. Interestingly, this may be one reason why cannabinoids may be used to replace or reduce the intake of other drugs and medications.

So, deadly overdose from natural cannabinoids looks to be more theoretical than practical. However, this doesn’t mean that a person may inadvertently “use a little bit too much cannabis” that leads to uncomfortable rather than deadly effects. Using too much cannabis (with THC being mostly implicated) can lead to anxiety, paranoia, nausea/vomiting, a loss of balance, fainting, an increase in heart rate and blood pressure (followed by decrease – both of which can be positive or negative, depending on condition and context), feeling overly tired/sleepiness (where this is not desirable), feeling “trapped” or “over-exposed”, a loss in short-term memory, and potentially feeling over-sensitive to external stimuli. Cannabinoid hyperemesis syndrome (CHS) is thought to develop from long-term cannabis intake, and could technically be a form of “taking in too many cannabinoids – or one specific cannabinoid – to an eventual detrimental effect”. Whether this counts as an “overdose” is a matter of debate.

So, is there anything that can be done to overcome the negative side-effects of cannabis? Well, first of all, we have to ask “which cannabinoid?” And frankly, we do not know enough about the mechanism of how each cannabinoid works, how they interact with other cannabinoids, at what concentration they may have negative effects, and what their long-term effects are to answer this definitively. However, there has not been a death associated with the use of natural cannabis alone, which is a good sign with regards to its safety. When it comes to the negative side-effects of THC, some would say use some CBD to “balance it out” and negate some of THC’s psychoactivity. Black peppercorns – which contain the terpene beta-caryophyllene (a CB2 agonist which is also found in many cannabis phenotypes) – may also help “break” a negative experience, but there is not much beyond anecdotal evidence for this. Staying hydrated and eating some healthy food may also help.

Whether or not foods high in certain types of terpenes (e.g. myrcene, found in fruits such as mangoes) “increase” psychoactivity is not known, but could be a possibility. Caffeine found in tea, coffee and chocolate may help, but may also increase anxiety in some, as well as acting as a diuretic. On the other hand, a warm drink and a quiet space may also relieve any anxiety associated with a negative cannabis experience – remembering that a deadly natural cannabinoid overdose is pretty much impossible and the negative effects will pass will usually help one overcome many difficulties. A non-caffeinated herbal tea may be appropriate for such instances. Chamomile tea, which has mild anxiolytic effects, may be a good alternative to caffeinated and sugary drinks.

Dark chocolate may also increase the body’s levels of anandamide and potentiate the effects of cannabis, but this again is theoretical. Increasing the body’s levels of anandamide may also increase the levels of FAAH, and could potentially help break THC down quicker, even if the initial effects of THC could be increased by combining it with dark chocolate. We do not have too many clinical trials in this area, so we can only speculate on what effect different foodstuffs have on cannabinoids. However, it is not too much of a stretch to believe that the terpenoids and other compounds found in herbs, spices, fruits and vegetables will influence the way cannabinoids behave in some way.

So, to summarize. No, it is not possible have a deadly overdose on natural cannabis alone, as its lethal dose level is extremely high, and ingesting 1,500 pounds of anything in 15 minutes would probably kill a person. Now, if there’s someone out there working on a type of cannabis or product that will deliver hundreds or thousands of pounds’ worth of cannabinoids in a matter of minutes, an overdose could be possible. Until then, it seems unlikely, and I am not sure if creating such a products is possible or even desirable. However, there is the potential of overdose on synthetic cannabinoids; and there is also the possibility of cannabinoids – natural or synthetic – reacting with other drugs and medications to produce potentially deadly effects. Natural cannabis, on the whole, looks to be relatively safe in comparison to many substances, licit or otherwise. The long-term effects of cannabinoids, we do not necessarily know, but this is the case for many types of medication. Hopefully, our willingness to test cannabis and cannabinoids leads to more long-term, longitudinal studies of other drugs and medications.


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