How Safe is Marijuana? A Toxicological Perspective

by David on March 25, 2013

I’ve been contemplating marijuana since Colorado and Washington passed ballot initiatives legalizing the stuff back in November.  Not as a user, mind you – but as a toxicologist entertaining the idea of a new recreational drug entering the fray currently ruled by alcohol and tobacco. What are the health hazards (or benefits?) associated with smoking a joint? Or five? Is cannabis really the nightmare drug that my elementary school D.A.R.E. program led me to believe? (Hint: it isn’t.) Or is it merely a misunderstood medicine? Fortunately, a handful of groovy scientists have been digging on the problem in recent years, and their findings may surprise you. 

I’m not sure which is worse: the fact that I’ve had this shirt for fifteen years, or the fact that it still fits. 

What’s the Dose? How Much Will Kill You?

The LD50 is one of the more recognizable classical toxicological data points, and it’s a good place to start our investigation: what is the Lethal Dose for 50% of a test population? delta 9-Tetrahydrocannabinol (THC) is the primary active compound in marijuana, and it’s LD50 in rodent studies (a general starting point for toxicological research) is absurdly high, as is the human LD50, which is theoretically between 15 and 70 grams. To put that in perspective, the casual user (once a month or so) generally only needs about 2-3 mg of THC to become intoxicated, while habitual users might need between five and ten times that amount. Since 3 mg = 0.003 g, a casual user would need to smoke about 5000 times their normal amount to approach a potentially lethal dose.

No word yet on the lethal dose of ice cream. Can we just assume there isn’t one?

Acute Effects  

Okay, so it probably won’t kill you. But what kind of negative acute effects are we dealing with? What bad stuff can happen upon first exposure? The most common negative acute side effects are panic, tachycardia (rapid heartbeat), impaired information processing and reaction time, and decreased motor coordination. In rare cases, marijuana use can precipitate or exacerbate latent schizophrenia, but I’ll get into that later.

The Big 3: Cancer, Developmental, and Reproductive Effects

One of the most important distinctions made in the toxicological assessment of chemicals is that of carcinogenic versus non-carcinogenic compounds, and for the moment, marijuana falls unsteadily into the latter category. There is a good chance that all that smoke inhalation is causing cancer of some sort, but the epidemiological studies have had a heck of a time trying to tease apart the confounding effect of cigarette smoking, since many people who use marijuana also smoke cigarettes, which are known to cause a variety of cancers.

Another important distinction is that of teratogenicity: does the compound cause birth defects? Again, at the moment, no, there isn’t any evidence that marijuana causes birth defects, although many researchers are quick to warn that there isn’t a tremendous amount of data on the subject yet.

Things aren’t looking too good on the reproductive health front, however. Emerging data suggests that chronic marijuana use can reduce fertility in women, and there evidence that THC can effect sperm count and motility.

“I was thinking about it, man, and like, why even bother to swim upstream?” “I feel you, salmon-bro.”

Neurological and Psychological Effects

For reasons that aren’t yet clear, there is a small chance that smoking marijuana will precipitate schizophrenia. But before you get to work on that Nancy Reagan shrine, there are a few things worth noting about this unusual phenomenon. For starters, there is a probable genetic component to this, and individuals that don’t have a family history of schizophrenia are extremely unlikely to develop it as a result of marijuana use. Secondly, only about 3% of heavy users are at risk for developing schizophrenia, and if the disease doesn’t manifest during puberty, it’s not likely to during adulthood. As Bostwick (2012) notes, moderate marijuana usage after the age of 18 is not associated with increased rates of mental illness.

In addition to possible schizophrenia, there are several other neuropsychological effects that were observed among adolescents that abused marijuana heavily, including: memory deficits, reduced information processing speed, susceptibility to mood and anxiety disorders, and greater likelihood of dependence. Much like alcohol and cigarettes, use and abuse of marijuana before and during puberty can have serious consequences for the developing brain and should be avoided at all costs.

(source: http://bit.ly/14isjxe) alright, fine, I agree with you: kids shouldn’t smoke pot.
NOW ARE YOU HAPPY NANCY

Hooked on Hashish: Marijuana Dependency

Contrary to what many would like to believe, marijuana can be addictive, and between 9 and 11 percent of those who toke will get hooked. However, this statistic only holds out for individuals who start using marijuana during their teen years and early 20s – the percentage of first-time users over the age of 25 who become dependent is practically zero. Also, a 1 in 10 addiction rate sounds bad until you consider the rates of dependence for first time users of alcohol (15%), opioid (23%), cocaine (17%), or nicotine (32%).

And the Rest: Other Chronic Effects

Chronic use (and to be clear, I’m talking about several joints a day, every day, for 10 years) of marijuana is associated with many of the same respiratory diseases that plague tobacco smokers, including emphysema and bronchitis. Since marijuana cigarettes tend to be unfiltered and the smoke is held in the lungs for longer, a lot more tar and nasty gunk is inhaled per drag. An increase in respiratory infections has also been noted among chronic users, as marijuana suppresses the immune system. Memory problems and other cognitive issues may develop over time, and the potential for cardiovascular complications increases as well.

Reefer? Pah, you’ll never see me TOUCH the stuff. It’s unfiltered Lucky Strikes for me, yessir.

The Thin Green Line

So to answer that original question – how safe is Marijuana? – we may need to start by saying “compared to what?” Taken together, the aforementioned data suggests that marijuana isn’t deadly, but that it does pose a non-trivial hazard to young persons and individuals with a genetic predisposition for schizophrenia, and that chronic use of marijuana may result in fertility problems, cardiovascular disease, and respiratory distress.

How’s that stack up to alcohol and cigarettes?

The WHO has stated that globally, tobacco is the single greatest cause of preventable death, lopping about 17 years off the lives of habitual smokers – to say nothing of the effects of secondhand smoke. Alcohol is associated with dozens of cancers, and liver and heart diseases. And both cigarettes and alcohol have dire consequences for embryonic development. Interestingly, there has been an ongoing debate about the role of cigarettes and the development of schizophrenia, some researchers finding it palliative, others finding it causative, and yet more finding it merely related.

So, Is Marijuana Safe? Well, from where I’m sitting, it’s no more or less safe than alcohol, cigarettes, or prescription opiates for that matter. Everything is toxic at some dose. The key, as always, is moderation and responsible use – and definitely no use among minors. And who knows, maybe if we can overcome our social vendetta against marijuana, we might uncover some medical benefits? Alas, that is a topic for another post.

Pictured: the undisclosed location where the author intends to hide from vitriolic comments.

Béranger March 25, 2013 at 7:45 am

I’ve found your refuge, it’s in Longues-sur-Mer! I’m coming after you. (I suppose you couldn’t help me with a joint, can you?)

It’s not normal for any “democratic” government to forbid and penalize the use of cannabis, opium, tobacco, alcohol, or whatever else. Why not outlaw parsley, lovage, oregano, rosemary, or onion?

David March 25, 2013 at 11:08 am

Ah! I’ve been discovered! Haha, sorry, friend, but I’m not fond of using the stuff – only studying it.

You do raise an interesting point about the criminalization of marijuana, since cannabis is simply a plant, and plants are not inherently good or evil – merely useful or not useful to humans. However, one must be careful about this line of reasoning, as coca leaves are also natural, but I am not prepared to argue for the legalization of cocaine.

Though to be fair, I don’t have to – cocaine is a schedule II drug, meaning that it has known medical use and can be prescribed by physicians: http://en.wikipedia.org/wiki/List_of_Schedule_II_drugs_(US).

Thanks for the comment!

Bridget March 25, 2013 at 2:43 pm

Thanks for the interesting article, David!

I would like to point out that the active ingredient in marijuana is available as an oral capsule. It is a schedule III drug marketed as the brand name Marinol (generic name dronabinol). It has a FDA labeled indication for prophylaxis of chemotherapy-induced nausea and vomiting in adults and pediatrics as well as an appetite stimulant for adult patients with AIDS. Additionally, dronabinol is used off-label for postoperative nausea and vomiting. The brand name comes as a 2.5, 5, or 10 mg capsule, and is approved for doses up to 20 mg of THC per day.

David March 25, 2013 at 4:26 pm

I’m glad you liked it, Bridget!

You raise an excellent point about dronabinol, the toxicology of which was rather instructive for me when I was writing this article. It is curious to me that the synthetic equivalent of THC is schedule III (accepted medical use, low to moderate addiction potential), while the natural compound is schedule I (no medical use, high addiction potential).

What do you think? Do you think they should be regulated separately?

Bridget March 25, 2013 at 8:38 pm

Regulatory decisions are a tough topic.

Do I think that marijuana has some legitimate medical use? Yes.

Do I think that they should be regulated separately? For now, yes. There’s no way to tell exactly how much THC would be absorbed from smoking. Additionally, how do you know how much THC is in an ounce? Is it the same across generations of plants, products? How do you assure users that they are receiving “adequate” doses? Also, how do you know where it came from or whether you’re inhaling other toxins (like pesticides)?

That being said, if it was regulated, I think it could be made into a safe alternative. I also believe that to be true about other herbal products.

The first example that comes to mind is fish oil. Each ‘brand’ of fish oil contains a different amount of Omega-3 fatty acids (O3FA). Let’s say Brand A is regulated and contains 1,000 mg O3FA. Since Brand A is regulated, you know that everytime you take one of those capsules, you are ingesting 1,000 mg of O3FA and that it has no extraneous ingredients that cause harm. Now let’s say we have an unregulated version called Brand B. Brand B does not follow good manufacturing practices. Although the bottle says each capsule contains 1,000 mg of O3FA, each capsule could actually contain more or less. Some herbal products contain poisons that are not listed on the label like arsenic.

[Side note: I like this brief Mayo Clinic article about precautionary supplement use: http://www.mayoclinic.com/health/herbal-supplements/SA00044

For the natural THC compound to be regulated the same (for medical purposes anyway), I think a version of ‘good manufacturing practices’ for marijuana would need to be in place, so that each ounce contained XX mg of THC.

Additionally, I think more studies would need to be performed. I still have questions. Some of which include:

1. What about other genetic polymorphisms that affect metabolism increasing serum THC concentrations? (http://www.nature.com/clpt/journal/v85/n3/abs/clpt2008213a.html)

2. What about herb-drug interactions that could change serum THC concentrations? I am only aware of one studied interaction: dronabinol-ritonavir = Coadministered ritonavir may significantly increase serum concentrations of dronabinol, resulting in dronabinol toxicity.

3. What about herb-disease interactions? Is it safe in patients with cardiac disease, psychiatric illness, or seizure disorders? Probably not.

4. What about the effects of eliminating organ dysfunction (i.e., liver and kidney)? THC has an active metabolite, 11-hydroxy-delta-9-tetrahydrocannabinol, that is ~15% eliminated via the kidneys. If somebody with kidney disease uses, how does that change their serum THC concentrations? Does the active metabolite build up to toxic concentrations?

David March 27, 2013 at 5:36 pm

Many excellent points, Bridget! I agree with you, that it’s prudent to extensively research THC if it’s to be used for recreation or medical purposes. The FDA has extremely stringent standards for drug development and I can’t imagine why they wouldn’t be applied to medicinal marijuana – though it may be a “natural compound” in the same way that fish oil is, I think there is a good analogy to be made to the use of aspirin, a derivative of willow bark.

And I definitely think necessary to regulate recreational cannabis if it’s to be legalized or decriminalized. Much like the regulation of tobacco or alcohol, standards would need to be set and enforced for recreational cannabis, and like tobacco or alcohol, it would be prudent to apply health warnings to packaging. The issue has found some currency in states considering legalization/decriminalization: http://www.dailynews.com/news/ci_16717030

The taboo associated with cannabis has severely hindered efforts to research its safety as a recreational drug and its efficacy as a medical drug, but hopefully this will change in the future.

Maia March 25, 2013 at 5:52 pm

This might be a strange curiosity, but do these studies take into account different “varietals” (not sure of the wording) of marijuana?

David March 25, 2013 at 7:13 pm

Interestingly enough, no, none of the articles that I read made any such distinction! However, the Lancet study (http://dx.doi.org/10.1016/S0140-6736(09)61037-0) acknowledged that different concentrations of THC are associated with different types of marijuana product (hash oil, hashish, dried buds, ect.) and the Mayo clinic review (http://dx.doi.org/10.1016/j.mayocp.2011.10.003) reported that the average potency of marijuana plants has been increasing over the past few decades.

Thanks for the comment!

Angela March 25, 2013 at 7:18 pm

Thanks for the post, David! I find the history of drug legality/illegality very fascinating in terms of reasoning and politics. About a hundred years ago, cocaine, opium etc were legal in the UK. I think Scott’s polar expedition was given large quantities of cocaine against snow blindness. In the US, it was an ingredient in Coca Cola. The renewed questioning of the justification of marijuana’s illegality has also been subject to controversy in the UK. The pointing out that marijuana isn’t as bad as some legal drugs (e.g. alcohol, tobacco) led to the sacking of the government’s drug adviser:
http://www.guardian.co.uk/politics/2009/oct/30/drugs-adviser-david-nutt-sacked

David March 25, 2013 at 8:11 pm

I’m glad you enjoyed it, Angela! I, too have been interested in the legal and cultural histories of drugs for many years. If you’re interested in the history of opiates, then this book http://amzn.to/YB3CIy is fantastic. Michael Pollan’s “The Botany of Desire” provides a masterful discussion of the grand and diverse cultural significance of marijuana across time and geography.

Amusingly enough, I was talking with Dr. Maynard about my post earlier today and he mentioned the sacking of Dr. Nutt – utterly outrageous, I think. But then, money and politics often have a way of prevailing over evidence-based science, particularly in matters such as drug use, which are prone to moralizing.

Angela March 25, 2013 at 8:38 pm

Thanks for the book recommendations!

Ian Mitchell March 26, 2013 at 12:09 pm

An excellent review. I am a big fan of Knowledge Translation – so good work for making this accurate and engaging. Just one thought on reading the respiratory section. I would remove the mention of emphysema (generally clinically referred to as chronic obstructive pulmonary disease – COPD), based on the most recent evidence:

Tashkin (CMAJ 2009) “Marijuana smoking by itself probably does not lead to COPD”

From the same issue: . “Smoking only marijuana was not associated with an
increased risk of respiratory symptoms or COPD” from Tan et al.

Lee and Hancox (Exp Rev Resp Med – 2011): “The evidence that smoking cannabis leads to features of chronic obstructive pulmonary disease, such as airflow obstruction and emphysema is not convincing.”

Pletcher (JAMA 2012): “Occasional and low cumulative marijuana use was not associated with adverse effects on pulmonary function

David March 27, 2013 at 9:15 pm

I’m glad you liked it, Ian! I am also very interested in presenting scientific concepts in engaging and digestible fashion. You raise an excellent point about the association between marijuana use and emphysema. Emphysema is certainly a rarer occurrence among marijuana smokers – not likely to be detected in epidemiology studies – but it can and does occasionally develop.

The Lee and Hancox (2011) paper does report that “The evidence that smoking cannabis leads to features of chronic obstructive pulmonary disease, such as airflow obstruction and emphysema is not convincing,” however, they go on to say that “there are numerous case reports of bullous emphysema among cannabis smokers. These findingshave not been confirmed in systematic analytical studies and probably represent uncommon adverse effects in very heavy cannabis smokers.”

One such case report: Landeghem et al. (2012) http://www.rbrs.org/dbfiles/journalarticle_1023.pdf

Rooke et al. (2013) also report that emphysema is an uncommon, but potential pathology that can result from extensive marijuana usage. http://dx.doi.org/10.1016/j.addbeh.2013.01.013

On balance, yes, I agree with you that emphysema is not a likely consequence, but in the interest of completeness, I thought it prudent to mention it as a potential pathology. I suppose that one could argue that it’s not necessarily relevant on a population scale, but when appraising a compound for toxicity, it’s important to be as thorough as possible. And besides, there will always be more vulnerable subpopulations that are more at risk for this sort of thing, and expanding the use and availability of marijuana (as seems to be the direction of things in the US) will surely make these populations more apparent.

Ian Mitchell March 26, 2013 at 12:14 pm

Just something to add to your comments about cigarettes and mental health. While there is some research showing that nicotine can help the symptoms of schizophrenia and it often seems cruel to patients to remove this comfort for them when they are admitted, the overall damage that cigarettes do to mental health patients will be felt for generations in terms of mortality and toxicity – it is shocking that the mentally ill in the US smoke more than 30% of the cigarettes consumed and a true mental health tragedy. http://healthland.time.com/2013/02/08/should-mentally-ill-patients-be-allowed-to-smoke/

David March 27, 2013 at 9:18 pm

Indeed, I did come across a number of papers that found cigarettes to assuage some of the symptoms of schizophrenia, and there is certainly a strong correlation between the mental illness and cigarette usage. As a public health student, however, I do agree with you that the benefits of cigarette use are heavily outweighed by the damage they cause.

Thanks for the insightful comment!

Alexander Lieflander March 28, 2013 at 8:00 am

First off, I liked the style of the article, it gave the facts in a straight forward fashion but still kept me interested. The idea that marihuana is not that bad, less so then tobacco is baffling to be. It’s strange to hear an opinion like this several years after we all had those generic anti-drug assemblies where we learned how “evil” every drug is. I didn’t know the addiction rate was only 1 in 10, again a huge ways off from what we learned in elementary school. I have never used marihuana, never plan to, but I must thank you for this interesting read! You said that smoking cigarettes shorten a persons life 17 years, how many years does marihuana take off?

Alexander Lieflander March 28, 2013 at 8:02 am

Forgot to leave the hash tag, please read the comment above… #SPX9

David April 3, 2013 at 8:54 pm

Thanks for the comment, Alexander! I’m glad you enjoyed the post. Yes, I was also rather surprised to learn that much of what I’d learned in school was misleading or inaccurate – I always learn a lot when I write these posts! From what I have read, there is no conclusive evidence that marijuana use alone is associated with earlier mortality, although there is still plenty of research to be done on the topic. Also, it’s important to remember that everyone is different and that there aren’t many hard and fast rules about how people will respond to different drugs – everyone is a little bit different.

Paul w March 28, 2013 at 8:22 am

What I liked about this post was that you shared you great information on this drug. Is marijuana safe? I enjoyed how you facts were great and told users what they can receive such as mental health or the production of cancer. This post shows how marijuana is not that safe and could damage your body. Just wondering has anyone died from this substance.#SPX9

David April 3, 2013 at 9:19 pm

I’m glad you liked it, Paul! In regards to your question: there are a scattered few case reports wherein Marijuana has been suggested as the cause of death, but these are extremely rare and inconclusive. However, there are plenty of instances where it has been found in conjunction with other drugs which caused a lethal overdose. So, that’s a qualified “no,” marijuana alone has never (to my knowledge) been definitively shown to cause mortality.

Claudio March 28, 2013 at 8:28 am

Great post David!
I really liked how you explained all the effects of marijuana and how you compared them to normal cigarettes and other types of addicting substances. I totally agree with you that everyone at my high school talks about how bad it is and that is one of the worst substances to smoke, although I just learned it is not. From the studies you’ve shown, marijuana is not a very addicting drug if taken after the age of 25 (basically no one becomes dependent to it) and only very few people around the age of 20 become addicted (9 to 11%). Fom this blog I learned that many people overestimate the effect of marijuana even if it is not proven that’s lethal for your body. It’s just as addicting and bad for your body than normal cigarettes, alcohol and other prescription drugs; the importance is to use moderation and responsible use, because everything as a certain dose can be toxic. One final question: how can marijuana arrive to kill someone in great doses if it’s not toxic in small doses?

David April 3, 2013 at 10:52 pm

Thanks, Claudio! I’m glad you enjoyed the post. As to your question, there are two parts to the answer.

1. One of the central tenets of toxicology is the “dose-response” paradigm, which is basically this: as you increase the dose of something that someone is exposed to, you expect to see a commensurate increase in that person’s response to the compound. As with everything (including water: http://bit.ly/VyQZJY), the amount of THC (the primary active ingredient in marijuana) that you are exposed to will determine how strongly you are effected by it – if you only exposed to a little, you will only have a little effect, but if you are exposed to a lot, then you could have a big effect. Alcohol is a good example of this: a little bit will not likely have a large negative effect, but a large amount may kill you! As you commented, moderation is key here.

2. There is no known lethal dose for THC, because only very small amounts are needed (and present in marijuana) for a person to experience an effect. The predicted LD50 is around 2 grams of pure THC, and the source that I read suggested that this entire volume of THC would have to be injected directly into a main artery to have a lethal effect. Suffice it to say, that no such arrangement has occurred with enough frequency (if it has indeed ever occurred) for anyone to become really concerned about it.

Matthew. A March 28, 2013 at 8:31 am

I really liked your topic because people are saying marijuana is horrible for you. Also other people would say its better than smoking cigarette because it dose not have the toxic that a cigarette dose. The main idea of this article is how safe is marijuana. A supporting fact about the main Ida is ” marijuana is no better than cigarettes and alcohol.” This article is about the use of marijuana and how safe it is, also the effects of marijuana and what it can do to you. Can you get addicted to marijuana if you try it once? #SPX9

David April 3, 2013 at 11:12 pm

Thanks for the comment, Matthew! I’m glad you enjoyed the post. It is possible to develop an addiction to marijuana after a single use, and the addiction rates I reference in the article reflect the likelihood of that occurring. As you can see, it’s less likely to cause addiction than alcohol, tobacco, cocaine, and even heroin after a single use. Additionally, the potential for addiction falls off to nearly zero after a person hits the age of 25.

Nelson April 3, 2013 at 4:53 pm

I wish everyone – on both sides of the debate – would read this post. It is excellently balanced and sourced. Of course, I may be a little biased since I feel the facts support my viewpoint. . . which may be because of a biased interpretation. [Insert Xhibit meme here.] Great post, regardless.

David April 3, 2013 at 11:12 pm

Thanks! I’m glad you enjoyed the post! :)

Mickle Bond April 4, 2013 at 6:34 am

I think. But then, money and politics often have a way of prevailing over evidence-based science, particularly in matters such as drug use, which are prone to moralizing.

David April 10, 2013 at 1:16 pm

Yes, that certainly seems to be the case here. Thanks for the comment!

Lindsay April 10, 2013 at 3:04 pm

Have any studies looked at the relationship between food and marijuana consumption? Dietary behaviors (due to reduced inhibitions or odd ingredient combos, see http://newyork.grubstreet.com/2013/04/der-menneken-wietsaus-weed-sauce.html?mid=twitter_nymag) could be affected.

A similar question could be asked about alcohol or tobacco consumption. I’m pretty sure the latter is associated with appetite suppression; the former…can’t find a study but theories abound!

David April 15, 2013 at 1:12 pm

I know that THC, synthetic THC, and other cannabinoid compounds have seen use in the treatment of nausea associated with chemotherapy, since they promote appetite.

Paradoxical findings have been noted regarding THC and weight loss or gain, see: http://dx.doi.org/10.1016/j.mehy.2013.01.019, http://dx.doi.org/10.1038/npp.2011.19. There appear to be some contexts in which THC acts as a suppressant and some in which it acts as a depressant, but in all cases, it most certainly has the ability to modulate appetite.

Thanks for reading!

Adrian May 10, 2013 at 10:38 pm

Thank you for citing your sources! I used a few in my essay. :)

David May 31, 2013 at 4:18 pm

Happy to be of help!

Miles Monroe May 27, 2013 at 8:02 pm

A well-presented analysis, though you might have also mentioned there is no reliably documented case–not even one!–in medical literature of human cannabiniod induced fatality in at least five thousand years of use.

Which makes your conclusion–that it’s no safer than alcohol, cigarettes, or prescription opiates–seem all the more inconsistent with the evidence you presented … ?

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