Disclaimer: I have never smoked pot. Not interested. But, I have been very interested in the decades-old debate about it. On one side you have people who claim it as a benign, useful substance that should be legal. On the other side, you have people who claim it is a dangerous and destructive and should be banned. I was surprised to realize to myself recently that I couldn't articulate a good argument for either side. I didn't know enough. 
So I wanted to do an experiment. But not that kind of experiment.

I wanted to play out the following hypothetical scenario that would never, ever happen in real life. I will describe it in story form. There is this person-- we'll call him Jimmy-- and someone offers him a joint in a dorm room. Jimmy has never tried it before and doesn't know very much about it, so he asks his friend if he could take a few hours to research marijuana on the NIH's biomedical research database PubMed before making up his mind. His friend is cool with that, so Jimmy runs up to the computer. He searches peer-reviewed journal articles exclusively. No Wikipedia, no Google, no blogs (sorry), no specialized sites. He just wants the pure, unadulterated good stuff of science. What would his decision be?

Well, the first thing Jimmy would find is that it isn't easy to research marijuana. Based on PubMed topic results by year, 2012 showed a record high of journal articles published that had something to do with marijuana (as examples, marijuana pubmed search results in 2000: 401. In 2012: 1275. Cannabis search results in 2000: 204. In 2012: 853). So, to make it practical for him to learn something in a few hours, he restricts his search to articles published in the last decade at most. He further restricts the articles he clicks on to those that have to do with the actual action of marijuana. He passes on all the social science, since he knows social scientists just make stuff up.

The first useful article he comes across is a good one: Micale et. al., published Dec 2012 inPharmacology and Therapeutics. In the article he learns the basics. The primary active component in marijuana is delta-9-tetrahydrocannabinol (THC), a lipid which acts as an agonist (activator) for receptors CB1 and CB2 in what is called the endogenous (naturally occurring) endocannabinoid system of the body. He further finds that THC is one of between 70-100 "terpenophenolic pharmacologically active compounds" found in Cannabis sativa which don't have the same psychoactive action as THC, but which interact with the body in different ways. He reads that the acute action of THC is antidepressive, anxiolytic (anxiety reducing), and stress relief, and can facilitate fear extinction.

So Jimmy thinks, Oh, that's all good. He further reads that "high doses or rapid administration of Δ9-THC as well as chronic Cannabis use are associated with transient psychotic syndrome, panicogenisis and bipolar disorders..."

Uh oh. 

Further reading shows that the effects can be very subjective based on a range of factors. OK. He also notes that the study of the endocannabinoid system is a target for people developing drugs specifically for mood disorders, but that the research has been hit or miss. In one study, use of a CB1 receptor antagonist to treat obesity was stopped because of evidence of increased depression, anxiety and thoughts of suicide (Van Gaal et al. 2005), and that led to the shutdown of similar studies in ensuing years for links to depression and anxiety. But the authors note that there's still hope for discovering the right compound.

Elsewhere in the article, it describes the location of CB1 and 2 receptors. CB1 is primarily in the brain, at high concentrations in the basal ganglia, frontal cortex, hippocampus and cerebellum (motor, decision making and memory systems), and low density nearly everywhere else. It's found primarily in GABAergic (generally inhibitory) neurons, but also in glutamatergic (excitatory) neurons and glia (non-neurons).  CB2 is also found in the brain, but also in immune tissues and inflammatory cells, including the spleen, and is in lymphocytes and macrophages.

Clearly, Jimmy wants to learn a little bit more about this THC compound, because clearly, if those systems get screwed up, it could be bad.To find out more about THC, he searches and runs across D'Souza et. al. 2005. This study injected 2.5 or 5 mg of THC directly into the blood of adult subjects who had tried marijuana before, and then measured all the dose-dependent effects on the subjects. They found that the effects of THC peaked after ten minutes, had effects that were "not severe", and then dissipated by 200 minutes.

Jimmy thinks, Oh, good, so the effects are temporary. Then he reads the extensive list of observations about the patients. They say the subjects showed "the quality of symptoms showed similarity to the positive symptoms reported by schizophrenia patients".

What? The subjects were also: less spontaneous, internally preoccupied, showed blunted affect, "spaced out", detached, saying bizarre things, had distorted time perception, feelings of unreality, altered body perception, somatic concern, guilt, tension, uncooperativeness, unusual thought content, and poor attention. Measures of anxiety and tiredness were up during the peak time, and feelings of calm actually went down. Feelings of panic didn't go up significantly, although one person had to drop out of the study because of a panic attack. No long-term medical affects were noted in the group. 

So, at this point, Jimmy is weighing the possible experience of the mind alterations with the repeated comparisons made with psychosis. But he notes that that study is just for straight-up THC. What about all the other compounds? Well, further searching shows that the second-most studied compound seems to be cannabidiol (CBD).

To his great interest, he finds papers like Bhattacharyya et al. 2010, which demonstrate that CBD actually has actions that counter the effects of THC. It is anxiolytic, perhaps even antipsychotic, has no memory effects, and is being investigated for pharmaceutical use, but how it works isn't clear yet (though it might involve 5-HT seratonin receptors).

So Jimmy reads this and thinks, Awesome. If marijuana contains both chemicals, they might cancel out the more severed effects of THC, making it a better experience. But then a quick search to find work measuring the relative abundance of both chemicals in marijuana produces Potter et al. 2008, which points out that available forms of cannabis have been used to promote the concentration of THC and the decrease of CBD so that the psychoactive effects are stronger, often with CBD containing less than .1% CBD in forms with concentrations of 4 to 14 to 40% THC.

Yikes.

By this time, Jimmy is getting tired of staring at the screen, so he starts searching more haphazardly. He finds that THC helps to keep inter-ocular pressure down in glaucoma patients, but he doesn't have the patience to find out why. He finds that there really aren't any recent papers specifically linking marijuana and addiction. The literature seems much more concerned with what happens when people with mood disorders, schizophrenia and other substance abuse addictions also use marijuana.

Jimmy wonders if there is a link between marijuana and cancer, and he finds Hall et al. 2005 which suggests that there may or may not be some association with respiratory system cancers, and points out that THC lowers feelings of nausea and increases appetite and eases pain (although Lee et al. pointed out this week that it isn't an actual analgesic; its affect is more at the higher levels of perception), making it a possible treatment for chemotherapy patients. And then he finds Larson et al. 2012, which reportedly confirms a link between marijuana use and a risk of tumors in the testes. That gives Jimmy a little pause. You don't mess with Jimmy's testes.

He wanders around to find out more about THC affects outside of the body, and runs across the findings of Karmaus et al. 2012 (both of them), which report that THC suppresses the inflammatory lung response to influenza, and has an effect on T-lymphocyte activity that operates independent of CB1 or 2 receptors. Now, both studies were done in mice, and Jimmy is no mouse. But it gives him pause.

Jimmy has to admit that Pubmed doesn't make marijuana sound very appealing. He tries searching "cannabis pleasure" and comes up with Cassidy et al., but by this time he's so tired of looking at the screen that he can't figure out exactly if the paper is helpful or not, because its more interested in how psychotic people feel about the anticipated pleasure of marijuana use compared to controls, and Jimmy isn't psychotic. Yet.

So, the result of roughly four hours of Pubmed searching came up with some interesting results. The reader is invited to try the same experiment and see if the overall impression of the appeal of marijuana is different using different search criteria and objectives (again, using only the science). Again, it's doubtful that anyone would ever take the time out to do research on pot when offered it, and if they did, they would go to far more accessible (and biased) parts of the internet.

You may be wondering what Jimmy did in the end. I'll tell you. His head got so fuzzy from all that research that he gave up and started browsing YouTube videos. Six hours later, he realized that he had forgotten all about his friend, and that it was 3 in the morning, and he resolved to seek help for his internet addiction by joining an online support group. But he never inhaled.