Why Are The Effects Of Marijuana So Unpredictable?

Alcohol is mostly predictable. When we drink a beer (or three), we know how we are going to feel. The effects of marijuana are a lot more difficult to judge for a number of reasons.

With alcohol, we can anticipate the buzz, the slackening of self-control, the impaired motor movements and the increased mind-wandering. In part, this is because alcohol is a tightly regulated psychoactive drug, and the alcohol content is clearly printed on every bottle. But it's also rooted in the predictable response of the brain to booze, and the fact that alcohol seems to have a fairly straightforward interaction with the GABA-A receptor.

But not all drugs are so predictable. Consider marijuana, which can trigger dramatically different symptoms depending on the strain and context. It's long been known that different strains of the drug contain various amounts of Tetrahydrocannabinol (THC), the main psychoactive ingredient. When people talk about the effects of the drug – such as giddiness, the munchies and a sudden desire to watch The Big Lebowski – they're typically referring to the effects of THC. (Interestingly, the same chemical can also make us paranoid. More on that later.) But THC doesn't work alone – marijuana also contains cannabidiol, a compound associated with calm and relaxation. The ratio of THC to cannabidiol seems to be the key variable: Skunk-type strains, for instance, contain a higher ratio of THC to cannabidiol than, say, hashish. (According to a paper in Neuropsychopharmacology, "Delta-9-THC and CBD can have opposite effects on regional brain function, which may underlie their different symptomatic and behavioural effects, and CBD's ability to block the psychotogenic effects of delta-9-THC.") In general, high levels of THC seem to be desired by marijuana users, which helps explain why levels of THC have increased dramatically in the last few decades.

Now for the bad news: These popular skunk-strains (high in THC, low in cannabidiol) seem to be uniquely associated with memory loss. That at least is the lesson of a recent paper in the British Journal of Psychiatry. Here's Nature News:

Curran and her colleagues travelled to the homes of 134 volunteers, where the subjects got high on their own supply before completing a battery of psychological tests designed to measure anxiety, memory recall and other factors such as verbal fluency when both sober and stoned. The researchers then took a portion of the stash back to their laboratory to test how much THC and cannabidiol it contained.

The subjects were divided into groups of high (samples containing more than 0.75% cannabidiol) and low (less than 0.14%) cannabidiol exposure, and the data were filtered so that their THC levels were constant. Analysis showed that participants who had smoked cannabis low in cannabidiol were significantly worse at recalling text than they were when not intoxicated. Those who smoked cannabis high in cannabidiol showed no such impairment.

The results suggest that cannabidiol can mitigate THC's interference with memory formation. This is the first study in human to show such effects. One previous study, led by Aaron Ilan, a cognitive neuroscientist at the San Francisco Brain Research Institute in California, failed to find variations in cognitive effects with varying concentrations of cannabidiol.

lan attributes the positive finding of Curran and her team to their more powerful methodology in analysing subjects' own smoking preferences. In the United States, government policy dictates that only marijuana provided by the National Institute on Drug Abuse can be used for research - and it "is notorious for being low in THC and of poor quality", says Ilan.

The larger message is that it's very difficult to generalise about the effects of most drugs. Just look at marijuana: One of the recurring mysteries of the drug is why the same compound can both relax us and make us paranoid; it sometimes causes uncontrollable laughter and sometimes leads to runaway anxiety. This suggests that the context of use – our mental state when smoking a joint, or eating a pot brownie – can profoundly influence the outcome. While it remains mostly unclear how or why this happens, there's some interesting new research on endocannabinoids in rough-skinned newts. (Endocannabinoids are a class of neuromodulators widely expressed in the brain. Their name gives away the punchline: THC binds to endocannabinoid receptors with ease.)  The basic moral of these studies is that the endocannabinoid system is tightly interwoven with the stress system. For instance, it's long been recognised that stressing out a male newt leads, not surprisingly, to a rapid surge of corticosterone, a stress hormone. As a result, these poor males have little interest in sex, even when exposed to a lovely female newt. Here's where the data gets surprising: The effects of the stress hormones seems to be mediated by the endocannabinoid system, so that when these endocannabinoid receptors are blocked stress has no effect. The males keep on having sex, even though they've just been through the ringer. Here are the scientists:

Thus, eCBs [endocannabinoids]regulate a variety of stress-related behaviours at distinct locations of the brain: sex behaviours at the level of the hindbrain, nociceptive-induced behaviours at the level of the midbrain, and anxiety-like behaviours at the level of the forebrain. We hypothesize that eCBs might be involved in coordinating multiple physiological and behavioral functions during acutely stressful events.

What does this have to do with humans and marijuana? (As the researchers note, the stress and EC pathways have been extremely well conserved in evolution: You get stressed just like a newt.) The reason marijuana has been around for thousands of years (and remains one of the most popular drugs in the world) is that it acts on an incredibly important neural system. EC receptors sit at the intersection of appetite and stress, pain and and anxiety. According to the newt data, EC receptor agonists – compounds that act like THC – induce the same blunting of the sex response as an acute stressor. (In other words, don't smoke a joint if you hope to perform well in bed.) Is this because the newts are suddenly paranoid? Or is it because they're too happy to bother with intercourse? The answer is that it depends. As the researchers note, the EC system, like the stress pathway it mediates, is largely context dependent, which is why the same the soup of cortical chemicals can produce a runner's high and the awful feelings of terror. This has also been demonstrated in newts: The scientists can block the effect of stress on sex if they expose the creatures to sex beforehand, or give them an injection of vasotocin. In other words, priming the males with happy thoughts seems to allow their EC system to shrug off the effects of acute stress. Their previous experience has reversed the symptoms of being poked and prodded by a scientist.

Behavioral biologists have long known that behavioral responses to environmental stress are context-specific. Given that the state of neural a system will vary with the behavioral state of an animal, it follows that synaptic events mediated by eCB retrograde signaling might contribute to context-specific behaviours.

Too often, we forget that drugs work their magic on a brain that's never the same. Who we are depends on when you ask the question. So it shouldn't be too surprising that a drug with many different strains (each of which has a slightly different THC/cannabinoid ratio) and that acts on a context-dependent neural pathway would display such a wide variety of symptoms, from carefree euphoria to its emotional opposite.

For more on the cannabinoid/memory story, check out Addiction Inbox.

Image via US Fish and Wildlife Service

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    Was Gizmodo paid to write this propaganda? this isn't even about gadgets I am sick of the media making up lies and brain washing the community about marijuana and while it isn't just in Australia that they do this, but while the rest of the world moves forward and is starting to accept and legalise it Australia once again moves backwards. I don't smoke marijuana and never will but no scientific studies show that it causes and mental problems that are worse then what alcohol causes I am sick of Australia and its backwards society and culture I am out of here.

      Where are you going?

      Ever had a family member go from being a normal, hard working, committed family man, and turn into a sloth like thief with paranoid schizophrenic mood swings so violent his family flees in the middle of the night never to return????? You are a foo, if you believe there is no link between pot and mental illness. Over 40% of the population have a predisposition to mental illnesses like schizophrenia triggered by pot. It is a fact!! You tell me why brother is a zombie without a job, no family and an overwhelming desire to steal from his family to feed his habit?? One answer. Marijuana. Don't be a fool, it destroys lives.

        Don't be such a fool Kroo, I'm sorry to be the one to tell you this, but your brother isn't stealing from you to feed his pot habbit, the real reason is far more serious that that. Open your eyes and don't be so naive. He appears to be using the the pot excuse as a cover to deflect attention from his real habbit, more than likely, addiction to heroine, cocaine or at worst ice. One thing though, I'm not saying he doesn't smoke pot over and above one of the aboves.

        No drug is inherently bad for you; only the relationships that the particular individual has with the drugs can be considered bad.

        And yes, most if not all drugs can bring up mental illnesses, that actually could have came about by anything else. There's no proof or links to marijuana causing mental problems. I'd be a lot more worried about the uppers and downers that get prescribed.

        It's a drug, people should be responsible.

        "I am 100 percent in favor of the intelligent use of drugs, and 1,000 percent against the thoughtless use of them, whether caffeine or LSD." - Timothy Leary

        lol kroo made an idiot out of himself, most if not all scientists would say that marijuana never caused that, correlation is not the same as causation, just because he smokes weed doesn't mean it caused it.

        I dont know where my orher comment went but that is not fact, dont claim things as fact when they aren't.

    Preditable for me - good times, relaxation and desire to watch anything science fiction.

    Adam, I read the article and it doesn't sound like propaganda....I myself smoke the occasional joint and have actually started to notice recently that my memory isn't the same as it used to be (im 20)..

    I haven't been as motivated as I once was to complete uni projects etc, I think after reading this article I may take a break from it all.

      I completely agree with you, I'm an avid smoker, 20 too, and I have definitely noticed an increase in memory loss, and I'm thinking of cutting down (or stopping altogether) due to this nasty side effect. As much as I love the feeling, I also am concerned about later in life. No joke, I'm even struggling now to even remember most of what I've just written.

        The memory effects will subside if you cut back or stop the pot smoking. I have many friends and myself included above the 30 mark who enjoy the occasional joint, and we are all surprise surprise, productive members of society and in high paying jobs. Treat yourself, don't make it a habbit.

        One more thing, while you are still fairly young, be aware that memory recall will get affected as you get older.

    Lets ignore the fact that this article has nothing to do with Gadgets as Adam so rightly points out...

    But can we not overlook the fact that this "journalist" also fails to mention that whether or not these studies were conducted under NORMAL circumstances and whether or not it was an unmodified plant strain?

    For reference, please refer to the Government tests on Chimpanzees for the effects of Marijuana.

      I don't think it was specific strain, this comment leads me to believe:

      "134 volunteers, where the subjects got high on their own supply".

    Umm the reason marijuana consumers are paranoid is because its not legal. Theres nothing in it to make u paranoid...

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