Alcohol is mostly predictable. When we drink a beer (or three), we usually have a pretty good sense of what it's going to feel like. 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. We also sense alcohol directly, so that the potency of a hard liquor tastes different than that of weak light beer. When we drink, we generally know how drunk we are going to be.

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, marijuana byproducts like 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 behavioral 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 traveled 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 percent cannabidiol) and low (less than 0.14 percent) 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 analyzing 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 generalize 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 recognized 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 behaviors at distinct locations of the brain: Sex behaviors at the level of the hindbrain, nociceptive-induced behaviors at the level of the midbrain, and anxiety-like behaviors 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 behaviors.

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.

UPDATE: A scientist who studies the neural effects of alcohol and THC writes in with an illuminating comment:

I would argue that the wide array of subjective effects of marijuana likely arises from the ubiquity of the EC system in most areas of the brain. Consequently, I think the different experiences people have with this drug are probably due to individual differences and the state a person is in immediately preceding and at the time of intoxication (I believe you said something to this effect in your article). However, if one examines the dose-response function of THC and other cannabinoid drugs in lab animals, you’ll find that at high doses these compounds produce sedation (not surprising), but at very low doses they have stimulatory effects (not unlike EtOH). Therefore, I think you probably have something like a three-way interaction (dose x self x state) which would be hard to predict for the average user especially because THC content in illicit cannabis is unregulated.

Image: US Fish and Wildlife Service