Psychedelic connoisseurs are usually well versed in "set and setting," or the the idea that both your state of mind, beliefs, and expectations (set) as well as your social and physical environment (setting) determine whether your trip is heavenly or takes you straight to hell. The concept has been a bedrock of psychedelic practice since acid guru Timothy Leary first promoted it in the 60s and 70s.
But research now shows that these non-drug influences are even more powerful than previously suspected—and can affect everything from how aggressive you get when drunk to your risk of addiction, your experience of pain and even whether or not you overdose. Expectations and environments can either harsh your mellow or heighten your high—and they change the way your brain processes information as they do so.
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According to Ted Kaptchuk, a leading researcher on placebo effects and professor of medicine at Harvard, "It depends on what you're targeting, but in issues like mood and in recreational drug use, the evidence suggests that [expectations] are pretty important."
For one, beliefs about whether or not you are actually receiving a drug can directly affect both your experience of it and the way your brain reacts. A recent study on smoking showed just how profound these effects can be.
Giving smokers cigarettes that contained nicotine—but telling them that they were nicotine-free—dramatically reduced their brains' physical responses to the drug. This almost certainly made the smoking less satisfying, because it lowered activity in brain regions that contain the neurotransmitter dopamine, which is linked to desire and pleasure.
What's more, the false belief that the cigarettes lacked nicotine actually changed the way the smokers made decisions about risk in an investment game, altering how much they valued their wins. Not only did their beliefs affect how they felt while smoking, they also altered subsequent behavior related to reward and motivation.
"It's a neat finding," says Tor Wager, director of the Cognitive and Affective Neuroscience Lab at the University of Colorado, who was not involved with the research.
The study's authors argue that the data has major implications for the understanding of addiction: basically, that beliefs about drugs can affect dopamine in much the same way that drugs themselves can, making the psychology of the condition critical. They write that the reduction in the "high," which comes from a false belief about getting a drug, indicates that "although it might account for physical dependence, DA [dopamine] abnormality alone is not sufficient to account for the whole collection of addictive symptoms."
Whether a culture sees drunkenness as shameful or as a badge of masculinity affects what anthropologists call "drunken comportment."
Beliefs are also widely known to affect drinking, with cultural ideas about what people do while drunk influencing how they behave while sloshed. "There's clearly some individual differences in how people behave when drunk and it's clearly also considerably structured by cultural expectations," says Robin Room, professor of alcohol policy research at the University of Melbourne in Australia.
For example, studies show beliefs about alcohol causing aggression can influence whether or not people become violent when drunk. Other types of beliefs about the specific effects of drinking on sensations like relaxation and stimulation also change how drunk you feel. Whether a culture sees drunkenness as shameful or as a badge of masculinity also affects what anthropologists call "drunken comportment."
"It varies a great deal by situation within a particular culture and who is doing the drinking," Room notes, mentioning gender as one factor. Biology, culture, environment, and psychology all play a role.
Stimulant highs are also changed by expectations. For example, when people with cocaine addictions (who weren't seeking treatment) were given IV methylphenidate (Ritalin) and told they would be getting a stimulant, their overall brain metabolism was 50 percent higher, their heart rates were faster and they reported a 50 percent increase in feelings of "liking" the drug and being "high," compared to those who believed they would be getting a placebo but were actually given the same dose of the drug.
And sometimes, the influence of expectations even goes beyond conscious awareness. "There's a lot of modification of the effects of medications and drugs by anticipation, either conscious or non-conscious," Professor Kaptchuk says.
In a study Kaptchuk and his colleagues just published, 49 people learned to associate pictures of specific faces with either high or low levels of heat-related pain applied to their forearms. Once this connection was learned, seeing the faces previously associated with greater pain made moderate pain worse— and seeing the faces associated with less pain provided relief.
That finding alone wasn't surprising; after all, prior studies had shown that cues previously associated with distress enhance pain, while those linked with pleasurable experience enhance pleasure. But what was intriguing in the new study was that even when participants couldn't really see the faces—they were masked so that the images could not be recognized consciously—the moderate pain was greater for the "high pain" faces compared to the low ones.
Unconsciously, the participants' brains had become conditioned to predict whether a particular face meant more or less pain. And so, even they couldn't consciously identify them, their brains responded to the faces, magnifying the pain they way they'd been trained to do.
Rats given drugs like heroin in the same cage repeatedly are more likely to die from getting a high dose if it is later given in a different environment.
This kind of unconscious conditioning doesn't just affect pain—it also alters many types of drug responses. For instance, research on both rats and humans suggests that tolerance for drugs like heroin and prescription painkillers relies to some extent on environmental cues. Rats given drugs like heroin in the same cage repeatedly are more likely to die from getting a high dose if it is later given in a different environment. In humans, this effect may account for some otherwise mysterious overdose deaths that occur when people take their usual dose in a new place— and could suggest new avenues for research on overdose prevention.
"It's a form of conditioning," Wager says. "Some parts of it you are aware of, some not." So tolerance to a drug, where you need more to get the same high, isn't just pharmacological, but also psychological. In part, your brain relies on unconscious cues related to where, how, and with whom you typically take the drug in order for tolerance to work.
Bizarrely, this means that expectations can either enhance or diminish drug highs. In the case of cocaine users given Ritalin, expecting the drug heightened their pleasure. But the expectation of taking a drug in the place where you usually do so can also make you tolerant and reduce the effects. Indeed, the effect is sometimes so large that when do you take the drug in a new situation, it can kill you.
"Some placebo effects mirror the drug experience, but another whole class are designed to prepare for what's coming, so they oppose the response," Wager says. And no one really knows what determines which type of effect will predominate.
The question of who becomes addicted to alcohol or other drugs is also heavily influenced by set and setting. A series of experiments from the 1970s, in which rats that were housed with other rats and given lots of toys and a stimulating environment ("Rat Park"), found that they took far less morphine when given the chance, compared to rats caged alone. Having a better social and physical environment made the rodents more resistant to addiction—and the same thing seems to be true for humans.
In fact, even when the researchers forced the Rat Park rats to become physically dependent and taught them that drinking water that contained morphine could relieve withdrawal, they took eight times less drug than the caged rats, whose lives were the equivalent of being in solitary confinement.
A study published in June found similar effects with cocaine. Mice that received extra stimulation—like being trained to find rewards of Honey Nut Cheerios—were less susceptible to developing a strong preference for a chamber where they later were exposed to cocaine. And other studies have shown that varying the conditions of an experiment—like whether animals get to socialize, their living conditions, or the way they are raised—affects whether rats prefer cocaine or sweets, which accounts for why headlines in the 80s suggested that crack was the most addictive substance and why headlines in the 2010s demonize sugar as being at least as bad.
It's safe to say that drugs themselves are only part of the story—and if we want better ways of addressing drug problems, we need to look beyond the brain. Getting addicted is much more than simply exposing your brain to a drug; it involves making repeated choices in a complex environment and unconsciously learning to associate the drug with relief. Recovery, likewise, involves complex learning—and is much easier in an environment that offers meaningful options and warm relationships. To conquer addiction and reduce drug-related harm, a basic understanding of set and setting is essential.