The concept of placebo -- Latin for "I will please" -- is central to psychoactive drug research and pharmacology. It is well known to medical science that given an inert substance and the expectation that the substance will have an effect, some percentage of people will experience (or at least report) some degree of effects as a result of their expectation. Consequently, in order to clearly demonstrate efficacy of a medication, researchers must establish that a compound's effects are greater than the expected placebo effect. This effect has a strong and pervasive influence on the design of medical research with humans. To understand modern medical research requires an understanding of the placebo effect.

While both positive and negative effects elicited by a pharmacologically inert substance have traditionally been refered to as "placebo effects", as research and debate on this topic have evolved, the term nocebo -- "I will harm" -- has also emerged. Researchers now sometimes use the term "nocebo" or "nocebo effect" to refer to negative effects caused by the belief that a substance is harmful. An example of this would be a subject in a chemotherapy drug study who experiences nausea after receiving an inert control pill because they have been told to expect nausea. In an example from anthropology, the nocebo effect can refer to real deleterious consequences of curses or "the evil eye" due solely to the expectations of the cursed individual.

Familiarity with the placebo/nocebo effect can contribute to a better understanding of one's own responses to psychoactive substances. If expectation can sometimes lead people to experience effects from inert substances, it's also quite likely that expectation impacts or alters the effects of pharmacologically active psychoactive substances. If someone is told that an active substance will have particular effects, their experience of the actual effects may be shifted in the direction of their expectations. With strong psychoactives, it is practically and theoretically difficult to separate expectation from reported experience. If somone believes they are ingesting a low quality or contaminated drug, they may experience more negative side effects than the same person told that the drug is pure. If someone thinks a supplement will enhance or end their psychoactive experience, they may experience just that.

One of the important distinctions between scientific research and self-reported experimentation is that a well-designed research protocol will attempt to account for the effects of expectation on experience. Especially in the field of psychoactive drug research, the influence of placebo effects cannot be discounted or ignored. Early psychedelic research often included an inactive or weakly active placebo (flushing niacin, for instance) and virtually all volunteers knew during the session that they had received placebo. Modern methods include using an active "control drug" with known physiological effects yet considered to lack the psychoactive effect being studied. The effects of the drug being researched are thus compared against the control drug rather than a placebo, which is by definition inactive. In the highly publicized psilocybin study published in 2006 by Griffiths et al., methylphenidate (Ritalin) was chosen as the control drug against which psilocybin was compared. This allowed participants (and part of the research team blinded to the procedure) to be unsure whether the drug given was the 'placebo' or the psilocybin.

In the case of uncontrolled anecdotal reports, it is often impossible to separate expectation from pharmacological effect. A product sold as a "smart drug" might make one person feel "clearer headed" while the same drug might not have any noticable effect on another. Because of the influence of expectation on experience, it is not easy to know whether the reported positive effect (or lack of effect) is the result of a direct pharmacological effect of the supplement taken or a result of the mindset of the person who took the product.

Finally, the placebo effect goes straight to one of the most interesting theoretical puzzles at the core of psychopharmacology and neurology — what is the relationship between consciousness and the biophysical processes of the brain? Interestingly, drug effects can be "simulated" by the brain without a pharmacologically-active agent. This was demonstrated in 1979 when researchers Levine et al. pre-treated pain-suffering research subjects with naloxone, an opioid antagonist that blocks the pain-relieving effects of opiate-like substances.1 They found that subjects given a placebo pain reliever were less likely to report pain relief if they had been pretreated with naloxone: blocking the opioid system in the body also blocked placebo-induced pain relief. This indicates that the placebo experience of pain relief uses chemical mechanisms similar to the pain-reducing mechanisms of opiates such as morphine and heroin. The expectation that something will relieve pain appears to trigger a biophysical response that actually causes a pharmacologically-mediated reduction in pain.