Hallucinogens are a class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mood, and perception, among other changes. Hallucinogens can be split into three sub-categories: psychedelics, dissociatives, and deliriants [1,2].

Many patients enrolled in studies of psychedelic products have preconceived expectations related to the upcoming experience, referred to as response expectancy. This confounder is a known issue in the field of psychiatry and has been discussed in relation to the study of antidepressants. For psychedelics, response expectancy can further undermine attempts to control for the placebo effect. This can result in subjective reports that indicate a greater positive effect with the psychedelic chemical and general absence of effect with the placebo.

For example, consuming psilocybin mushrooms can produce a psychedelic effect. However, the concentration of psilocybin (the chemical responsible for this effect) present varies from 0.37% to 1.3% depending on the exact species of mushroom consumed. Further, samples of psilocybin mushrooms obtained from various sources have yielded psilocybin concentrations that vary by a factor of four to ten [9,10,11]. For most plants, the time of year that harvesting occurs, as well as the methods used to harvest and process the plant, can also significantly alter chemical composition.

Purified psilocybin, however, can be given in very exact doses, similar to a prescription drug. When psilocybin is evaluated in clinical research, it is provided and dosed in the purified form, ensuring consistent potency and reproducible effects. The use of psilocybin mushrooms, on the other hand, would be expected to provide less consistent effects and potency.

When potency concerns are raised, many people immediately consider the impact on therapeutic and psychedelic effects. However, variable potency can also lead to the development of significant and unexpected adverse effects that do not occur consistently with each use. There are many case reports of whole psychedelic plants causing serious adverse effects and even death in people with a history of use [119].

As might be expected, psychedelic substances have traditionally been used in doses that are intended to exert a hallucinogenic effect. Most often, psychedelics are taken in single doses or isolated doses taken weeks or months apart from each other. Similar doses are also used in clinical research and tend to be considered "therapeutic" doses for these chemicals.

However, there has been interest in the use of very small doses that are not expected to exert a hallucinogenic effect. These small doses, referred to as microdoses, are not strictly defined, but are often about 10% of the amount that would be expected for a "medium to high" single therapeutic dose, taken either every three days or two to four times per week [9,12].

The theory behind this dosing strategy is that regular use of nonpsychedelic doses will boost mood and energy and reduce anxiety without causing a hallucinogenic high. Unfortunately, any research on this theory is very limited and most publications provide only anecdotal reports. Currently, people who utilize this dosing strategy have self-selected for this use and have determined their own dosing regimen. Thus, this form of treatment is thought to be particularly prone to response expectancy and a placebo effect [9,13].

Regardless of the specific ingredients used, ayahuasca brews contain DMT, a known psychedelic chemical. Some other constituents, including harmine and tetrahydroharmine, may act to enhance the psychedelic effects of DMT [19,21,22,23,24]. DMT is classified as a Schedule I controlled substance by the DEA [121].

Although many drugs may have minor serotonergic activity, the drug classes most commonly associated with serotonin syndrome include:

Hawaiian baby woodrose (Argyreia nervosa), also referred to as elephant creeper, is a flowering vine that grows in Florida, California, and Hawaii. The seeds of this plant are sometimes touted online as "natural LSD" due to the presence of a chemical called lysergic acid amide (LSA), which is structurally similar to LSD. This plant and others containing LSA have been used in shamanistic rituals in South America [111].

All known safety information is specific to ibogaine, as opposed to the whole plant. In general, ibogaine is known to cause multiple adverse effects, which may range from mild to very severe. The most common adverse effects reported with pure ibogaine are ataxia, confusion, diarrhea, headache, nausea, and vomiting. Multiple case reports have also associated the use of ibogaine with ventricular arrhythmias, cardiac arrest, and QT interval prolongation. QT interval prolongation progressed to torsades de pointes in some cases. In many of these reports, the patients had no prior history of heart disease [46,47,48,54,55,56,57,58,59,60,114].

The largest study conducted to date enrolled 59 patients and compared psilocybin 25 mg, taken as two separate doses three weeks apart, to escitalopram 20 mg daily for six weeks. The patients in this study were also receiving psychological support. The study found that psilocybin and escitalopram were equally effective for reducing symptoms of depression. Additionally, 57% of patients taking psilocybin achieved remission, compared with 28% of those taking escitalopram. However, it is unclear if these effects persisted beyond the six-week time period [81].

There is significant interest in the use of psilocybin as a treatment for various forms of addiction and substance use disorder, including alcohol, tobacco, and opioids. Clinical research in this area is very limited and has mostly involved small, uncontrolled exploratory studies.

The highest quality study to date was conducted in patients with alcohol dependence. This study, which enrolled 93 patients, suggests that psilocybin may be modestly beneficial for further reducing alcohol intake when compared with diphenhydramine. However, it did not increase rates of total abstinence, and it is unclear if it would be beneficial in patients with more severe alcohol use disorder. In this study, psilocybin was provided as a single dose of 25 mg per 70 kg in the fourth week and a single dose of 25–40 mg per 70 kg in the eighth week [86].