_________________________________________________________________________ Natural Psychedelics
Controlled Environment Research on the use of psychedelics to date has typically provided the study subjects with a highly controlled, positive environment in which to experience the effects of the substance. For example, many studies allow or require the subject to remain in a clinic environment, with access to a therapist, for eight hours after dosing. If the intent is for patients to take the substance outside of a clinic, this experience is dissimilar from the intended use of psychedelic chemicals. However, to date, therapeutic use of psychedelics has been limited to controlled clinical settings. When these individual limitations are considered together, their potential to result in an overestimation of the treatment effect becomes even greater. Experts in the field have recommended standard assessments of blinding/masking and response expectancy to provide a clearer picture of the risk of bias in any given study. These limitations should be kept in mind when interpreting the literature in this area.
Although the federal regulatory status of psychedelics in the United States has remained the same since the 1970s, other changes are occurring. For example, the U.S. Food and Drug Administration (FDA) has designated some psilocybin-based therapies as breakthrough therapies for treatment-resistant depression [6]. This status is intended to expedite the development and review of drugs that may treat a serious condition. Also, some municipalities and states have moved toward decriminalizing certain psychedelic substances, typically psilocybin, and developing laws that allow for the supervised use of these substances [7]. Over the past two decades, research has begun to suggest that certain psychedelic substances may carry a low potential for dependence and provide possible therapeutic benefits. If these findings are replicated in high-quality research, this may prompt a review of the Schedule I classification for certain chemicals [1]. RESEARCH LIMITATIONS Although higher-quality research on some psychedelic chemicals has recently become available, much of the older research in this area is limited to anecdotal reporting. This introduces a risk for reporting bias, a situation in which there may have been a tendency to report on positive, but not negative, outcomes. Additionally, even though many of the studies being conducted today are utilizing a randomized, controlled design, even these studies are subject to inherent weaknesses that occur with the use of psychedelic chemicals [8]. Appropriate Placebo Selection There is still significant controversy on the selection of an appropriate placebo for psychedelic research. Examples of placebos used in recent clinical trials include very low, nontherapeutic doses of the same psychedelic substance being evaluated, as well as treatment doses of drugs with known neurologic effects, such as diphenhydramine. However, the majority of patients in these studies have been able to accurately guess the treatment group to which they were assigned. Inadequate blinding and masking prevent studies from appropriately controlling for a placebo effect, which may skew study results. Subject Expectations 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.
OTHER SPECIAL CONSIDERATIONS Whole Plant versus Isolated Chemical
Some people may choose to consume a fresh or dried plant for psychedelic effects. Others may choose to consume psychedelic chemicals that have been purified from these plants. These differing sources are often discussed interchangeably by the media and consumers. However, it is important to recognize that these two different sources may provide very different effects. 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. This consideration is important for all natural psychedelics, as the psychedelic effects of any given plant are mostly obtained from one or two constituents found in that plant. Some examples include: • Ayahuasca: This concoction is made from whole plants and contains DMT. • Iboga: This plant contains the psychedelic alkaloids ibogaine, ibogaline, and ibogamine
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