After several decades of dormancy, research involving the administration of classical hallucinogens to humans has been recently renewed (Frecska and Luna, 2006; Harvard Mental Health Letter, 2006; Lancet, 2006; Morris, 2006; Sessa, 2005; Winkelman and Roberts, 2007). Although animal research during the intervening decades has substantially advanced our understanding of underlying neuro-pharmacological mechanisms of the hallucinogens, the fact that human research with this historically important and widely used class of compounds remained inactive is remarkable (Nichols, 2004). Renewed human administration research began with the work of Rick Strassman, who initiated research on the effects of the N,N-dimethyltryptamine (DMT) at the University of New Mexico in the early 1990s (Strassman, 1991, 1996, 2001; Strassman and Qualls, 1994; Strassman et al., 1994, 1996). Subsequently, investigators both in the United States and in Europe have developed human research programs with hallucinogens. This new research has included basic-science studies that have administered hallucinogens as tools for investigating cognitive neuroscience and perception (Gouzoulis-Mayfrank, Heekeren et al., 1998; Gouzoulis-Mayfrank et al., 2002; Umbricht et al., 2003; Carter et al., 2004; Carter, Pettrigrew, Burr et al., 2005; Carter, Pettrigrew, Hasler, et al., 2005), time perception (Wittmann et al., 2007), hallucinogen pharmacokinetics and metabolism (Hasler et al., 1997, 2002), model psychosis (Gouzoulis-Mayfrank, Heekeren et al., 1998; Vollenweider et al., 1997, 1998, 1999, 2007; Vollenweider and Geyer, 2001; Gouzoulis-Mayfrank et al., 2005, 2006), and, recently in our laboratory, hallucinogens’ reported facilitation of experiences having enduring personal meaning and spiritual significance (Griffiths et al., 2006). Recent clinical studies have administered hallucinogens to evaluate their safety and efficacy in the treatment of psychiatric disorders: specifically, anxiety related to advanced-stage cancer (Grob, 2005) and obsessive-compulsive disorder (Moreno et al., 2006). In addition, several studies have examined the effects of ayahuasca (also known as hoasca or yagé; an admixture containing DMT) in human volunteers outside of the United States (e.g., Grob et al., 1996; Riba et al., 2001). Because the United States Supreme Court has recently ruled in favor of the União do Vegetal (UDV; a syncretic Brazilian church that uses ayahuasca in the context of religious ceremonies) in their claim that the UDV’s use of ayahuasca is protected under the Religious Freedom Restoration Act (Gonzales v. O Centro Espirita Beneficiente União do Vegetal, 2006), ayahuasca use within this church setting may receive increased scientific investigation within the United States.

We use the word “hallucinogen” herein to refer to the classical hallucinogens, sometimes called “psychedelics,” “psychotomimetics,” or “entheogens” (Ruck et al., 1979; Grinspoon and Bakalar, 1979; Ott, 1996; Metzner, 2004). Admittedly, the term “hallucinogen” is not ideal for these substances because perceptual changes are only one domain of their effects, and the typical perceptual changes engendered by hallucinogens at typical doses rarely include frank hallucinations (Grinspoon and Bakalar, 1979; Nichols, 2004; O’Brien, 2006). However, we use this term because it is the most widely used in the scientific literature. Although the term “psychedelic” is widely used, it has the disadvantage of carrying considerable cultural connotation (i.e., its use as a descriptor of a style of music or art associated with Western counter-culture of the 1960s). The terms “psychotomimetic” (emphasizing model psychosis) and “entheogen” (emphasizing mystical-type experiences, i.e., phenomenologically indistinguishable from classically described mystical experiences) highlight only a single aspect (which may not occur reliably) of the much broader range of hallucinogen effects.

Hallucinogens can be divided structurally into two classes of alkaloids: the tryptamines, including psilocybin (prodrug constituent of Psilocybe and several other mushroom genera), the semi-synthetic d-lysergic acid diethylamide (LSD), and DMT; and the phenethylamines, including mescaline (principle active constituent of peyote) and certain synthetic compounds (Grinspoon and Bakalar, 1979; Shulgin and Shulgin, 1991, 1997; Metzner, 2004, Nichols, 2004). The effects of these substances are primarily mediated by agonist action at 5-HT2A receptors (Glennon et al., 1984; Nichols, 2004; González-Maeso, 2007) and produce a generally similar profile of subjective effects (Hidalgo, 1960; Hollister, 1962; Wolbach, Isbell and Miner, 1962; Wolbach, Miner and Isbell, 1962; Shulgin and Shulgin, 1991, 1997). Other classes of substances have sometimes been identified as “hallucinogens,” including 3,4-methylene-dioxymethamphetamine or MDMA (perhaps more appropriately labeled an entactogen [Nichols et al., 1986] or empathogen [Metzner, 1985]); dissociative anesthetics such as ketamine, phencyclidine, and dextromethorphan; and anticholinergic agents such as scopolamine and atropine (Nichols, 2004). However, this paper uses the term “hallucinogen” to refer specifically to classical hallucinogens.

The purpose of this paper is to provide guidance in the safe administration of high doses of hallucinogens (e.g., ≥ 25 mg psilocybin or 200 μg LSD). Some aspects of these recommendations may also apply to studies employing lower doses, although, as with other drug classes, the likelihood of potential adverse effects will be related to dose. Similarly, some aspects of these recommendations may also apply to studies administering the other drug classes mentioned in the preceding paragraph: entactogens, dissociative anesthetics, and anticholinergic agents. However, the clinical effects and mechanisms of action of these agents are sufficiently different from the classical hallucinogens that safety recommendations concerning their administration are beyond the scope of this manuscript. First, so that the historical context in which current human hallucinogen studies are conducted will be clear, we will briefly discuss the history of sacramental hallucinogen use by indigenous cultures, and the history of human hallucinogen research before it became dormant in the 1970s. The decades-long virtual dormancy of human hallucinogen research stands as a unique case in the history of modern clinical pharmacology. It is important for researchers going forward to understand the role that safety factors, as well as sociological and political factors, played in the history and cessation of human hallucinogen research. Also, because of the historical legacy of sensationalism surrounding hallucinogens, researchers should appreciate the precarious position of current human hallucinogen research, and recognize that very high safety standards will help to ensure that human research continues into the decades to come. Next, we will provide a detailed description of the unique risks of hallucinogen administration. We will then present the proposed guidelines for conducting high-dose hallucinogen research in each of several domains including volunteer selection, study personnel, physical environment, preparation of volunteers, conduct of sessions, and post-session procedures.

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