Swirling around these drugs are so many claims and counterclaims, hopes and fears, information and misinformation. How do we make sense of this groundswell of interest—scientific, cultural, media, spiritual, and commercial? I begin this handbook with psychedelics’ history. Many of these substances occur in the natural world, and Indigenous people have been using them for millennia; for example, psilocybin in “magic” mushrooms, DMT in ayahuasca, mescaline in peyote, 5-methoxyDMT in toad venom, ibogaine in the iboga plant, and salvinorin A in Salvia divinorum. Modern Western psychedelic research began by identifying and isolating these compounds, and later characterizing and synthesizing them. Using these natural substances as building blocks, new synthetic psychedelics later appeared: LSD, ketamine, and MDMA. Next, I provide a general description of how psychedelics make us feel—physically and emotionally, their effects on what we hear and see, our thought processes and sense of self. The altered states of consciousness psychedelics produce share features with other, nondrug, altered states like psychosis, dreams, and spiritual experiences. These similarities have led to the extraordinary number of names people have given these drugs. I will unpack these names and suggest that what we call psychedelics to a considerable extent determines what they do. I discuss what we have learned about these drugs’ potential benefits over the last fifty years, both therapeutic and as tools to enhance wellness. No drugs as powerful as psychedelics are only “good,” however, and here I will also review adverse effects. The next three chapters summarize what we know about how psychedelics work: biologically and psychologically. These “mechanisms of action” chapters provide me the opportunity to indulge in one of my favorite topics—medieval metaphysics—and how this ancient discipline may shed light on understanding the complex effects of psychedelics. And how about the “spiritual” properties of psychedelics? What are they, how do they come about, and how might our beliefs about them lead down a slippery slope of religious intolerance? More than any other drugs, psychedelics bridge the mind-body gap. Their biological and psychological effects are impossible to separate. The biological effects of the drug modify our experience, and our experience modifies the biological effects of the drug. This leads us into the critical idea of “set and setting.” “Set” refers to who we are at the time of drug ingestion, and “setting” to where we take it. These two factors determine how any individual psychedelic drug experience takes its unique form. Experiences that are positive or negative, helpful or harmful, full of ideas or full of pleasure all turn on issues of set and setting. Set and setting may therefore help explain the panacea-like effects of psychedelics. Whatever we wish for them to do in either giving or taking them, they do. I believe the set and setting phenomenon points to how psychedelics may help solve the mystery of the placebo response—how our beliefs and subjective experience modify our biology. One piece of this puzzle is exciting new research that demonstrates that psychedelics stimulate the growth of new neurons in the brain as well as increasing the complexity of their connections. These are psychedelics’ “psychoplastogenic” effects. Next, I write about individual psychedelic drugs—their history, botany, pharmacology, usual doses, and how one takes them. I will review each drug’s time course, unique psychological and/or biological effects—including adverse ones—and their legal status. Any handbook must, by definition, provide practical how-to advice. This book’s longest chapter therefore does just that. While neither I nor Ulysses Press advocates taking drugs nor breaking the law, there are those who are curious enough to venture into this territory to accept the attendant risks. Therefore, it is important to do everything possible to maximize benefit and minimize negative outcomes. In that chapter I will also address the growing public awareness of sexual and other types of abuse at the hands of those who administer psychedelics in various settings. Microdosing—taking non-psychedelic doses of a psychedelic—is increasingly popular. I will summarize what we know, and more to the point, what we do not know, about microdosing. The legal landscape of psychedelics is rapidly changing, and the next to last chapter will help you navigate current trends in “decriminalization” and “legalization.” In my concluding remarks, I underline my intention for writing this handbook—that is, as an educational resource—and share my enthusiasm for future developments in the field.