This chapter briefly describes the fascinating journey from ancient betel nuts to modern muscarinic therapeutics. The composite street drug, colloquially referred to as “betel” or “betel nut” or “betel quid,” is one of the most frequently used psychoactive substances in the world. It carries a cultural legacy spanning over 10,000 years and a current user base numbering in the hundreds of millions. Its primary psychoactive constituent is arecoline, a well-established parasympathomimetic agent. Now, developments in psychopharmacology and our growing understanding of neurochemical brain circuitry have unlocked a new mechanism of action by which arecoline-derived medications interact with dopaminergic processes to improve outcomes for schizophrenia patients. One such medication, xanomeline-trospium (Cobenfy), has emerged as the first such agent to receive FDA approval for the treatment of schizophrenia and represents an entirely new class of pro-cholinergic medication within the field of psychiatry.

This chapter delves into the historical and societal aspects of the use of drugs for recreational, ritual, and medical purposes. It explores the evolution of drug laws, the criminalization of recreational drugs, and the emerging evidence challenging the dichotomy between recreational and medical pharmacotherapies. The chapter discusses key historical events such as the legal use of cocaine by Sigmund Freud and the criminalization of drugs like cannabis and psychedelics. It also highlights the changing legal landscape, the role of activists in drug reform, and the complexities of translating research on recreational drugs into clinical practice. The chapter aims to provide a balanced and evidence-based exploration of repurposing recreational drugs as medical therapies, considering the pharmacology, controversies, and politics surrounding these substances.

Schizophrenia is a severe and disabling psychiatric illness that profoundly affects a person’s ability to think clearly, perceive reality, manage emotions, and engage in daily activities. While antipsychotic medications have long been the cornerstone of treatment, debates persist around their long-term use and potential impact on brain structure and function. In our review, we examine whether antipsychotic medications improve or worsen long-term outcomes in schizophrenia, particularly when treatment is refused or discontinued. Drawing from randomized controlled trials, large-scale observational studies, forensic outcome data, international guidelines, and neuroimaging research, the findings demonstrate that sustained antipsychotic treatment significantly reduces relapse, improves functional outcomes, and may protect against neurobiological deterioration. In contrast, untreated or inconsistently treated psychosis is associated with higher relapse rates, treatment resistance, cognitive decline, and progressive brain changes. While treatment must be personalized and compassionate, the cumulative evidence supports the critical role of early and continuous antipsychotic use in preserving health, autonomy, and long-term recovery for individuals living with schizophrenia

Schizophrenia spectrum disorders are brain diseases that are developmental dementias (dementiapraecox). Their pathology begins in utero with psychosis most commonly becoming evident in adolescence and early adulthood. It is estimated they afflict the U.S. population at a prevalence rate of approximately 0.8%. Genetic studies indicate that these brain diseases are about 80% determined by genes and about 20%determined by environmental risk factors. Inheritance is polygenic with some 270 gene loci having been identified as contributing to the risk for schizophrenia. Interestingly, many of the identified gene loci and gene polymorphisms are involved in brain formation and maturation. The identified genetic and epigenetic risks give rise to a brain in which neuroblastsmigrate abnormally, assume abnormal locations and orientations, and are vulnerable to excessive neuronal and synaptic loss, resulting in overt psychotic illness. The illness trajectory of schizophrenia then is one of loss of brain mass related to the number of active psychotic exacerbations and the duration of untreated illness. In this context, molecules such as dopamine, glutamate, and serotonin play critical roles with respect to positive, negative, and cognitive domains of illness. Acutely, antipsychotics ameliorate active psychotic illness, especially positive signs and symptoms. The long-term effects of antipsychotic medications have been debated; however, the bulk of imaging data suggest that antipsychotics slow but do not reverse the illnesstrajectory of schizophrenia. Long-acting injectable antipsychotics (LAI) appear superior in this regard. Clozapine remains the “gold standard” in managing treatment-resistant schizophrenia.

The link between creativity and serious mental illness (SMI) is widely discussed. Jackson Pollock is one example of a giant in the field of art who was both highly creative and experiencing an SMI. Pollock created a new genre of art known as abstract expressionism (“action painting”) defined as showing the frenetic actions of painting. The question arises whether his SMI playedany role in the way he created his drip paintings, especially when he was overactive and manic. Furthermore, did visual hallucinations or enhanced visual perception associated with mania or psychosis facilitate Pollock in embedding and camouflaging images under layers of thrown paint? Seeing images in Pollocks drip paintings has been a controversy ever since these paintings were created. Some experts attribute this to pareidolia—perceiving specific images out ofrandom or ambiguous visual patterns—a phenomenon known to be enhanced by fractal fuzzy edges such as seen in Rorschach ink blots as well as in Pollock drip paintings. So, are Pollock’s drip paintings merely giant Rorschach images, or did Pollock insert polloglyphs—images that are encrypted that tell a story about Pollock’s inner being—into his paintings and then disguise them with drippings? Here, we explore answers to these questions and discuss images that Pollock included in his earliest sketches and used repeatedly in his abstract paintings and later in his drip paintings to argue that these images are not accidental.

This chapter follows the story of Jordon, a young man with schizophrenia who becomes entangled in the criminal justice system due to his untreated illness. The narrative highlights the challenges faced by individuals with severe mental illness, the failures of the mental health system, and the impact of policy and legal structures on their lives. Through the experiences of healthcare professionals and experts in the field, the chapter explores the need for a paradigm shift in the treatment of psychosis, advocating for humane and effective care for individuals across the spectrum of illness severity. The narrative culminates in a call to action to revolutionize the treatment of psychosis in America, emphasizing the importance of understanding, compassion, and evidence-based interventions for those affected by severe mental illness.