With over 100 apparently unique metabolites in the Cannabis plant, there are a plethora of potential molecular targets. The molecular actions of Δ9-tetrahydrocannabinol are the best-investigated, which have centred mostly on a relatively high-potency, low-efficacy action at the CB1 cannabinoid receptor. By contrast, cannabidiol has a multitude of lower potency molecular targets identified in vitro, but with limited clarity about their relevance for the effects of cannabidiol in humans. This review highlights the incomplete nature of studies of the major phytocannabinoids, particularly the acid phytocannabinoids.
Cannabinoids are increasingly being used to manage pain resulting from a variety of conditions. Both preclinical animal models and human studies have played a crucial role in advancing our knowledge of cannabinoids, their involvement in pain mechanisms, and their potential utility as novel analgesics. This chapter first reviews basic pain neurobiology and the most common experimental pain paradigms, which provide a basis for our discussion of preclinical, human laboratory, and clinical research characterizing the effectiveness of cannabinoids for managing pain. While a substantial body of literature exists describing these effects, findings are complex and largely mixed, dependent on the cannabinoid administered, route of administration, and pain modality/syndrome tested. Herein, we highlight the need for more rigorous, placebo-controlled research defining the therapeutic efficacy of cannabinoids. The chapter concludes by emphasizing the need for further investigation of other cannabis constituents (e.g., minor cannabinoids and terpenes), potential interactions between cannabinoids and other analgesic medications, as well as other emerging issues in the intersection between cannabinoids and pain management.
Cannabis use disorder (CUD) is increasingly prevalent, and there are no FDA-approved medications to facilitate its treatment. Research on the development of CUD pharmacotherapies lags compared to other substance use disorders (SUDs), partly due to the difficulty in establishing robust preclinical models of cannabinoid self-administration. This chapter evaluates the translational pipeline, from preclinical and human laboratory models to randomized controlled clinical trials for CUD, reviewing medication effects observed within these models and discussing the challenges in translating preclinical and human laboratory findings, particularly regarding efficacy endpoints (e.g., prolonged abstinence versus a reduction in use). The chapter concludes by addressing future directions for improving translational validity and optimizing therapeutic development for CUD.
Numerous studies carried out in the last 30-40 years have strongly demonstrated that the endocannabinoid system exerts important modulatory functions in the central nervous system (CNS). These neuromodulatory functions encompass the whole life of animals, with specific activities during neurodevelopment (prenatal, postnatal and adolescent periods), adulthood and possibly senescence too. However, this is the life stage less investigated in relation with the endocannabinoid system to date. In the aged brain, the activity of this system appears to be altered, which contributes to subtle impairments that typically occur during ageing in learning and memory, motor behaviour, social behaviour and other neurobiological functions. Some of the changes in endocannabinoid activity may represent a process to attenuate ageing-related impairment in the brain function, which is consistent with its role as a pro-homeostatic system. An important observation is that these alterations become extreme when normal brain ageing acquires pathological characteristics, as happens in chronic neurodegenerative disorders. This includes the cannabinoid type-1 (CB1) receptor downregulation or impairment in its signalling and the increase in endocannabinoid-inactivating enzymes, both hypothesised to contribute to pathogenic events. By contrast, elevated levels of endocannabinoids due to a reduced Fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) expression and the upregulation of cannabinoid type-2 (CB2) receptors may in turn serve as endogenous pro-homeostatic adaptations against brain impairment. This review synthesises information on: (i) subtle alterations in the endocannabinoid system in the senescent brain in the absence of pathology, with the purpose of demonstrating that these alterations are representative of the extreme changes experienced by this system in the brain pathological ageing; and (ii) the development of neuroprotective therapies based on the pharmacological management of specific endocannabinoid targets to combat neurodegenerative pathologies. Together, research in this area comes at a critical time as global lifespan is increasing, incidence of age-related neurodegenerative disorders is expanding, and the unmet need for efficacious neuroprotective treatments is a public health necessity.
This chapter will review the basic pharmacology of the canonical cannabinoid receptors. The endocannabinoid system is a complex signalling network involved in a wide range of physiological processes, including pain modulation, appetite regulation, and synaptic plasticity. The canonical cannabinoid receptors, CB1 and CB2, are central in orchestrating this system. CB1 is highly enriched in the central nervous system (CNS), where it plays a crucial role in modulating neurotransmitter release and synaptic plasticity. In contrast, CB2 is predominantly expressed in peripheral tissues and immune cells, participating in anti-inflammatory processes. Here, we focus on cannabinoid receptor distribution, intracellular signalling, and receptor regulation. We describe the intracellular signalling pathways activated by CB1, including the modulation of ion channels, second messengers, and protein kinases. Overall, this chapter provides an overview of the canonical cannabinoid receptors and their role in the regulation of neuronal signalling and plasticity, highlighting the molecular and cellular mechanisms underlying their effects in the CNS.
In the last two decades, the endocannabinoid system has emerged as a crucial modulator of motivation and emotional processing. Due to its widespread neuroanatomical distribution and characteristic retrograde signaling nature, cannabinoid type I receptors and their endogenous ligands finely orchestrate somatic and axon terminal activity of dopamine neurons. Owing to these unique features, this signaling system is a promising pharmacological target to ameliorate dopamine-mediated drug-seeking behaviors while circumventing the adverse side effects of, for instance, dopaminergic antagonists. Despite considerable preclinical efforts, an agreement on the efficacy of endocannabinoid-targeting compounds for treating drug substance use disorders in humans has not been reached. In the following chapter, we will summarize preclinical and clinical evidence addressing the therapeutic potential of cannabinoids and endocannabinoid-targeting compounds in substance use disorders. To bridge the gap between animal and clinical research, we capitalize on studies evaluating the impact of endocannabinoid-targeting compounds in relevant settings, such as the management of drug relapse. Finally, we discuss the therapeutic potential of novel cannabinoid compounds that hold promise for treating substance use disorders.
Cannabis sativa has been used therapeutically since early civilizations, with key cannabinoids Δ9-tetrahydrocannabinol (THC) 3.1 and cannabidiol characterized in the 1960s, leading to the discovery of cannabinoid receptors type 1 (CB1R) and type 2 (CB2R) and the endocannabinoid system (ECS) in the 1990s. The ECS, involving endogenous ligands like 2-arachidonoylglycerol (2-AG) 1.1, anandamide (N-arachidonoylethanolamine (AEA)) 1.2, and various proteins, regulates vital processes such as sleep, appetite, and memory, and holds significant therapeutic potential, especially for neurological disorders. Small molecule-derived pharmacological tools, or chemical probes, target key components of the ECS and are crucial for target validation, mechanistic studies, pathway elucidation, phenotypic screening, and drug discovery. These probes selectively interact with specific proteins or pathways, enabling researchers to modulate target activity and observe biological effects. When they carry an additional reporter group, they are referred to as labeled chemical probes. Developed through medicinal chemistry, structural biology, and high-throughput screening, effective chemical probes must be selective, potent, and depending on their purpose meet additional criteria such as cell permeability and metabolic stability.This chapter describes high-quality labeled and unlabeled chemical probes targeting ECS constituents that have been successfully applied for various research purposes. CB1R and CB2R, class A G protein-coupled receptors, are activated by 2-AG 1.1, AEA 1.2, and THC 3.1, with numerous ligands developed for these receptors. Imaging techniques like single-photon emission computed tomography, positron emission tomography, and fluorescently labeled CB1R and CB2R probes have enhanced CB receptor studies. CB2R activation generally results in immunosuppressive effects, limiting tissue injury. AEA 1.2 is mainly degraded by fatty acid amide hydrolase (FAAH) or N-acylethanolamine acid amidase (NAAA) into ethanolamine and arachidonic acid (AA) 1.3. FAAH inhibitors increase endogenous fatty acid amides, providing analgesic effects without adverse effects. NAAA inhibitors reduce inflammation and pain in animal models. Diacylglycerol lipase (DAGL) is essential for 2-AG 1.1 biosynthesis, while monoacylglycerol lipase (MAGL) degrades 2-AG 1.1 into AA 1.3, thus regulating cannabinoid signaling. Multiple inhibitors targeting FAAH and MAGL have been generated, though NAAA and DAGL probe development lags behind. Similarly, advancements in inhibitors targeting endocannabinoid (eCB) cellular uptake or trafficking proteins like fatty acid-binding proteins have been slower. The endocannabinoidome (eCBome) includes the ECS and related molecules and receptors, offering therapeutic opportunities from non-THC cannabinoids and eCBome mediators. Ongoing research aims to refine chemical tools for ECS and eCBome study, addressing unmet medical needs in central nervous system disorders and beyond.
The range of phenomena that can be induced by psychedelic substances is broad and variable, including effects on perception, cognition, and emotion. The umbrella term "psychedelic phenomenology" is used to refer to a combination of altered experiential features, such as hallucinations or ego dissolution, which together constitute a psychedelic experience. However, there is no consensus on the set of alterations of consciousness that qualifies an altered state to be a "psychedelic state." In this chapter we summarize the most commonly discussed changes in subjective experiences which could be seen as "core features" of psychedelic experiences. While acknowledging the rich history of pioneering phenomenological work of the last century, this chapter focuses on more recent developments in the quantitative work on the assessment of these phenomena. We also address the under-researched phenomenology of distressing effects, often referred to as "challenging experiences" or "bad trips," and point to their importance in understanding the therapeutic potential and risks associated with psychedelic phenomenology. Historically, one can find many links between psychedelic phenomenology and the phenomenology of psychopathology. We stress the importance to refine the assessment and description also of distressing effects, to identify factors that promote acute experiences which are beneficial and limit those which can have potentially harmful long-term effects.
Despite using the recommended anti-emetic treatments, control of nausea and vomiting is still an unmet need for cancer patients undergoing chemotherapy treatment. Few properly controlled clinical trials have evaluated the potential of exogenously administered cannabinoids or manipulations of the endogenous cannabinoid (eCB) system to treat nausea and vomiting. In this chapter, we explore the pre-clinical and human clinical trial evidence for the potential of exogenous cannabinoids and manipulations of the eCB system to reduce nausea and vomiting. Although there are limited high-quality human clinical trials, pre-clinical evidence suggests that cannabinoids and manipulations of the eCB system have anti-nausea/anti-emetic potential. The pre-clinical anti-nausea/anti-emetic evidence highlights the need for further evaluation of cannabinoids and manipulations of eCBs and other fatty acid amides in clinical trials.
Cannabis-based medicine (CBM) is used in a wide variety of different neurological disorders. While the use of CBM in the treatment of pain, AIDS wasting, loss of appetite, and spasticity is well established, CBM application in movement disorders and neurodegenerative disorders is still an emerging topic. The purpose of this chapter is to summarize current evidence behind the use of CBM in selected neurological diseases, mainly movement and neurodegenerative disorders. The best evidence for efficacy of CBM is for Tourette syndrome resulting in an improvement of tics and psychiatric comorbidities. In this indication, delta-9-tetrahydrocannabinol (THC)-containing CBMs are recommended. There is limited evidence that CBMs are also effective in Parkinson's disease in which they may improve tremor, but also non-motor symptoms such as pain and sleeping problems. With respect to other neurodegenerative diseases, there is limited evidence that CBMs may improve behavioral symptoms in Huntington's disease. In addition, it has been speculated that CBMs may have neuroprotective effects, but this has not yet been confirmed in the clinical setting.
During the past 30 years, the endocannabinoid system (ECS) has emerged as a major signalling system in the mammalian brain regulating neurotransmission in numerous brain regions and in various cell populations. Endocannabinoids are able to regulate specific physiological functions and thus modify their behavioural manifestations and allostatic alterations of the ECS linked to different pathological conditions. As discussed in detail in other chapters of this book, endocannabinoids are involved in learning and memory, stress, and anxiety, feeding, energy balance, development, and ageing. Likewise, many CNS disorders (e.g. schizophrenia, epilepsy, substance use disorders, and multiple sclerosis) are associated with dysregulation of the ECS. Discerning the physiological functions of the synthetic and degrading enzymes of endocannabinoids and their receptors is a challenging task because of their distinct and complex expression patterns. Techniques of genetic engineering have been able to shed light on a number of complex ECS-related tasks during the past years. In this chapter, first, we take a critical look at the toolbox available to researchers who would like to investigate cannabinoid effects using genetic engineering techniques, then we comprehensively discuss genetically modified rodent models in various neuronal and non-neuronal cell populations, both within and outside the nervous system.
Psychedelic Harm Reduction and Integration (PHRI) is a transtheoretical and transdiagnostic clinical approach to working with patients who are using or considering using psychedelics in any context. The ongoing discussion of psychedelics in academic research and mainstream media, coupled with recent law enforcement deprioritization of psychedelics and compassionate use approvals for psychedelic-assisted therapy, make this model exceedingly timely. Given the prevalence of psychedelic use, the therapeutic potential of psychedelics, and the unique cultural and historical context in which psychedelics are placed, it is important that mental health providers have an understanding of the unique motivations, experiences, and needs of people who use them. PHRI incorporates elements of harm reduction psychotherapy and psychedelic-assisted psychotherapy, and can be applied in both brief and ongoing psychotherapy interactions. PHRI represents a shift away from assessment limited to untoward outcomes of psychedelic use and abstinence-based addiction treatment paradigms and toward a stance of compassionate, destigmatizing acceptance of patients' choices. Considerations for assessment, preparation, and working with difficult experiences are presented.
Among the complications associated with the use of classic psychedelics, flashbacks, hallucinogen persisting perception disorder (HPPD) and reactivations are most specifically linked to their use. These three phenomena share the occurrence of perceptual disturbances resembling those experienced under the acute effects of psychedelics, but HPPD differs from flashbacks and reactivations due to its persistent nature.Existing evidence suggests that HPPD has a generally low relative prevalence, though in some cases, it may reach considerable clinical relevance. In contrast, flashbacks and reactivations may be more common but are less frequently documented, as they typically do not result in significant distress or treatment-seeking behavior.Many patients presenting with post-psychedelic complications assume they have HPPD; however, only a minority actually meet diagnostic criteria, with others suffering from different psychedelic-related complications. This complicates epidemiological estimates of HPPD and underscores the importance of comprehensive differential diagnostic assessment. Subsuming non-pathological phenomena like flashbacks to HPPD inappropriately inflates prevalence estimates.In very rare cases, HPPD may develop into a chronic condition requiring long-term pharmacological treatment, while in most cases, HPPD spontaneously subsides within one year or diminishes to a tolerable level. It is therefore essential to avoid emphasizing negative prognoses, as they may influence treatment outcomes.This chapter provides an overview of the phenomenology, epidemiology, diagnostic classification, and differential diagnoses of flashbacks, HPPD, and reactivations. As evidence-based treatment options are not yet available, current knowledge is derived from case reports and clinical experience.
Psychedelic substances have been increasingly recognised for their potential in treating various mental health conditions, yet they can also induce what we call ontologically challenging psychedelic experiences (OCPEs), a concept developed in our research to describe experiences that profoundly disrupt an individual's sense of self, reality, and existence. We present OCPEs not as a diagnostic category but as a phenomenological and harm reduction perspective on certain destabilising psychedelic experiences.While some individuals integrate OCPEs with ease, others struggle with ontological instability, existential distress, and impairments that persist long after acute effects. Importantly, ontological challenges are not always negative: for many, when they feel adequately resourced, they form part of the therapeutic mechanism and are a valued opportunity for personal development and growth. Drawing on our qualitative studies alongside other psychological research, we examine the phenomenology of OCPEs and their challenging aftermath, as well as strategies that may help facilitate recovery and integration. Grounding techniques, cognitive (re)framing, and supportive structures are discussed as potentially beneficial approaches and resources.Finally, we outline ethical and practical implications for clinical and harm reduction practice. We highlight the limits of informed consent in psychedelic therapy and argue for the value of preparation and post-experience support that is attuned to ontological disruptions. As empirical evidence remains limited, further research is needed to refine best practices. The development of an ethically responsible approach, informed by the phenomenology of OCPEs, can help maximise benefits of psychedelic substances while minimising long-term harm.
Touch has long been an essential element in human communication and healing. In the field of psychedelic-assisted therapy (PAT), the role of touch (and by extension, non-touch) presents complex ethical and practical challenges, particularly due to the heightened vulnerability of individuals in altered states of consciousness. Recent public discourse, including reports of boundary violations and abuse, has sharpened the political and ethical discussion around physical contact in PAT settings.This chapter approaches the topic from a harm reduction perspective, acknowledging the risks of misuse and the need for clear boundaries, transparency, informed consent, and cultural sensitivity. At the same time, we argue that touch can offer grounding, emotional support, and therapeutic value when used with care and responsibly. We explore both touch and non-touch interventions in PAT, examining their historical roots, therapeutic potentials, and outlining the ethical frameworks necessary to navigate this complex and sensitive terrain. Our aim is to contribute to an informed and nuanced dialogue on the topic, which supports safe, ethical, and effective therapeutic practices.
Alongside the important contributions of the harm reduction movement to improving public health in secular settings, communities that use psychedelics as religious sacraments (i.e., entheogens) have developed their own frameworks for supporting safety within their spiritual practices and hold their own conceptualizations of risk and harm. In order to understand better the lived realities of substance use, safety practices, and potential harms among entheogenic communities, researchers can collaborate closely with these communities in the formulation and conduct of their studies in this shared pursuit. The integration of community-based participatory research (CBPR) practices can not only help center these communities in the co-creation of research but also improve engagement, generate trust, and illuminate local priorities for knowledge production. The current work presents preliminary findings from a CBPR study with entheogenic communities. We share "lessons learned" from forming the study's community advisory board (CAB) and initial pilot data gathering in order to encourage biomedical investigators to consider CBPR approaches for their own research with psychedelic communities. Lessons include consultation with community engagement experts; considerations for compensation and confidentiality; utilizing multimodal strategies for recruiting study participants and CAB members; and the importance of considering the unique historical context of these communities. These lessons support the development of best practices for current and future psychedelic research as well as subsequent policies and public education efforts focused on psychedelic harm reduction and the community-based uses of psychedelics more broadly.
Classic psychedelics such as LSD, psilocybin, and DMT from unregulated markets pose considerable risks through unknown adulterants and potencies. In this chapter, we explore the importance of drug checking in minimizing harm among users of classic psychedelics and examine the opportunities and challenges associated with intervention settings, analytical techniques, and risk communication strategies. Gas chromatography (GC) and liquid chromatography (LC) coupled with mass spectrometry (MS) provide the most reliable and comprehensive analysis results for classic psychedelics. However, they are relatively costly, stationary, and require legal permission to obtain reference standards. Combined presumptive tests, such as thin-layer chromatography (TLC) and reagent testing, offer a time-efficient and cost-effective approach to initial substance screening. For certain compounds, Fourier-transform infrared spectroscopy (FTIR) serves as a valuable complementary technique, although potent psychedelics, such as LSD and NBOMe on blotter paper or in diluted solution, and complex botanical matrices challenge its detection limit, requiring the use of multiple analytical methods to confirm results. Such combination can effectively prevent acute risks, while confirmatory instrumental analysis remains essential for ongoing monitoring and public health efforts. Alongside robust testing procedures, drug checking's consultative component is crucial for clarifying analytical constraints, promoting safer use practices, and offering referrals to health services. By identifying mislabeled samples and ensuring tailored risk communication, drug checking not only protects individual users but also informs the public and health professionals regarding dangerous or novel substances. This chapter situates drug checking as a key public health measure that reduces acute harm from misrepresented psychedelic substances while supporting monitoring efforts.
Depersonalization (DP) and Derealization (DR) refer to perceptual changes of "as-if-character" where the self (→DP) or the surroundings (→DR) are experienced as unreal. These symptoms are highly prevalent in individuals with mental disorders. If these symptoms persist most of the day for months, the diagnosis of depersonalization-derealization-disorder (DDD) is likely. DDD is a common disorder with a high comorbidity with depression, anxiety disorders, and personality disorders.The intake of classic psychedelic drugs often elicits DP/DR symptoms, which cease in most cases when the drug is eliminated. DDD is frequently precipitated by drug intoxication (cannabis and classic psychedelics). Patients and some researchers assume, therefore, that drug intoxication is the cause of DDD and frame it as a "never-ending trip." Researchers base their assumption on the potential of psychedelics to elicit DP/DR symptoms and on case series of individuals reporting long-lasting uncomfortable symptoms after drug intake. Arguments are presented that demonstrate this is a reductionist conclusion and that this assertion may lead to false illness perceptions, hinder awareness of emotional conflicts, and erode patients' self-efficacy. The main arguments are that, first, DDD is a mental disorder resulting from the avoidance of aversive emotional states. DDD is related to functional alterations of brain networks rather than organic brain damage. Second, psychedelics act as a catalyst that accelerates the onset of DDD in vulnerable individuals by mobilizing complex anxiety-laden unconscious emotions from early attachment traumas.The treatment of DDD encompasses psychoeducation about the nature of the disorder, challenging false causal attributions to external causes (such as drug intake) and helping the patient experience and process their emotions adaptively. To achieve remission, patients usually need long-term psychotherapy of 50-100 sessions.
