Dialogues in Clinical Neuroscience最新文献

The use of cannabis as a drug has undergone a remarkable change of direction: considered as a symbol of countercultures in past decades, it is presently being hailed as a cure for any number of diseases and conditions. Thus, despite concerns about the safety of cannabis and cannabinoids, quite a few drugs that contain cannabinoids have recently been approved by several drug agencies, and the medicinal and recreational use of cannabis has been legalized in various countries and states. The promise of cannabinoids for therapeutic use, as well as potentially detrimental health risks and regulatory issues, will need to be carefully weighed.
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This article retraces the story of cannabis from the earliest contacts of humans with the plant to its subsequent global expansion, its medicinal uses, and the discovery of the endocannabinoid system in the 20^th century. Cannabis was attested to around 12 000 years ago near the Altai Mountains in Central Asia, and since then, cannabis seeds have accompanied the migration of nomadic peoples. Records of the medicinal use of cannabis appear before the Common Era in China, Egypt, and Greece (Herodotus), and later in the Roman empire (Pliny the Elder, Dioscorides, Galen). In the 19^th century, orientalists like Silvestre de Sacy, and Western physicians coming into contact with Muslim and Indian cultures, like O'Shaughnessy and Moreau de Tours, introduced the medicinal use of cannabis into Europe. The structure of the main psychoactive phytocannabinoid, tetrahydrocannabinol (THC), was determined in Israel by Mechoulam and Gaoni in 1964. This discovery opened the gate for many of the subsequent developments in the field of endocannabinoid system (ECS) research. The advances in the scientific knowledge of the ECS place the debate on cannabis liberalization in a new context.
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The endocannabinoid system (ECS) is a highly versatile signaling system within the nervous system. Despite its widespread localization, its functions within the context of distinct neural processes are very well discernable and specific. This is remarkable, and the question remains as to how such specificity is achieved. One key player in the ECS is the cannabinoid type 1 receptor (CB₁), a G protein-coupled receptor characterized by the complexity of its cell-specific expression, cellular and subcellular localization, and its adaptable regulation of intracellular signaling cascades. CB₁ receptors are involved in different synaptic and cellular plasticity processes and in the brain's bioenergetics in a context-specific manner. CB₂ receptors are also important in several processes in neurons, glial cells, and immune cells of the brain. As polymorphisms in ECS components, as well as external impacts such as stress and metabolic challenges, can both lead to dysregulated ECS activity and subsequently to possible neuropsychiatric disorders, pharmacological intervention targeting the ECS is a promising therapeutic approach. Understanding the neurobiology of cannabinoid receptor signaling in depth will aid optimal design of therapeutic interventions, minimizing unwanted side effects.
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The last decades have seen a major gain in understanding the action of cannabinoids and the endocannabinoid system in reward processing and the development of addictive behavior. Cannabis-derived psychoactive compounds such as Δ⁹-tetrahydrocannabinol and synthetic cannabinoids directly interact with the reward system and thereby have addictive properties. Cannabinoids induce their reinforcing properties by an increase in tonic dopamine levels through a cannabinoid type 1 (CB₁) receptor-dependent mechanism within the ventral tegmental area. Cues that are conditioned to cannabis smoking can induce drug-seeking responses (ie, craving) by eliciting phasic dopamine events. A dopamine-independent mechanism involved in drug-seeking responses involves an endocannabinoid/glutamate interaction within the corticostriatal part of the reward system. In conclusion, pharmacological blockade of endocannabinoid signaling should lead to a reduction in drug craving and subsequently should reduce relapse behavior in addicted individuals. Indeed, there is increasing preclinical evidence that targeting the endocannabinoid system reduces craving and relapse, and allosteric modulators at CB₁ receptors and fatty acid amide hydrolase inhibitors are in clinical development for cannabis use disorder. Cannabidiol, which mainly acts on CB₁ and CB₂ receptors, is currently being tested in patients with alcohol use disorder and opioid use disorder.
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