Cannabinoids and Psychosis

Clearly the majority of people who use marijuana do not develop schizophrenia. Yet, the human literature suggests that there is a modest association between cannabis exposure (particularly in adolescence) and later development of schizophrenia--whether or not this association is causal is hotly debated. This chapter reviews some of the evidence for and against such a causal relationship. The chapter concludes with the suggestion that individuals with a family history of schizophrenia, with prodromal symptoms, or who have experienced discreet episodes of psychosis related to cannabis use, may be best served not using THC-predominant marijuana.

An Introduction to Cannabis

Although cannabis has been used throughout human history, the scientific investigation of its effects only began with the isolation of THC in the 1960’s. Once discovered it was another 20 years before the mechanism by which THC produces its psychoactive effects in the brain, the CB1 receptor, was discovered. Cannabis contains over 80 cannabinoid compounds, but THC is the only intoxicating compound. Recent preclinical research is being directed towards evaluating the therapeutic potential of other cannabinoid compounds found in cannabis, including CBD. The pharmacokinetics of THC, methods of administration, and dosing issues are explored in Chapter 1.

Where Do We Go from Here?

In the final chapter, areas of future research in gaining a better understanding the functions of the endocannabinoid system and the effects of cannabis on this system are envisioned. It is critical to investigate the effects produced by various strains of marijuana with different ratios of THC:CBD and other cannabinoids. As well, little is understood about the interaction between marijuana and other drugs, in particular alcohol. Cannabinoid designer drugs, for example Spice, are discussed. Some of the difficulties in conducting valid and reliable human clinical research with marijuana are discussed. A special case is made for palliative care. Finally, risks and benefits of marijuana use for both medicinal and recreational purposes are discussed.

Cannabinoids and Neurodegenerative Disorders

Cannabinoids play a neuroprotective function in the brain by reducing the release of excitatory glutamate release and by their anti-oxidant and anti-inflammatory effects. THC acts on both CB1 and CB2 receptors, both of which have been shown to be important in the neuroprotective effects of the endocannabinoid system, such as reducing the damage produced by stroke. The best human clinical trial evidence for the effectiveness of cannabis as a medicine is in the treatment of painful spasticity in Multiple Sclerosis (MS) patients. Preclinical research suggests that the endocannabinoid system is also involved in symptomatology of Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease and Amyotropic Lateral Sclerosis, suggesting that treatments with activate this system, may be useful treatments for a range of neurogenerative disorders of the nervous system.

Cannabinoids and Pain

The most common medical use of cannabis today and throughout human history is for the treatment of chronic pain, which is usually accompanied by some other disability or mood disorder. Estimates indicate that approximately 20 percent of the world’s population suffers from chronic pain (...

Cannabinoids and Nausea

The treatment of nausea has lagged behind the treatment of chemotherapy-induced vomiting, despite its prevalence. The first recognized medicinal benefit of THC after its discovery was for chemotherapy-induced nausea and vomiting. Since the discovery of the endocannabinoid system, our understanding of the mechanisms by which cannabinoids reduce nausea and vomiting has been greatly improved. CB1 agonists reduce nausea in preclinical models. CBD and CBDA also show promise as non-psychoactive treatments. As well treatments that boost the endogenous cannabinoid system by inhibiting the degrading enzymes FAAH (elevating AEA) and MAGL (elevating 2-AG) or both have shown promise to treat nausea in preclinical models. New research identifies the interoceptive insular cortex as a region which may regulate the experience of nausea and its amelioration by 2-AG.

Cannabinoids, Reward, and Addiction

Dopamine is a neurotransmitter critical for reward processing and is elevated by most addicting drugs. The effect of THC and other CB1 agonists moderately elevate dopamine in reward related regions of the rodent brain; however, there is less consistent evidence in humans for marijuana-induced changes in dopamine release or for morphological changes in brain reward areas. In humans, cannabis use disorder has been identified, which shows similar features of other substance use disorders, but not in the same extremes as opiates, psychostimulants or alcohol. This chapter discusses the interaction between cannabis and other drugs in relapse to drugs use, with a special case for the interaction between cannabinoids and opiates. Finally, the relationship between cannabinoid effects on men and women in sexual behaviour is discussed.

Cannabinoids, Learning, and Memory

Global activation of CB1 receptors produces actions on hippocampal neurons, which results in interference with short tem memory and consolidation of memories that are currently being processed. However, such CB1 receptor activation does not impair recall of previously established memories. Evidence suggests that the acute effects of cannabis on memory depend in part on the type of cannabis that is used. THC acts to impair short-term memory and the consolidation of new memories, but CBD protects against the memory impairing effects of THC. There is conflicting human evidence that chronic exposure to cannabis can produce permanent changes in learning and memory processes and/or can modify the human adolescent and adult brain functioning. This evidence is reviewed.

Cannabinoids and Emotional Regulation

Marijuana is often used for relaxation, therefore, it is not surprising that the endocannabinoid system is critically involved in the regulation of emotion, anxiety and mood. In preclinical animal models, THC and other CB1 agonists produce a biphasic effect on anxiety, with low doses reducing anxiety (by blocking the release of the excitatory neurotransmitter glutamate) and high doses promoting anxiety (by blocking the release of the inhibitory neurotransmitter, GABA). As well, CBD reduces anxiety in both preclinical and clinical research, but by a non-CB1 mechanism of action. One of the most promising treatments for cannabinoids is post-traumatic stress disorder (PTSD). Considerable preclinical animal research and small-scale clinical trials have shown that activation of the endocannabinod system may promote extinction of aversive memories. The endocannabinoid system regulates the action of the Hypothalamic-Pituitary-Adrenal (HPA) Axis, which controls the release of stress hormones.

Cannabinoids and Epilepsy

Cannabis has historically been drug of choice in treating epilepsy, particularly in the 1800’s. However, there have been no modern controlled clinical trials on the effectiveness of cannabis or THC in treating seizures in humans. Preclinical research suggests that CB1 agonists reduce seizures in animal models, however, there is also some evidence that THC may be proconvulsant. It is now known epilepsy can substantially modify the endocannabinoid signalling system, by modifying the relative activation of excitatory glutamate and inhibitory GABA transmission. Considerable recent media interest has focussed on the potential of CBD to reduce seizures in a childhood form of epilepsy called Dravet’s syndrome. The evidence for the anti-convulsant potential of CBD and other cannabinoids is reviewed in this chapter.