Cannabis on the Brain: Is It Neurotoxic or Neuroprotective?(*)

TLDR: A review of the most recent evidence relating to the neurotoxic and europrotective effects of cannabis and cannabinoids on the brain and to critically evaluate their significance argues that there is increasing evidence that many cannabinoids have neuroprot protective effects, and may be useful in the treatment of some neuropsychiatric disorders.

Abstract: Recent studies have further confirmed that cannabis produces its psychological and behavioural effects by acting on specific cannabinoid receptors in the brain and that the brain also contains naturally occurring cannabinoids known as `endocannabinoids'. Although some recent studies suggest that cannabis may be neurotoxic and that this may explain the effects of cannabis on short-term memory, this review argues that this evidence is not convincing and that there is increasing evidence that many cannabinoids have neuroprotective effects, and may be useful in the treatment of some neuropsychiatric disorders. The aim of this review is to provide a summary of the most recent evidence relating to the neurotoxic and europrotective effects of cannabis and cannabinoids on the brain and to critically evaluate their significance. In doing so I will not attempt to provide an exhaustive summary of the increasingly vast field of cannabinoid neuropharmacology but will focus on key recent developments which have occurred in the last 2 years. The term `cannabinoid' will be used throughout to refer to chemicals which activate the cannabinoid receptors. Some of these are chemically similar to the active ingredient in cannabis - [delta.sup.9]-tetrahydrocannabinol ([delta.sup.9]-THC) - others are synthetic and chemically dissimilar but in some cases still activate the cannabinoid receptors. Collectively, all of these substances are now referred to as `cannabinoids' in a way that is analogous to the term `opioids', which is used to refer to natural and synthetic morphine-like compounds that activate, opiate receptors (Mechoulam, Fride & Di Marzo, 1998). A Brief History Of Cannabinoid Neuroscience Until the 1980's, [delta.sup.9]-tetrahydrocannabinol ([delta.sup.9]-THC) was thought to affect neurons in the brain by dissolving into the lipid (i.e., fatty acid) component of their membranes and disrupting cellular function in a non-specific way. Since cannabis is highly soluble in lipids, it seemed very likely that this was the way that cannabis produced its various psychological and behavioural effects. However, cannabinoid pharmacology changed in the late 1980's when William Devane and colleagues at the University of St Louis Medical School in Missouri demonstrated a specific receptor protein for cannabinoids on the surface of neurons (i.e., an extracellular receptor) which appeared not to bind any other neurochemical (Devane, Dysarz, Johnson, Melvin & Howlett, 1988; see Feldman & Glass, 1998; Ameri, 1999 for recent reviews). This finding was quickly replicated and the study of cannabinoids became one of the most active fields of neuropharmacology throughout the 1990's. It was also demonstrated in these early experiments that activation of the cannabinoid receptor resulted in biochemical effects within neurons, in particular a reduction in the intracellular second messenger, cyclic adenosine-3',5' monophosphate (cAMP). Activation of the cannabinoid receptor produced this effect by activating a so-called `G-protein' (guanine nucleotide binding protein), which acted as a switching mechanism to produce biochemical effects inside neurons (Bidaut-Russell, Devane & Howlett, 1990). By the early 1990's, cannabinoid receptors had been extensively mapped in almost every area of the central nervous system (CNS), including the post-mortem human brain, and the cannabinoid receptor gene had also been identified and cloned (see Feldman & Glass, 1998; Ameri, 1999 for reviews). Cannabinoid receptors were divided into 2 categories: the CB1 receptors which are located in the nervous system (both the central and peripheral nervous systems) and the testis; and the CB2 receptors which are located in many other areas of the body, including various parts of the immune system (see Feldman & Glass, 1998; Ameri, 1999 for recent reviews). In addition to their numerous functions in the nervous system, it is now clear that cannabinoid receptors exist in sperm and may regulate their function; they may influence the response of the immune system to bacterial and viral infections, and they may also be important in cardiovascular function (see Feldman & Glass, 1998; Mechoulam, Fride & Di Marzo, 1998; Ameri, 1999, for reviews). …