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Beneficial and Deleterious Effects of Cannabinoids in the Brain: the Case of Ultra-Low Dose THC

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Beneficial and Deleterious Effects of Cannabinoids in the Brain: the Case of Ultra-Low Dose THC THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 2019, VOL. 45, NO. 6, 551–562 https://doi.org/10.1080/00952990.2019.1578366 REVIEW Beneficial and deleterious effects of cannabinoids in the brain: the case of ultra-low dose THC Yosef Sarne Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel ABSTRACT ARTICLE HISTORY This article reviews the neurocognitive advantages and drawbacks of cannabinoid substances, and Received 17 September 2018 discusses the possible physiological mechanisms that underlie their dual activity. The article Revised 8 January 2019 further reviews the neurocognitive effects of ultra-low doses of Δ9-tetrahydrocannabinol (THC; Accepted 29 January 2019 3–4 orders of magnitude lower than the conventional doses) in mice, and proposes such low KEYWORDS doses of THC as a possible remedy for various brain injuries and for the treatment of age-related Tetrahydrocannabinol; cognitive decline. neuroprotection; neurotoxicity; cognitive decline; aging; biphasic dose-dependency Introduction with cannabinoid receptors will modify the balance between the various signaling systems within the brain. Cannabis (marijuana) is still defined as an illicit drug of The acute, short-term suppressive effects of cannabis on abuse in most countries around the world. On the other memory, learning, executive functions, and attention in hand, a growing number of countries and states recog- humans are well recognized (2,9–11). A similar suppressive nize the same plant (Cannabis sativa) and its active influence on memory and learning has also been docu- ingredients (the phytocannabinoids) as beneficial for mented in experimental animals (12–14). On the other the treatment of various disorders. Previous reviews hand, the long-term consequences of chronic exposure to have described the deleterious outcomes of cannabis cannabis have been the subject of considerable debate use in detail (see, for example (1–3)), while others among scholars. Epidemiologic studies in humans are sub- have highlighted its therapeutic potential (4–7). The ject to serious drawbacks, including the selection of sub- present article aims to provide a brief review of the jects, the use of multiple drugs, duration of washout, dual influence of cannabinoids on the brain in both evaluation of doses and frequency of cannabis use, as well experimental animals and human subjects, and to sug- as the choice of test used to determine possible cognitive gest several mechanisms that may underlie these appar- damage. Most studies have been carried out on young users ently contradictory effects. In addition, the article will who are more vulnerable to the deleterious effects of can- present the case of an ultra-low dose of Δ9-tetrahydro- nabis on cognitive functions (15). Even when cognitive cannabinol (THC, the main psychoactive ingredient of tests failed to demonstrate a major decline in performance, cannabis), review its neurotoxic and neuroprotective functional MRI showed that chronic users of the drug had effects, discuss the rationale for this dual activity, and to mobilize more neuronal resources in order to succeed in highlight the advantages of using ultra-low doses of agiventest(16,17). Furthermore, structural MRI studies THC for specific clinical conditions. showed a reduction in white and gray matter in the brains of chronic users (18,19). Cannabinoid suppression of cognitive Animal experiments are easier to control for possible performance experimental pitfalls. Chronic exposure of rats to THC resulted in a persistent reduction in learning (20–22). The main mechanism of cannabinoid action in the Morphological changes in the hippocampus of rats brain involves activation of presynaptic cannabinoid repeatedly treated with cannabinoids, including neuro- receptors and inhibition of transmitter release, includ- nal death and a reduction in synaptic density and ing the release of the major excitatory (glutamate) and dendritic length of pyramidal neurons, were also inhibitory (GABA) neurotransmitters (for review see reported (22–25). (8)). Hence, it is expected that drugs which interact CONTACT Yosef Sarne [email protected] Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel © 2019 Taylor & Francis Group, LLC 552 Y. SARNE The deleterious effects of chronic cannabis on the Cannabinoids have also been shown to protect brain are in accordance with the neurotoxic effects of against neurodegenerative diseases in a variety of experi- cannabinoids shown in various in vitro studies (26–29). mental animal models (48). Early studies pointed to the therapeutic potential of cannabinoid drugs in models of Alzheimer’s(49), Parkinson’s(50), and Huntington’s Beneficial effects of cannabinoids in the brain ( 51) diseases. At least some of these protective effects Different cannabinoid drugs, including phytocannabi- were attributed to the anti-inflammatory activity of the noids, endocannabinoids, and synthetic cannabinoid cannabinoids (52), since an inflammatory response is analogs, have been shown to exert neuroprotection in a common feature of all neurodegenerative diseases a variety of experimental models. Thus, cannabinoid and is responsible for exacerbating the damage due to agonists protected against global and focal ischemic the primary pathology. Nevertheless, the possibility of damage (WIN-55,212,1–10mg/kg (30)), ouabain- a direct effect of the cannabinoid drugs on the pathologic induced neurotoxicity (THC, 1mg/kg (31) and AEA, process itself has also been suggested (53–55). Regardless 1–10 mg/kg (32)), head injury (2-AG,5mg/kg (33)), of the specific disease and the suggested mechanism of MDMA neurotoxicity (THC, 3 mg/kg (34)), and action, the effects required the continuous presence of against glutamate receptor-mediated excitotoxicity a sufficiently high concentration of cannabinoid and (AEA, 10 mg/kg (35)). All these studies, and many hence the experimental animals were chronically admi- more that have been performed during the last two nistered conventional (high) doses of cannabinoids. decades, share two common features: (a) they used Similar chronic administration of conventional doses the conventional doses of cannabinoids (0.5–20 mg/ of cannabinoids has been shown to improve the cogni- kg) that are known to induce the conventional acute tive performance of aging rodents: a continuous infusion cannabinoid effects in rodents, and (b) they injected the of the cannabinoid agonist WIN-55,212–2 (2 mg/kg/d drugs a few hours before, or a few hours after the insult. for 21 days) improved spatial memory in old rats (56), When the injection of the cannabinoid was postponed and a continuous infusion of THC (3 mg/kg/d for by 1 hour (33) or by 8 hours (35), it failed to protect the 28 days) restored cognitive functions of old mice (57). brain. The experimental requirement for a high enough These two chronic treatments induced morphological dose and the limited duration of a therapeutic time- and biochemical changes in the brain: WIN-55,212–2 window are in accordance with the physiological triggered neurogenesis in the hippocampus of the aging mechanisms that have been suggested to explain these rats (58), and THC promoted synaptogenesis and neuroprotective effects. One such mechanism is the induced the expression of various genes known to be inhibitory effect of cannabinoids on calcium influx involved in synapse formation, neuronal plasticity, and (36,37) and on glutamate release (38). If the drug is cognitive functions in the hippocampus of the aging expected to block the entry of the toxic ion calcium and mice (57). the release of the excitatory transmitter glutamate that is responsible for the spread of the damage, it is neces- The origin of cannabinoid duality sary to have a high enough concentration of the canna- binoid drug in the brain around the time that damage The opposing (deteriorating and ameliorating) effects occurs. Other mechanisms that have been suggested to of cannabinoids have been often reported in different explain the neuroprotective effects of cannabinoids studies that used different experimental setups, includ- include inhibition of NO synthesis (39), inhibition of ing different cells, animals, drugs, doses and assays; the release of pro-inflammatory cytokines (40), induc- hence a conclusive insight into the origin of the oppos- tion of hypothermia (41), induction of vasodilation ing effects was not straightforward. Some studies, how- (42), and anti-oxidative action (43). All these direct ever, have directly approached the issue of explaining effects of cannabinoids require the presence of the the dual nature of the cannabinoid effects. cannabinoid agonist in the brain at the time of insult The effect of cannabinoids is mediated by at least two (see below for an alternative mechanism of action). cannabinoid receptors (CB1 and CB2) that may activate The wide range of protective effects by cannabinoid different signaling pathways. In contrast to previous drugs, together with the finding that the level of endo- distinction between neuronal (CB1) and non-neuronal cannabinoids was elevated in the brain following the (CB2) cannabinoid receptors, it is currently well estab- induction of insult (33,44) led to the suggestion that the lished that both CB1 and CB2 receptors are expressed by endocannabinoid system can serve as a compensatory neurons in the brain (59–62). Other target sites are also mechanism that is mobilized in response to neuronal activated by various cannabinoids, including
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