THE AMERICAN JOURNAL OF 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- (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 , 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 , 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 -mediated 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 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 serotonin, damage in order to rescue the brain (45–47). adrenalin, and vanilloid receptors, as well as some THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 553 orphan receptors (GPRs 18, 55 and 119) (8,63–65). Since and inhibitory (GABAergic) signals may underlie the pro- most phytocannabinoids (including THC), endocanna- and anti-convulsant effects of different cannabinoid ago- binoids (including anandamide and 2-AG), and many nists (76). An additional source for the heterogeneity of synthetic cannabinoids, are not CB1/CB2-selective ago- the cannabinoid effect might reside in the different nists, the outcome of their action is dependent on the amount and rate of desensitization that is induced by available receptor and its downstream signaling path- full and partial cannabinoid agonists, especially in light way. The introduction of selective CB1 and CB2 agonists of the multiple mechanisms by which the cannabinoid and antagonists, has revealed that the activation of either receptor is regulated (77). CB1 or CB2 receptors (co-present in the rat atrium, Special attention should be paid to the dependency of similar to their co-presence in the brain) resulted in the effect on the dose (or the concentration) of the can- either inhibition or stimulation, respectively, of cAMP nabinoid drug. Biphasic dose-dependency, sometimes production and muscle contractility (66). Moreover, called “hormesis”, is a common phenomenon in pharma- different agonists may evoke different cellular pathways cology, and is seen with many drugs, hormones, and even when they activate the same CB1 receptor, depend- neurotransmitters (for review see (78)). Cannabinoids ing on the induced conformational change of the recep- are no exception: for example, high or low doses sup- tor (67). The effect of the cannabinoid is additionally pressed or augmented motor activity and phagocytosis dependent on the physiological (68) or the metabolic (79); were orexigenic or anorexigenic (75); and induced (69) state of the cell. A similar state-dependency of the aversive or rewarding effects (80), respectively. Similar cannabinoid effect was found in vivo, where THC biphasic dose-dependent effects were also reported improved memory in Alzheimer-inflicted mice but in vitro: in contrast to the classical inhibitory effect of impaired memory in their normal controls (55). It was cannabinoids on calcium channels that was achieved by previously shown that THC had a differential effect on the conventional (high) concentrations of cannabinoid cortical neurons in neonates compared to adult rats (70). agonists (in the micro-molar range) (36,37), much lower With respect to age, the negative effects of chronic expo- concentrations (in the nano-molar range) stimulated cal- sure to cannabinoids on cognitive functions was cium entry into cells (81,82). It was later demonstrated detected in young but not in old rodents (56,57), and that the stimulatory effect was mediated by CB1 receptors was more pronounced in adolescent, as compared to and Gs GTP-binding proteins and was more sensitive to adult humans (71,72). the cannabinoid, while the inhibitory (“classical”) effect Since cannabinoid receptors are widely distributed all was mediated by CB1 receptors and Gi GTP-binding over the brain, and are involved in numerous neuronal proteins, and was less sensitive (lower efficacy) but stron- systems, it might be expected that systemic administra- ger in magnitude (higher potency) than the stimulatory tion of cannabinoid drugs could activate different net- pathway (82,83). Hence, the classical inhibitory effect works and give rise to opposing effects. Thus, the dominated in response to high concentrations, while the injection to rats of WIN-55,212-2 induced both transient stimulatory effect was revealed when the concentrations stimulation and prolonged inhibition of hippocampal were lower. The discovery of the cellular mechanism that acetylcholine release when the stimulatory effect was underlies the biphasic effect of cannabinoids on calcium mediated by CB1 receptors in the septum and involved at the cellular level led us to test the effect of ultra-low D-1 dopamine receptors, while the inhibitory effect was doses of THC in vivo. mediated by CB1 receptors in the hippocampus and involved D-2 dopamine receptors (73). A similar disso- The case of ultra-low doses of THC ciation between the reward and aversive effects of THC was recently demonstrated by local micro-injection of the Our in vitro findings (82,83) that a thousand times lower drug. In this case, reward was induced by THC in the concentration of the cannabinoid agonist DALN trig- anterior nucleus accumbens and involved mu opioid gered cellular processes that antagonized the classical receptors, while aversion was induced by THC in the effects of conventional concentrations of cannabinoids, posterior nucleus accumbens and involved kappa opioid raised the possibility of a similar situation in vivo. If, as receptors (74). Another example of two opposing endo- was argued above, at least part of the neuroprotective genous systems that are activated by cannabinoids is the effect of cannabinoids stems from their activity to sup- bimodal control of food intake, with cannabinoid- press calcium influx and glutamate release, then the induced hyperphagia mediated by glutamatergic neuro- stimulation of calcium influx by extremely low doses transmission and cannabinoid-induced hypophagia may cause damage to the brain. This original idea had mediated by GABAergic neurotransmission (75). been first presented by us in a theoretical assay (84), and A similar imbalance between stimulatory (glutamatergic) was later tested in a series of behavioral studies (85–87). 554 Y. SARNE

As a first step, we determined the range of effective (“metrazol”)-induced seizures, carbon monoxide- “ultra-low doses”. Behavioral studies in rodents usually induced hypoxia, pentobarbital-induced deep anesthesia, employ doses of THC (as well as many other agonists) in MDMA (“ecstasy”)-induced neurotoxicity, or lipopoly- the range of 0.5–20 mg/kg. In our control experiments, saccharide (LPS)-induced . The ultra- we validated previous observations that 1–10 mg/kg of low single dose of THC worked either it was injected THC induced the expected effects of analgesia, 1–7daysbeforeor1–7 days after the insult. The protective hypothermia, and immobility in mice. In contrast, how- effect of THC was mimicked by an ultra-low dose of the ever, we discovered that 3–4 orders of magnitude lower selective CB1 agonist ACEA, and was blocked by the doses (i.e., 0.001–0.002 mg/kg) of THC, induced hyper- selective CB1 antagonist SR14176A (95), indicating med- algesia (measured by tail-flick latency), hyperthermia iation of the effect by CB1 receptors. Importantly, the (rectal temperature), and hyper-activity (evaluated in protective effects persisted for at least seven weeks and the open field test and by counting grooming move- were accompanied by long-lasting biochemical changes in ments) (87,88). Subsequently, we used these doses to various regions of the mouse brain (see below). We found test our hypothesis and to study the possible deleterious that the ability of ultra-low THC to preserve cognitive effects of ultra-low THC. Our results showed that inject- functions did not result from a direct effect on the dama- ing the mice with 0.001 mg/kg THC had a deleterious ging incident itself, since neither the duration nor the effect on their memory and learning in the Morris’ water severity of the insults (seizures, anesthesia, hypoxia, or maze (87). Surprisingly, this cognitive deficit was ) were affected by THC. These observations, detected even 3 weeks after a single injection of the ultra- together with the general neuroprotection found in multi- low dose, and lasted for at least 4 months. Similar long- ple experimental models involving different insults, sug- lasting cognitive deficits were later found in other stu- gested to us that THC activated an endogenous dies that used different behavioral tests to measure var- compensatory mechanism(s) that protected, or even ious aspects of memory and learning (85,86). These healed the damaged brain (see below for mechanism of deteriorating effects of ultra-low THC were blocked by action). It should be mentioned here that previously SR14176A, indicating the involvement of CB1 receptors reported pre- and post-conditioning effects were not (86). It should be emphasized that the deleterious effects restricted to the brain, and similar protective phenomena of THC on learning were mild, and the mice were able to were seen in other organs such as the liver, kidney, and cope with the insult and reach maximal performance heart (96). Interestingly, in additional studies, we found after a few more trials (see, for example, Figure 1 in that the same ultra-low dose of THC (0.002 mg/kg) that (87) and Figure 2 in (86)). protected the brain, also protected the heart (97)andthe liver (98) from ischemic damage. Ultra-low THC: from neurotoxicity to neuroprotection Ultra-low THC and the elderly brain Minor insults are known to evoke compensatory mechan- It is generally accepted that at least part of the cognitive isms designed to protect the organism from other, more decline that accompanies aging results from the accu- severe insults (“conditioning”). In “pre-conditioning”,the mulation of minor insults such as short episodes of minor noxious stimulus protects from a subsequent more hypoxia, transient seizures, micro emboli, exposure to severe insult (89,90), while in “post-conditioning” the neurotoxins, or local inflammatory events that occur protective stimulus is applied following the insult (91). during the lifetime. In light of the general neuroprotec- Various stimuli, such as mild ischemia, hypoxia, trauma, tive effects of ultra-low THC against various induced or hyperthermia can protect against different, more inten- insults in young mature mice, and the assumed activa- sive insults (“cross-conditioning”). The therapeutic time- tion of a putative compensatory mechanism in the window for both pre- and post-conditioning is very long, brain, we hypothesized that ultra-low THC might be and the protecting minor insult can be delivered several able to rescue the old brain and prevent, or even days before or after the major damage (92). Following our reverse, age-related cognitive impairments. This was previous findings on the mild deleterious effects of ultra- proved to be the case in our recent study (99) where low THC (85–87), we hypothesized that such a low dose a single injection of 0.002 mg/kg THC to 24-month old may protect the brain from more severe damage when mice, improved their cognitive performance in applied either before or after the insult. This hypothesis a battery of six different behavioral assays that mea- was tested in a series of studies (93–95). Thus, a single sured different aspects of memory and learning. THC- injection of 0.002 mg/kg of THC prevented the long- treated old mice performed significantly better than lasting cognitive deficits that followed phenothiazide vehicle-treated old mice, and had a similar performance THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 555 to young (2-month old) control mice. The beneficial activation (phosphorylation) of CREB (cAMP response effects of the single injection of THC lasted for at least element-binding protein) and the level of BDNF (brain- 7 weeks and was accompanied by long-lasting biochem- derived neurotrophic factor) were increased for at least ical changes in the brain (see below). Furthermore, the 7 weeks after a single injection of ultra-low THC (94). single administration of ultra-low THC induced long- These two proteins are known to participate in long- lasting structural changes that could be detected by term memory formation and synaptic plasticity (104– magnetic resonance imaging (MRI). Five weeks after 106), and to be involved in pre-conditioning (107–110). the injection of THC, DTI (diffusion tensor imaging) It is interesting to note that the activation (phosphoryla- revealed a lower mean diffusivity indicating higher tion) of CREB was previously found to accompany the tissue density in 11 regions of the brain, while T2 reversal of age-related cognitive decline by the transfu- (relaxation time) images indicated an increase in the sion of young blood to old mice in heterochronic para- volume of the entorhinal cortex, the prefrontal cortex biosis experiments (111), and the restoration of and the posterior hippocampus. It should be empha- cognitive functions in old mice by chronic treatment sized that the beneficial effects of ultra-low THC were with THC (57). restricted to old mice, while, as mentioned above, the In our study on elderly mice (99), we also found that same application of THC to naïve young mice caused the level of sirtuin1 was elevated in the hippocampus and minor, though significant, long-lasting cognitive defi- frontal cortex for at least 7 weeks following a single cits (85–87). Similar age-dependent dual effects on injection of an ultra-low dose of THC. Sirtuin1 is cognitive performance of rodents was previously a nicotinamide adenine dinucleotide (NAD)-dependent reported for the chronic application of conventional protein deacetylase that is involved in synaptic plasticity, doses of cannabinoid drugs. Thus, the infusion of memory formation, learning capability, neuronal devel- WIN-55,212–2 (2 mg/kg/d) for 21 days in rats (56) opment, and neuroprotection (112–116). Sirtuin1 was and the infusion of THC (3 mg/kg/d) for 28 days in also found to mediate the protective effects of resvera- mice (57) improved the cognitive performance of old trol, melatonin, and calorie restriction (117–119), and to animals, but worsened the performance of their young reverse cognitive decline in a mouse model of acceler- counterparts. The endogenous cannabinoid system has ated senescence (118). Furthermore, it was claimed that already been shown to have a dual, age-dependent role the beneficial effects of sirtuin1 involved phosphorylated in the regulation of cognitive functioning: it was found CREB and BDNF (120,121), two molecules that were that the deletion of the CB1 receptor gene improved elevated in the brain by the extremely low doses of memory and learning in young mice, while it impaired THC (94). Taken together, these results suggest that memory and learning in old mice (100). the beneficial cognitive effects of ultra-low THC are probably related to the long-lasting activation of an array of functional proteins that regulate neuroplasticity Ultra-low THC: mechanism of action within the brain. One should notice, however, that these As was suggested above, a single administration of an correlative findings do not prove a causal relationship ultra-low dose of THC activated an endogenous between any of the modified proteins and the improved mechanism(s) that protected, and even healed a brain cognitive function. that has been challenged by either external insults or the At least two different (but not mutually exclusive) natural process of aging. In order to investigate the mechanisms can explain how the levels of various pro- biochemical events responsible for this phenomenon, teins (such as BDNF and sirtuin1) remain elevated in the we examined the amount and level of activation of brain many weeks after a single injection of such a low several functional proteins that are known to be involved dose of THC. One explanation assumes that the drug in neuroplasticity. The MAP kinase ERK (extracellular induces an epigenetic effect, namely, a persistent expres- regulated kinase) has been previously shown to partici- sion of genes that continuously regulate the production of pate in the formation of long-term memory and functional proteins long after the trigger (THC) has been strengthening of synaptic connectivity (101), and to be washed out. Epigenetic effects of chronic application of involved in the protective effect of pre-conditioning conventional (high) doses of cannabinoids have been (102,103). We found that 3–7 weeks following a single previously reported (57,122–124). The epigenetic effects injection of ultra-low THC, and in parallel with the of cannabinoids were shown to be mediated by several improvement in cognitive performance, the activity molecular mechanisms, such as histone methylation (phosphorylation) of ERK was elevated in the hippocam- (125), histone phosphorylation (126), or DNA methyla- pus and frontal cortex of the mice, two regions that are tion (127). Recent reviews have described the involvement related to memory and learning (94). Similarly, the of epigenetic processes in neurodegenerative disorders 556 Y. SARNE

(128) and brain conditioning (129), and highlighted the feature of neurodegenerative diseases, and since ultra-low potential benefits of employing epigenetic strategies to THC protects the brain from neuroinflammation (95), it treat neurological disorders. The question of whether may also be expected to combat and slow down cognitive a single administration of an extremely low dose of deterioration in neurodegenerative diseases. In our opi- THC can trigger similar epigenetic mechanisms is cur- nion, the most appealing clinical implication of ultra-low rently being studied by us together with Prof. Noam THC resides in the treatment of age-related cognitive Shomron of Tel Aviv University. An alternative explana- decline. The increase in life expectancy in developed tion for the long-lasting effects of ultra-low THC assumes countries renders a larger proportion of the human the formation of new neurons that either replace dying population cognitively challenged. Unfortunately, there neurons in the damaged brain, or create new neuronal is currently no effective treatment available for this aggra- networks (“neurogenesis”). New neurons are continu- vating condition, even though preventive measures such ously formed in at least two regions of the adult brain – as physical exercise, mental activity, and balanced diet the sub-granular layer of the hippocampal dentate gyrus, have been suggested to slow down the mental deteriora- and the sub-ventricular zone of the lateral ventricle, from tion that begins already in midlife. Treatment with extre- which the newborn neurons migrate to the olfactory bulb mely low doses of THC may provide a solution for this (for review see (130)). can be stimu- growing malady with its enormous clinical, social and lated by several manipulations, including chronic expo- economic burden. sure to high doses of cannabinoids (58,131–134). In our Synthetic THC (“dronabinol”) is already approved current study (Rachmany and Sarne, in preparation), we for the treatment of anorexia in people with AIDS and found that doublecortin, a protein that is selectively for nausea and vomiting in people undergoing che- expressed in newborn neurons and serves as a marker motherapy. This is available as oral capsules for neurogenesis (135,136), is elevated in the hippocam- (“Marinol”) in doses of 2.5–10 mg to be taken up to 6 pus and in the olfactory bulb of old mice 3–12 days times a day. “Medical marijuana” is approved for lim- following a single injection of 0.002 mg/kg of THC. This ited clinical indications and it is used (often several led us to propose that the rejuvenation of the aging brain times a day) in doses of 1–20 mg THC that correspond seen after treatment with ultra-low levels of THC might to the range of self-titrated doses smoked by users of be attributable to the formation of new neurons and their recreational marijuana. Similarly, the oromucosal spray successful integration in the insulted brain. nabiximols (“Sativex”) that is authorized in several countries for treating spasticity, con- tains 2.7 mg of THC per spray, and patients administer Ultra-low THC: clinical implications 4–12 sprays daily. As was reviewed above, chronic In addition to various pathological conditions, brain application of THC in these conventional doses may injuries may result from a variety of everyday situations result in long-lasting cognitive deficits, and may be including head trauma in car accident or football game; accompanied by a reduction in white and gray matter suffocation during diving or exposure to heavy smoke; in the brain. Moreover, considerable rates of adverse hypoxia due to heart arrest or cerebral ; or may effects have been reported following the use of cannabis even be an unfortunate consequence of medical interven- for medical purposes (137). Even a single exposure to tions such as poorly monitored deep anesthesia or cardi- a conventional dose of THC can cause dizziness and opulmonary bypass. Each of these conditions may lead to impair memory, orientation, attention, and motivation transient or permanent impairment of cognitive perfor- for several hours. This interference with optimal func- mance. With respect to clinical conditions, cognitive tioning in everyday life represents a substantial disad- functions may deteriorate as a result of neurodegenera- vantage especially to the elderly or fragile patient. tive pathologies such as in Alzheimer’s, Parkinson’s, or Here we suggest that much lower doses of THC might Huntington’s diseases. Even when no specific pathology have the potential to protect the brain and potentiate is detected, a spontaneous decline in cognitive functions cognitive functions. An appropriate conversion of drug takes place along aging. The finding that an extremely doses from animals to humans should be normalized for low dose of THC rescues cognitive functions in multiple body surface area (138) in compliance with indications experimental models of brain injury in mice (including by the Food and Drug Administration of the USA. seizures, hypoxia, anesthesia, neurotoxicity, and neuroin- Hence, the dose of 0.002 mg/kg in mice is equivalent to flammation), together with its wide (days) therapeutic 0.0002 mg/kg in humans, yielding a dose of 0.014 mg (or time-window (93–95), make THC an excellent candidate 14 micrograms) for an average patient of 70 kg body to treat humans at risk of cognitive damage due to acute weight. This extremely low dose is 100 times lower than incidents. Moreover, since inflammation is an inherent the threshold for the conventional behavioral effects of THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 557

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