For all of the studies suggesting neurotoxicitiy there are as many showing the opposite or inconclusive results. Here's a summary of a few:
Ali et al., (1989) also investigated what neurochemical effects chronic THC administration produced in the rat after a significant washout phase. Rats were dosed orally for 90 days, 5 days a week, with 0, 10 or 20mg/kg THC, then sacrificed, either directly after the last dose, or after a 2-week washout phase. It was reported that when rats were sacrificed directly after the last dosing, neither the high or low dose groups had any significant alteration in the Bmax of GABA, muscarinic acetylcholine, dopaminergic, or mu, kappa and delta opioid receptors in the hippocampus in comparison to the controls or in dihydroxyphenylacetic acid (DOPAC), 5-HT or 5-hydroxyindoleacetic acid (5-HIAA) concentration in the hypothalamus, septum or caudate nucleus. In rats sacrificed after a 2-week washout phase there was found to be a significant decrease in the Bmax of GABA receptors in the high dose group, though no other changes were found. In order to repeat these results and to see whether chronic THC treatment had any effect on the properties of sigma opioid receptors or various allosteric GABAA receptor sites, a second experiment was designed. In this experiment, rats were treated in the same fashion as the first experiment with the addition of a fourth dosage group that received 20mg/kg Mondays-Thursday and 60mg/kg on Friday. In this experiment, binding was only investigated after a 2-week washout phase. It was reported that there was no significant alteration in the Bmax of sigma receptors, GABA receptors, or any of the GABAA allosteric sites at any dosage level, in disagreement with their earlier results. In the end, these results are inconclusive, and no other study has looked into the effect of chronic cannabinoid treatment of the GABA receptor since.
Ali et al., (1991) examined the effects of chronic THC or cannabinoid treatment in rats and the rhesus monkey respectively. Rats were dosed with orally with 10 or 20mg/kg of THC 5 days a week, for 90 days and sacrificed 2 hours or 2 months after the last dose. It was reported that at either 2 hours or 2 months, neither of the doses produced a significant effect on the Bmax of muscarinic acetylcholine receptors in comparison to vehicle treated controls. Rhesus monkeys were treated for either 2 or 7 days a week for 1 year with the smoke of 1 2.6% cannabis cigarette, the smoke of an ethanol extracted cannabis cigarette, or no smoke and then sacrificed 7 months after the last treatment. It was reported that there were no statistically significant dose-related changes in dopamine, DOPAC, serotonin or 5-HIAA concentration in either the caudate nucleus or the hypothalamus.
Westlake et al., (1991) investigated whether chronic treatment with THC altered the Bmax or Ki of the cannabinoid receptor in either rats or rhesus monkeys. Rats were dosed with 0, 10 or 20mg/kg , 5 days a week or 20mg/kg Monday to Thursday and 60mg/kg Friday for 90 days and sacrificed 60 days after the last dose. It was reported that there were no significant changes induced by any dose in either the Bmax or the Ki of the cannabinoid receptor in the cortex, striatum, cerebellum, hippocampus or brainstem in comparison to the control. Rhesus monkeys were exposed to the smoke of either ethanol extract cannabis or 2.6% THC cannabis, 7 days a week for a year and then sacrificed 7 months after the last exposure. It was reported that there were no significant changes in the Bmax or the Ki of the cannabinoid receptor in the cortex, caudate nucleus or the cerebellum in comparison to the control.
The first study into the effect that cannabinoids have on neuronal morphology was Harper et al., (1977). This study reported that rhesus monkeys exposed to the smoke of 1 to 3 2.6% THC cannabis cigarettes a day or 0.7mg/kg THC a day for 6 months showed widening of the synaptic cleft, material in the synaptic cleft and nuclear inclusion bodies after an 8-month washout phase. Unfortunately there were many methodological problems with this study. There was no statistical analysis, the sample sizes were extremely small, consisting of one active cannabis smoke treated animal, one IV treated animal and the controls, two completely untreated monkeys and one monkey who smoked alcohol extracted cannabis leaf, which was presumed to be THC free. Indeed, the apparatus in which the animals were placed in order to administer the cannabis smoke, a procedure that most of the control animals were free of, seemed to be so constrictive and unnatural, that it could be a serious source of bias. Scallet et al., (1990) repeated this experiment, with larger sample numbers and showed that after a wash out phase of 7 months, rhesus monkeys who were exposed to the smoke of a single cannabis cigarette containing 2.6% THC, every day for 12 months, showed no statistically significant changes in synaptic characteristics, neuronal size, the number of apical or basilar dendrites or the number or length of dendritic branches, in comparison to monkeys who were either non-exposed or smoked ethanol-extracted cannabis. Andrews et al., (1989, as cited by Scallet et al., 1991) also found no neurohistological changes after dosing moneys IV with either 0.1 or 1mg/kg of THC for 90 days.
Pope et al., (2001) investigated the cognitive function of chronic cannabis users over a 28-day abstinence period. There were 3 groups: subjects who had used cannabis at least 5000 times and were smoking daily at the start of the study, subjects who had used cannabis at least 5000 times but had used cannabis 12 times or less in the last three months, and the control group, who had used cannabis no more than 50 times. The subjects were tested on a battery of tests on day 0, 1, 7 and 28 of abstinence. The former users showed no significant difference in any of the tests. The current users showed significant differences in many of the tests on day 0, 1 and 7, but by day 28 there was only one test where they performed significantly worse. When the test was controlled for verbal IQ, this difference was no longer significant. The experiment shows that washout phases of 19-72 hours, as used in other experiments, are probably not long enough to remove the residual effects of cannabinoids. Interestingly, the mean time of use for the cannabis using group was 13 years. When compared to the results of Fletcher et al., (1996) this time length is far closer to the young group (9 years) who showed no negative cognitive impact from cannabis use. Perhaps this indicates that cannabis use needs to continue for more than 13 years to be damaging.
Pope and Yurgelun-Todd (1996) compared the cognitive function in heavy and light cannabis using college students. The rational behind the study was that if heavy users were compared to light users, the difficulty of matching controls would be avoided, as it was presumed that light and heavy cannabis users would come from the same socio-economic background. Light users were defined as subjects who had smoked cannabis a maximum of 9 times in the last month, and had no urinary traces of cannabinoids. Heavy users were defined as subjects who had smoked cannabis a minimum of 22 times in the last month and had traces of cannabinoids in their urine. Subjects had 19 hours of supervised abstinence before they received a battery of cognitive tests. It was reported that the heavy users did not performed significantly worse than the light users in any test apart from the Wisconsin card sorting test and the California verbal learning test. However, these results did not reach significance if the genders were compared individually. Because of the short abstinence period, this difference could be attributed to both residual cannabinoid action (because if there were cannabinoids in the urine, there could be cannabinoids in the blood) or withdrawal effects.
Block et al., (2000a) were the first to investigate the possibility of brain atrophy induced by chronic cannabis use using magnetic resonance imaging. The cannabis using subjects had used cannabis for at least 2 years, on average every day. It was found that the cannabis users had no significant differences in gross brain, frontal lobe, temporal lobe, parietal lobe, occipital lobe, cerebellar and hippocampal volume in comparison to the controls.
Co et al., (1977) and Kuehnle et al., (1977) used CAT scans to look for any gross cerebral atrophy in groups of 12 and 19 chronic cannabis users, respectively. Despite a lack of control for any factor apart from sex, there were found to be no significant changes in cerebral volume in comparison to controls.
Nakamura et al., (1991) investigated the effects that chronic THC administration had on performance in a variation of the 8-arm radial maze in the rat. Rats were dosed with 5mg/kg THC I.P. 6 days a week for 90 days. During administration the rats were trained in an 8-arm radial maze where, after entering 4 arms, the rats were removed from the maze for 5 seconds or 1 hour, and then placed back in the center. During treatment, THC treated animals made significantly more errors in both the 5-second and 1-hour delay than the vehicle treated controls. 15 days after discontinuation of THC treatment the THC treated animals still made significantly more errors than the controls, but after 30 days the difference was no longer significant. Because the behavioural deficit corrected after such a short time, it could be possible that it was just due to residual THC. Unfortunately, plasma THC was not recorded, so this possibility can not be addressed.
Stiglick and Kalant (1982) examined the effects of chronic cannabinoid administration on the performance in an 8 or 12-arm radial maze. Rats were dosed orally with an ethanolic cannabis extract so that they received 20mg/kg daily for 3 or 6 months. After a 1-month washout phase, the animals that were dosed for 3-month were tested with an 8 or 12-arm radial maze, and the animals that were dosed for 6-months were tested with an 8-arm radial maze. It was reported that after the 1-month washout phase, all cannabinoid treated animals learned the radial arm maze significantly slower than the vehicle treated controls. It was reported that the control and cannabinoid treated animals did not eat significantly different amounts and hence this result is unlikely to be because of a lowered motivation to eat food caused by cannabinoid treatment. Stiglick and Kalant (1983) conducted a similar experiment, although this time pure THC was used and the behaviour of rats chronically treated with THC in a two-way shuttle box avoidance test and a 12-arm radial maze was also investigated. Rats were treated orally with 20mg/kg THC daily for 3 months. Testing in the 12-arm radial maze began after a 34-day washout phase. Rats were then tested in an open field test after a 77-day washout phase, then a differential reinforcement of low rate responding-20 (DRL-20) test after a 92-day washout and finally the shuttle box avoidance test after a 132-day washout. It was reported treatment with THC had no effect on open field test exploratory behaviour in comparison to control. It was shown that THC treatment affected the animal's ability to learn the 12-arm radial maze in comparison to the vehicle treated control, but that this effect was restricted to the first 11 days of performance. It was reported that THC treated animals received significantly less food rewards during the DRL-20 test in comparison to controls, but that this effect only lasted for the first 13 days of testing. It was shown that THC treatment had no significant effect on the performance in the shuttle box avoidance task.
And for all of these conflicting studies on cannabis' alleged neurotoxic properties, there are many more looking into the medical potential of cannabis' neuroprotective properties:
Cannabinoids inhibit neurodegeneration in models of multiple sclerosis.
Pryce G, Ahmed Z, Hankey DJ, Jackson SJ, Croxford JL, Pocock JM, Ledent C, Petzold A, Thompson AJ, Giovannoni G, Cuzner ML, Baker D.
Department of Neuroinflammation, Institute of Neurology, University College London, London, UK.
Multiple sclerosis is increasingly being recognized as a neurodegenerative disease that is triggered by inflammatory attack of the CNS. As yet there is no satisfactory treatment. Using experimental allergic encephalo myelitis (EAE), an animal model of multiple sclerosis, we demonstrate that the cannabinoid system is neuroprotective during EAE. Mice deficient in the cannabinoid receptor CB1 tolerate inflammatory and excitotoxic insults poorly and develop substantial neurodegeneration following immune attack in EAE. In addition, exogenous CB1 agonists can provide significant neuroprotection from the consequences of inflammatory CNS disease in an experimental allergic uveitis model. Therefore, in addition to symptom management, cannabis may also slow the neurodegenerative processes that ultimately lead to chronic disability in multiple sclerosis and probably other diseases.
The therapeutic potential of the cannabinoids in neuroprotection.
Grundy RI.
Neurology CEDD, GlaxoSmithKline, New Frontiers Science Park (North), Coldharbour Road, Harlow, Essex, CM19 5AW, UK.
After thousands of years of interest the last few decades have seen a huge increase in our knowledge of the cannabinoids and their mode of action. Their potential as medical therapeutics has long been known. However, very real concerns over their safety and efficacy have lead to caution and suspicion when applying the legislature of modern medicine to these compounds. The ability of this diverse family of compounds to modulate neurotransmission and act as anti-inflammatory and antioxidative agents has prompted researchers to investigate their potential as neuroprotective agents. Indeed, various cannabinoids rescue dying neurones in experimental forms of acute neuronal injury, such as cerebral ischaemia and traumatic brain injury. Cannabinoids also provide symptomatic relief in experimental models of chronic neurodegenerative diseases, such as multiple sclerosis and Huntington's disease. This preclinical evidence has provided the impetus for the launch of a number of clinical trials in various conditions of neurodegeneration and neuronal injury using compounds derived from the cannabis plant. Our understanding of cannabinoid neurobiology, however, must improve if we are to effectively exploit this system and take advantage of the numerous characteristics that make this group of compounds potential neuroprotective agents.
Therapeutic potential of cannabinoids in CNS disease.
Croxford JL.
Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois 60610, USA.
The major psychoactive constituent of Cannabis sativa, delta(9)-tetrahydrocannabinol (delta(9)-THC), and endogenous cannabinoid ligands, such as anandamide, signal through G-protein-coupled cannabinoid receptors localised to regions of the brain associated with important neurological processes. Signalling is mostly inhibitory and suggests a role for cannabinoids as therapeutic agents in CNS disease where inhibition of neurotransmitter release would be beneficial. Anecdotal evidence suggests that patients with disorders such as multiple sclerosis smoke cannabis to relieve disease-related symptoms. Cannabinoids can alleviate tremor and spasticity in animal models of multiple sclerosis, and clinical trials of the use of these compounds for these symptoms are in progress. The cannabinoid nabilone is currently licensed for use as an antiemetic agent in chemotherapy-induced emesis. Evidence suggests that cannabinoids may prove useful in Parkinson's disease by inhibiting the excitotoxic neurotransmitter glutamate and counteracting oxidative damage to dopaminergic neurons. The inhibitory effect of cannabinoids on reactive oxygen species, glutamate and tumour necrosis factor suggests that they may be potent neuroprotective agents. Dexanabinol (HU-211), a synthetic cannabinoid, is currently being assessed in clinical trials for traumatic brain injury and stroke. Animal models of mechanical, thermal and noxious pain suggest that cannabinoids may be effective analgesics. Indeed, in clinical trials of postoperative and cancer pain and pain associated with spinal cord injury, cannabinoids have proven more effective than placebo but may be less effective than existing therapies. Dronabinol, a commercially available form of delta(9)-THC, has been used successfully for increasing appetite in patients with HIV wasting disease, and cannabinoid receptor antagonists may reduce obesity. Acute adverse effects following cannabis usage include sedation and anxiety. These effects are usually transient and may be less severe than those that occur with existing therapeutic agents. The use of nonpsychoactive cannabinoids such as cannabidiol and dexanabinol may allow the dissociation of unwanted psychoactive effects from potential therapeutic benefits. The existence of other cannabinoid receptors may provide novel therapeutic targets that are independent of CB(1) receptors (at which most currently available cannabinoids act) and the development of compounds that are not associated with CB(1) receptor-mediated adverse effects. Further understanding of the most appropriate route of delivery and the pharmacokinetics of agents that act via the endocannabinoid system may also reduce adverse effects and increase the efficacy of cannabinoid treatment. This review highlights recent advances in understanding of the endocannabinoid system and indicates CNS disorders that may benefit from the therapeutic effects of cannabinoid treatment. Where applicable, reference is made to ongoing clinical trials of cannabinoids to alleviate symptoms of these disorders.
Neuroprotection by Delta9-tetrahydrocannabinol, the main active compound in marijuana, against ouabain-induced in vivo excitotoxicity.
van der Stelt M, Veldhuis WB, Bar PR, Veldink GA, Vliegenthart JF, Nicolay K.
Department of Bio-Organic Chemistry, Bijvoet Center for Biomolecular Research, 3584 CH, Utrecht University, Utrecht, The Netherlands.
Excitotoxicity is a paradigm used to explain the biochemical events in both acute neuronal damage and in slowly progressive, neurodegenerative diseases. Here, we show in a longitudinal magnetic resonance imaging study that Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the main active compound in marijuana, reduces neuronal injury in neonatal rats injected intracerebrally with the Na(+)/K(+)-ATPase inhibitor ouabain to elicit excitotoxicity. In the acute phase Delta(9)-THC reduced the volume of cytotoxic edema by 22%. After 7 d, 36% less neuronal damage was observed in treated rats compared with control animals. Coadministration of the CB(1) cannabinoid receptor antagonist SR141716 prevented the neuroprotective actions of Delta(9)-THC, indicating that Delta(9)-THC afforded protection to neurons via the CB(1) receptor. In Delta(9)-THC-treated rats the volume of astrogliotic tissue was 36% smaller. The CB(1) receptor antagonist did not block this effect. These results provide evidence that the cannabinoid system can serve to protect the brain against neurodegeneration.
Neuroprotective antioxidants from marijuana.
Hampson AJ, Grimaldi M, Lolic M, Wink D, Rosenthal R, Axelrod J.
Laboratory of Cellular and Molecular Regulation, NIMH, Bethesda, Maryland 20892, USA.
Cannabidiol and other cannabinoids were examined as neuroprotectants in rat cortical neuron cultures exposed to toxic levels of the neurotransmitter, glutamate. The psychotropic cannabinoid receptor agonist delta 9-tetrahydrocannabinol (THC) and cannabidiol, (a non-psychoactive constituent of marijuana), both reduced NMDA, AMPA and kainate receptor mediated neurotoxicities. Neuroprotection was not affected by cannabinoid receptor antagonist, indicating a (cannabinoid) receptor-independent mechanism of action. Glutamate toxicity can be reduced by antioxidants. Using cyclic voltametry and a fenton reaction based system, it was demonstrated that Cannabidiol, THC and other cannabinoids are potent antioxidants. As evidence that cannabinoids can act as an antioxidants in neuronal cultures, cannabidiol was demonstrated to reduce hydroperoxide toxicity in neurons. In a head to head trial of the abilities of various antioxidants to prevent glutamate toxicity, cannabidiol was superior to both alpha-tocopherol and ascorbate in protective capacity. Recent preliminary studies in a rat model of focal cerebral ischemia suggest that cannabidiol may be at least as effective in vivo as seen in these in vitro studies.
Cannabis: old medicine with new promise for neurological disorders.
Carter GT, Weydt P.
Department of Rehabilitation Medicine, University of Washington School of Medicine, Seattle 98531, USA.
Marijuana is a complex substance containing over 60 different forms of cannabinoids, the active ingredients. Cannabinoids are now known to have the capacity for neuromodulation, via direct, receptor-based mechanisms at numerous levels within the nervous system. These have therapeutic properties that may be applicable to the treatment of neurological disorders; including anti-oxidative, neuroprotective, analgesic and anti-inflammatory actions; immunomodulation, modulation of glial cells and tumor growth regulation. This article reviews the emerging research on the physiological mechanisms of endogenous and exogenous cannabinoids in the context of neurological disease.
Medical marijuana: emerging applications for the management of neurologic disorders.
Carter GT, Ugalde V.
Department of Rehabilitation Medicine, University of Washington School of Medicine, 1959 NE Pacific Avenue, Box 356490, Seattle, WA 98195, USA.
Marijuana contains over 60 different types of cannabinoids, which are its medicinally active ingredients. Cannabinoids have the capacity for neuromodulation--through direct, receptor-based mechanisms--at many levels within the nervous system, providing therapeutic properties that may be applicable to the treatment of neurologic disorders. These include antioxidation, neuroprotection, analgesia, anti-inflammation, immunomodulation, modulation of glial cells, and tumor growth regulation. This article reviews the current and emerging research on the physiologic mechanisms of endogenous and exogenous cannabinoids and their applications in the management of neurologic disease.
[Cannabis and cannabinoid receptors: from pathophysiology to therapeutic options]
[Article in French]
Derkinderen P, Valjent E, Darcel F, Damier P, Girault JA.
Service de Neurologie et Centre d'investigations cliniques, CHU de Nantes, Hopital Laennec, Nantes.
BACKGROUND: Although cannabis has been used as a medicine for several centuries, the therapeutic properties of cannabis preparations (essentially haschich and marijuana) make them far most popular as a recreational drugs. STATE OF THE ART: Scientific studies on the effects of cannabis were advanced considerably by the identification in 1964 of cannabinoid D9-tetrahydrocannadinol (THC), recognized as the major active constituent of cannabis. Cloning of the centrally located CB1 receptor in 1990 and the identification of the first endogenous ligand of the CB1 receptor, anandamide, in 1992 further advanced our knowledge. PERSPECTIVE AND CONCLUSIONS: Progress has incited further research on the biochemistry and pharmacology of the cannabinoids in numerous diseases of the central nervous system. In the laboratory animal, cannabinoids have demonstrated potential in motion disorders, demyelinizing disease, epilepsy, and as anti-tumor and neuroprotector agents. Several clinical studies are currently in progress, but therapeutic use of cannabinoids in humans couls be hindered by undesirable effects, particularly psychotropic effects. CB1 receptor antagonists also have interesting therapeutic potential.
Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells.
Iuvone T, Esposito G, Esposito R, Santamaria R, Di Rosa M, Izzo AA.
Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy.
Abstract Alzheimer's disease is widely held to be associated with oxidative stress due, in part, to the membrane action of beta-amyloid peptide aggregates. Here, we studied the effect of cannabidiol, a major non-psychoactive component of the marijuana plant (Cannabis sativa) on beta-amyloid peptide-induced toxicity in cultured rat pheocromocytoma PC12 cells. Following exposure of cells to beta-amyloid peptide (1 micro g/mL), a marked reduction in cell survival was observed. This effect was associated with increased reactive oxygen species (ROS) production and lipid peroxidation, as well as caspase 3 (a key enzyme in the apoptosis cell-signalling cascade) appearance, DNA fragmentation and increased intracellular calcium. Treatment of the cells with cannabidiol (10(-7)-10(-4)m) prior to beta-amyloid peptide exposure significantly elevated cell survival while it decreased ROS production, lipid peroxidation, caspase 3 levels, DNA fragmentation and intracellular calcium. Our results indicate that cannabidiol exerts a combination of neuroprotective, anti-oxidative and anti-apoptotic effects against beta-amyloid peptide toxicity, and that inhibition of caspase 3 appearance from its inactive precursor, pro-caspase 3, by cannabidiol is involved in the signalling pathway for this neuroprotection.
Cannabinoids: mechanisms and therapeutic applications in the CNS.
Drysdale AJ, Platt B.
Department of Biomedical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK.
Cannabinoids comprise three classes of compounds, the active components of marijuana (Cannabis sativa), as well as endogenous and synthetic derivatives. To date, two distinct cannabinoid receptors (CB1 and CB2) have been discovered, but evidence for further receptor types has been brought forward. The potential use of cannabinoids for medicinal purposes has long been known, but the mechanisms of action of both exogenously applied and endogenous cannabinoids are only partly established. For nervous system disorders, cannabinoids may be useful by modulating neurotransmission and calcium homeostasis as well as by anti-inflammatory and anti-oxidant actions. Some cannabinoids can also trigger cell death, which may be of therapeutic benefit in the treatment of malignant tumours. A number of both in vitro and in vivo models have provided promising but diverse evidence for cannabinoid protection in glutamate-mediated excitotoxicity, hypoxia and glucose deprivation, brain trauma, epilepsy and MS. Subsequent to many preclinical investigations, clinical trials are now underway in a variety of the above applications. Overall, the understanding of the therapeutic relevance of cannabinoids will rely on further investigations into the neuroprotective and neurotoxic potency of cannabinoids in animal models and humans, as much as on a further advancement of our general understanding of the endocannabinoid system and the development of specific compounds devoid of unwanted psychoactive side effects.
I refuse to accept that cannabis is a benign drug
Thing is....I never said it was.
and the culture associated with it is embarrassing.
Ok, so you have an issue with the culture associated with cannabis.
![:\](https://bluelight.org/xf/BL_Images/Orig_Emoji/wrygrin.gif "wry grin :\")
