Joey
Bluelighter
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Δ9-Tetrahydrocannabinol Prevents Methamphetamine-Induced Neurotoxicity
Δ9-Tetrahydrocannabinol Prevents Methamphetamine-Induced Neurotoxicity
Methamphetamine (METH) is a potent psychostimulant with neurotoxic properties. Heavy use increases the activation of neuronal nitric oxide synthase (nNOS), production of peroxynitrites, microglia stimulation, and induces hyperthermia and anorectic effects. ...
www.ncbi.nlm.nih.gov
Discussion
In the present study, we showed that Δ9-THC, the principal constituent of cannabis, attenuates the neurotoxic effect of METH by reducing two markers of neuronal damage, overexpression of nNOS and astrogliosis. Specifically, METH-induced astrogliosis and nNOS overexpression were reduced by pre- and post-treatment with Δ9-THC in the CPu and PFC, respectively.NO plays a key role in METH-induced neurotoxicity [7], [8]. NO is a free radical gas, and highly reactive molecule, that functions as a neurotransmitter or neuromodulator, when synthesized by the enzyme, nNOS [38], and is an important mediator in a variety of central nervous system disorders, including METH-induced neurotoxicity. The increase in extracellular glutamate caused by neurotoxic doses of METH activates NMDA receptors, resulting in increased intracellular Ca2+ that leads to activation of nNOS via, a Ca2+-calmodulin-dependent mechanism, and production of NO. METH-induced neurotoxicity is prevented by co-administration of NOS inhibitors [39]; the neuroprotective effect of these inhibitors might also involve the reduction of METH-induced hyperthermia [40]. Several studies have described interactions between cannabinoids and NOS, indicating that the neuronal CB1 receptor is involved in the regulation of NO synthesis. Indeed, cannabinoids prevent NO-mediated neurotoxicity of retinal neurons [41] and protect neurons from NMDA toxicity in vitro and in vivo through a mechanism that involves the activation of nNOS and protein kinase A [42]. Notably, nNOS activity in the cerebral cortex is higher in CB1 receptor knockout than in wild-type mice [42].
METH-induced increases in extracellular glutamate also leads to astrocyte activation; this activation leads to the release of pro-inflammatory cytokines that stimulate glutamate release and inhibit glutamate uptake [43] which increases NOS synthase activity and ROS production, eventually causing neuronal damage [8]. Repeated in vivo METH treatment induces a significant increase of GFAP levels in the striatum, cortex, and hippocampus [6]. Anti-inflammatory drugs (i.e. ketoprofen, indomethacin, tetracycline, and minocycline) protect against METH-induced gliosis and neurotoxicity [44], [45].
In the present study, we found a significant increase in the number of positive nNOS neurons and GFAP immunostaining in the CPu and PFC of METH-treated rats. These data confirm the involvement of nNOS and astrocytes activation in METH-induced neurotoxicity [6], [29]. The findings of hyperthermia and the pattern of nNOS and GFAP immunostaining observed in the present study are consistent with those reported previously [3], [29], which support our proposed model of METH-induced neurotoxicity. The validity of our model of METH neurotoxicity is further strengthened by the finding that a METH dose lower than that we used here (4 mg/kg) administered accordingly to the same “binge” schedule (4 administrations, 2 hours apart) is able to induce toxicity on 5-HT and DA innervations. Indeed, 3 and 7 days following the last METH administration we reported a loss of DAergic and 5-HTergic terminals measured by means of immunohistochemical detection of their transporters (5-HTT and DAT) [46]. Moreover, this model of METH administration (4×10 mg/kg, 2 h apart) is currently the most frequently used rat model of METH neurotocivity, and is associated with striatal dopamine and serotonin depletion, hyperthermia and high mortality [7]. However, other studies have reported no differences nNOS expression [47], a discrepancy likely due to differences in animal species and strains [48] as well as procedural differences, such as drug doses, METH administration schedule, and time intervals between drug treatment and immunohistochemical studies. Interestingly, pre- and post-treatment with Δ9-THC significantly decreased the overexpression of striatal nNOS and METH-induced gliosis in the rat PFC and CPu, suggesting a neuroprotective effect of cannabinoid agonists likely mediated, at least in part, by their anti-inflammatory properties. Cannabinoid agonists have been shown to inhibit NO in microglia, neurons, and macrophages [49]. METH-induced neurotoxicity and THC exposure are associated with hyperthermia [3], [8] and hypothermic effects, respectively. We therefore tested the effects of Δ9-THC on METH-induced neurotoxicity, but contrary to previous findings [36] showing a decreasing effect of Δ9-THC on NMDA-induced hyperthermia, in our study pre-treatment with Δ9-THC failed to prevent METH-induced hyperthermia. This suggests that the observed Δ9-THC neuroprotection is temperature-independent.
In this study, we choose to use multiple rather than chronic Δ9-THC treatment to avoid negative emotional states (e.g., anxiety, depression, lack of motivation) [50], [51], and the reduction in the white and gray matter in the cerebellum often described in chronic cannabis users [52], [53]. Animal studies have reported long-lasting cognitive and memory deficits following chronic Δ9-THC exposure [54], [55], as well as neuronal death and reduced synaptic density of pyramidal neurons in the hippocampus [55], [56]. Δ9-THC doses used in this study are within the range of doses that have been shown to induce neuroprotective effects [11], [35], [36].
The lack of dose-response of the attenuating effect of Δ9-THC on METH-induced nNOS overexpression and astrogliosis suggests that the maximal level of neuroprotection might have been obtained at 1 mg/kg of Δ9-THC (ceiling effect). Notably, an intraperitoneally administration of 0.002 mg/kg has been found to induce long-term neuroprotection after repeated administration of MDMA [11], [57]. This finding has been attributed to the pre- and post-conditioning phenomena, in which a minor noxious stimulus (Δ9-THC) protects a subsequent or preceding insult (neurotoxicity). Thus, we cannot exclude that the protective effect of Δ9-THC observed in our study could also be obtained with lower doses [57]. Therefore, future studies will evaluate whether lower doses can induce Δ9-THC-mediated neuroprotection. Moreover, our data showing that post-treatment 3 mg/kg THC had less effect than 1 mg/kg THC on GFAP-IR were completely unexpected. At the moment we don't have any plausible hypothesis to explain these findings.
Microglial cells and CB2 receptors are also likely to play a role in the neuroprotective effects of Δ9-THC on METH-induced neurotoxicity observed in this study. Cannabinoid CB2 receptors are present in both microglia and astrocytes [58], and their activation mediates immunosuppressive effects, limits inflammation, and is associated with tissue injury under several pathological conditions, including those associated with neurodegeneration [59]. Repeated administration of the CB2 receptor agonist JWH-105 reduces the inflammatory response to MDMA and provides partial protection against 5-hydroxytriptamine neurotoxicity [60]. Stimulation of CB2 signaling elicits a series of molecular and cellular events that attenuates delayed neurodegeneration [34]. Future studies should be performed in order to evaluate the potential role of CB2 receptors in both neurons and microglia in THC-induced neuroprotection.
Finally, we pretreated rats subjected to METH and Δ9-THC post-treatment with the CB1 receptor antagonist SR to determine whether Δ9-THC inhibition of METH-induced nNOS overexpression and gliosis occurred through a CB1-mediated mechanism. In the CPu, SR attenuated the neuroprotective effect of Δ9-THC on METH-induced nNOS overexpression. This effect is most likely due to action on either CB1 receptors located presynaptically in glutamatergic terminals or on astrocytes, which could result in increased glutamate excitoxicity. With regard to METH-induced astrogliosis, SR did not revert the decreasing effect of Δ9-THC on METH-induced GFAP-immunostaining both in the striatum and PFC. These findings suggest that Δ9-THC-mediated inhibition of METH-induced astrogliosis is likely to occur through a CB2-receptor dependent mechanism, as recently reported for the suppression of MDMA-induced astrocytes activation [36].
Unexpectedly, we found that SR suppressed METH-induced astrogliosis in both brain areas, an effect that to our knowledge has not been described previously. SR has been reported to exert neuroprotective effects in animal models of cerebral ischemia, trauma, and neuronal damage induced by NMDA [61], [62]. In animal models of cerebral artery occlusion, SR was found to exert a neuroprotective effect which was associated with (i) an increase in the striatal content of anandamide (AEA), (ii) an enhanced activity of N-acylphosphatidylethanolamine-hydrolyzing phospholipase D, and (iii) reduced expression and activity of fatty acid amide hydrolase (FAAH) [63], [64], [65]. A possible role for the transient receptor potential vanilloid 1 (TRPV1) on the neuroprotective effect of SR has been suggested by Pegorini et al. 2006 [66] who demonstrated that the neuroprotective effect shown by SR in an animal model of transient forebrain ischemia was prevented by the TRPV1 antagonist capsazepine. These findings suggest that SR may protect against excitotoxicity by blocking CB1 receptors and preventing their activation by the endogenously generated AEA, which accumulates during brain injury [67]. Since AEA activates, although with different affinity, both CB1 and TRPV1 receptors [68] and up-regulates genes involved in pro-inflammatory related responses [69], the increased concentration of AEA activates and desensitizes the TPRV1 [66], inducing a neuroprotective effect. Moreover, N-acyl-phosphatidylethanolamine (NAPE) and N-acylethanolamine (NAE), including AEA, are produced in neurons in response to the high intracellular Ca2+ concentrations that occur in injured neurons [70].
As glutamate excitotoxicity is one of the mechanisms through which METH induces neurotoxicity, in our model, SR protects against METH-induced neurotoxicity by signaling the increased accumulation of AEA to TRPV1 receptors, leading to desensitization and inducing a neuroprotective effect. Alternatively, the effect of SR on glutamate release may be mediated by a CB1-independent mechanism, as reported in vitro in hippocampal synaptosomes of rats and mice [71].
In conclusion, although comorbid cannabis and METH use might worsen mental health problems in drug users [72], this study provides the first evidence that Δ9-THC reduces METH-induced brain damage via inhibition of striatal nNOS expression by both CB1-dependent and -independent mechanisms and of striatal and cortical astrocyte activation by CB1-independent mechanisms only.
In short, THC when used on meth addicted rats was found to be neuroprotective. Even in ways the researchers didn't expect when suppressed meth induced astrogliosis.
"Astrogliosis (also known as astrocytosis or referred to as reactive astrogliosis) is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons from central nervous system (CNS) trauma, infection, ischemia, stroke, autoimmune responses or neurodegenerative disease." -Wikipedia https://en.wikipedia.org/wiki/Astrogliosis
This is extremely positive news. This basically suggests that some THC thrown in with your meth use could help prevent strokes. It could keep the autoimmune system from being compromised by meth use. It could help prevent infection. Also, neurodengeration. Meth is neurodegenerative, and that is the reason why chronic meth users experience things like meth psychosis. This will be detailed later in the CBD section of this post. Coming up next.
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CBD May Promote Resilience to Cocaine and Meth Use DIsorders
This study is one about a collection of other studies, pre-clinical trials. It's suggesting that CBD could work well on a lot of the issues with cocaine and meth addiction. It could help prevent inflammation and demyelination of the neurons. It could reduce anxiety and paranoia. It might slow the process of meth use becoming a meth use disorder, and in the case of someone with a meth use disorder who's gotten clean - CBD may help prevent relapse. The relapse rate for meth is very high, over 90% relapse within 3 years of getting clean.
There's some information for all you antipsychotic guys, I'm looking at you @Atelier3
CBD, like most antipsychotics, is a partial agonist of DA D2 receptors. Therefore, it should have a similar action on the brain these antipsychotics have when you're on meth. It should calm you down.
"The dopamine D2 receptor is the main receptor for most antipsychotic drugs." - Wikipedia https://en.wikipedia.org/wiki/Dopamine_receptor_D2
CBD can also help reverse alterations in the autoimmune system and reverse neuroinflammation induced by psychostimulant drugs.
GIven the effects of CBD when studied on neurodegenerative disorders like Alzheimers and Multiple Sclerosis (the ultimate demyelinating disease), and schizophrenia as well which is a mental health disease caused by degeneration of the myelin sheath - or the grey/white matter which protects your neurons, it may be a very good drug for methamphetamine users as well. Regular meth use over time causes demyelination, which on an MRI resembles schizophrenia. This is what causes meth psychosis. Here's a study which covers the resemblance of meth pychosis to schizophrenia. https://sci-hub.se/https://dx.doi.org/10.3389/fpsyt.2018.00491
CBD could very well be the drug to save a lot of meth users a lot of damage, or even reverse the damage which has already occured. This is just speculation, but I think it's a really good shot by the looks of it.
If you read the study further, it goes on to explain that CBD may reverse the cognitive deficits induced by psychostimulant drugs. It may alleviate the mental disorders comorbid with psychostimulant abuse. And again, if you've gotten clean. It may help prevent relapse.
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