There have been a few posts on the forum lately about The anti androgen effects of THC.
In addition to this, it seems THC is a potent inflammatory agent:
Below I have posted several quotes from articles relating to the inflamitory cascade caused by CB-1 stimulation.
“Cisplatin significantly increased endocannabinoid anandamide content, activation of p38 and JNK mitogen-activated protein kinases (MAPKs), apoptotic and poly (ADP-ribose)polymerase-dependent cell death, enhanced inflammation (leucocyte infiltration, tumour necrosis factor-α and interleukin-1β) and promoted oxidative/nitrosative stress [increased expressions of superoxide-generating enzymes (NOX2(gp91phox), NOX4), inducible nitric oxide synthase and tissue 4-hydroxynonenal and nitrotyrosine levels] in the kidneys of mice, accompanied by marked histopathological damage and impaired renal function (elevated creatinine and serum blood urea nitrogen) 3 days following its administration. Both genetic deletion and pharmacological inhibition of CB1 receptors with AM281 or SR141716 markedly attenuated the cisplatin-induced renal dysfunction and interrelated oxidative/nitrosative stress, p38 and JNK MAPK activation, cell death and inflammatory response in the kidney.
Other studies show it releases arachidonic acid "THC neurotoxicity is attributable to activation of the PLA 2 - COX pathway in neurons, THC should stimulate arachidonic acid release. Treatment of cultured hippocampal neurons with THC induced the release of arachidonic acid from cultured hippocam- pal neurons, which was completely blocked by SR141716A, the CB1 receptor antagonist (Fig. 6).
and: Link: “Here we show that synaptic and cognitive impairments following repeated exposure to Δ9-tetrahydrocannabinol (Δ9-THC) are associated with the induction of cyclooxygenase-2 (COX-2), an inducible enzyme that converts arachidonic acid to prostanoids, in the brain. COX-2 induction by Δ9-THC is mediated via CB1 receptor-coupled G-protein βγ subunits.
This was quite surprising to me. I didn't know THC and PUFA/inflammation had anything to do with each other.
I guess its not shocking that THC can kill brain cells, harm memory, but this was the first time I had seen the mechanism spelled out.
The implications of this are vast. for example: I heard @haidut say on Paul's podcast something about HNE-4 which i mentioned above being connected to alzheimers or dementia (forget which one); (as well as countless warnings about COX and the Prostaglandins and the wonders of Asprin.)
Another one: “"In summary, treatment of hippocampal neurons with THC induces transcriptionally dependent cell death. This suggests that memory loss associated with marijuana treatment of rodents, and perhaps humans, may be attributable to THC neurotoxicity. The identification of a specific signal transduction system responsible for THC toxicity and the discovery that aspirin and vitamin E inhibit this neurotoxicity suggest pharmacological tools to block THC-induced cell death" (I will discuss some additional tools for this later in the post)
Pharmacological or genetic inhibition of COX-2 blocks down-regulation and internalization of glutamate receptor subunits and alterations of the dendritic spine density of hippocampal neurons induced by repeated Δ9-THC exposures. Ablation of COX-2 also eliminates Δ9-THC-impaired hippocampal long-term synaptic plasticity, spatial, and fear memories.”
It seems Cox inhibitors are very protective against the harms cannabis, without reducing the “high”.
Interestingly, some of the non psychoactive cannabinoids have been shown to be potent anti inflammatory, blocking the cox enzymes and completely inhibiting the cox2 action of thc. The structure of the “acidic” cannabinoids (cbda, cbga, thca)(all non psychoactive) have a salicylic acid molecule in their center. Specifically, cbg and cbga were shown to inhibit cox the most.
(some other interesting side notes on these non psychoactive cannabinoids.)
1. I found that cbga is an extremely potent a2a andrenergic agonist, similar to clonidine. This could be an effective agent for lowering noradrenaline
Cbg also reduces nitric oxide ive read
2. Cbda is an extremely potent 5ht1a receptor agonist (100x the potency at 5ht1a as cbd), could be useful in keeping serotonin low. (an agonist at 5ht1a will actually conterintuitively lower serotonergic tone.
In addition, stimulation of the 5ht1a receptor has been shown in the literature to :
3. Cbd is a “negative allosteric modulator” of the cb1 receptor, possible supplement for someone looking to reduce cb1 tone (Although I read it can inhibit FAAH, the enzyme that breaks down endogenous cannabinoids , thus increasing endogenous cannabinoids such as 2-ag, so maybe not)
4. All cannabinoid have a wide range of effects on what are known as TRP-V channels
5 Thcv works in the opposite mechanism of thc, blocking the cb1 receptor (similar to the failed drug rimonabant, expect it is not a “suicidal” “inverse agonist”. Thus, it is not dangerous like the pharma drug.
It has potential in insulin resistance and has been shown to increase glucose utilization/sucrose preference (Can’t find source at the moment)
In lowering cb1 tone, the cb1 antagonist “thc-v” as well negative allosteric modulation of the cb1 receptor (both pregnenalone and cbd are NAMs) could be of medical use.
I wonder however if pharmalogical blockade would provide an ill effects. I still don't understand what the endocannabinoid system is/does.
I would like to understand the endocannabinoid system better, as it seems to be an integral part of the human body. It is the largest receptor coupled G protein receptor in the human brain, for example. This alone makes understanding it essential for a complete understanding of biochemistry.
It has been suggested modulating (raising or lowering CB1 tone) ". According to Pal Pacher and Geroge Kunos, leading scientists with the U.S. National Institutes of Health, “[M]odulating endocannabinoid system activity may have therapeutic potential in almost all diseases affecting humans, including obesity/metabolic syndrome, diabetes and diabetic complications, neurodegenerative, inflammatory, cardiovascular, liver, gastrointestinal, skin diseases, pain, psychiatric disorders, cachexia, cancer, chemotherapy-induced nausea and vomiting among many others.”
...of course, they are coming at this with a mentality of creating pharmaceutical drugs with this statement, rather than the natural plant (which is unpatentable). This didn't work out great on their first attempt - Rimonabant: depression and suicide - PubMed
In addition to this, it seems THC is a potent inflammatory agent:
Below I have posted several quotes from articles relating to the inflamitory cascade caused by CB-1 stimulation.
“Cisplatin significantly increased endocannabinoid anandamide content, activation of p38 and JNK mitogen-activated protein kinases (MAPKs), apoptotic and poly (ADP-ribose)polymerase-dependent cell death, enhanced inflammation (leucocyte infiltration, tumour necrosis factor-α and interleukin-1β) and promoted oxidative/nitrosative stress [increased expressions of superoxide-generating enzymes (NOX2(gp91phox), NOX4), inducible nitric oxide synthase and tissue 4-hydroxynonenal and nitrotyrosine levels] in the kidneys of mice, accompanied by marked histopathological damage and impaired renal function (elevated creatinine and serum blood urea nitrogen) 3 days following its administration. Both genetic deletion and pharmacological inhibition of CB1 receptors with AM281 or SR141716 markedly attenuated the cisplatin-induced renal dysfunction and interrelated oxidative/nitrosative stress, p38 and JNK MAPK activation, cell death and inflammatory response in the kidney.
The endocannabinoid system through CB1receptors promotes cisplatin-induced tissue injury by amplifying MAPK activation, cell death and interrelated inflammation and oxidative/nitrosative stress. These results also suggest that inhibition of CB1receptors may exert beneficial effects in renal (and most likely other) diseases associated with enhanced inflammation, oxidative/nitrosative stress and cell death”Other studies show it releases arachidonic acid "THC neurotoxicity is attributable to activation of the PLA 2 - COX pathway in neurons, THC should stimulate arachidonic acid release. Treatment of cultured hippocampal neurons with THC induced the release of arachidonic acid from cultured hippocam- pal neurons, which was completely blocked by SR141716A, the CB1 receptor antagonist (Fig. 6).
and: Link: “Here we show that synaptic and cognitive impairments following repeated exposure to Δ9-tetrahydrocannabinol (Δ9-THC) are associated with the induction of cyclooxygenase-2 (COX-2), an inducible enzyme that converts arachidonic acid to prostanoids, in the brain. COX-2 induction by Δ9-THC is mediated via CB1 receptor-coupled G-protein βγ subunits.
This was quite surprising to me. I didn't know THC and PUFA/inflammation had anything to do with each other.
I guess its not shocking that THC can kill brain cells, harm memory, but this was the first time I had seen the mechanism spelled out.
The implications of this are vast. for example: I heard @haidut say on Paul's podcast something about HNE-4 which i mentioned above being connected to alzheimers or dementia (forget which one); (as well as countless warnings about COX and the Prostaglandins and the wonders of Asprin.)
Another one: “"In summary, treatment of hippocampal neurons with THC induces transcriptionally dependent cell death. This suggests that memory loss associated with marijuana treatment of rodents, and perhaps humans, may be attributable to THC neurotoxicity. The identification of a specific signal transduction system responsible for THC toxicity and the discovery that aspirin and vitamin E inhibit this neurotoxicity suggest pharmacological tools to block THC-induced cell death" (I will discuss some additional tools for this later in the post)
Pharmacological or genetic inhibition of COX-2 blocks down-regulation and internalization of glutamate receptor subunits and alterations of the dendritic spine density of hippocampal neurons induced by repeated Δ9-THC exposures. Ablation of COX-2 also eliminates Δ9-THC-impaired hippocampal long-term synaptic plasticity, spatial, and fear memories.”
It seems Cox inhibitors are very protective against the harms cannabis, without reducing the “high”.
Interestingly, some of the non psychoactive cannabinoids have been shown to be potent anti inflammatory, blocking the cox enzymes and completely inhibiting the cox2 action of thc. The structure of the “acidic” cannabinoids (cbda, cbga, thca)(all non psychoactive) have a salicylic acid molecule in their center. Specifically, cbg and cbga were shown to inhibit cox the most.
(some other interesting side notes on these non psychoactive cannabinoids.)
1. I found that cbga is an extremely potent a2a andrenergic agonist, similar to clonidine. This could be an effective agent for lowering noradrenaline
Cbg also reduces nitric oxide ive read
2. Cbda is an extremely potent 5ht1a receptor agonist (100x the potency at 5ht1a as cbd), could be useful in keeping serotonin low. (an agonist at 5ht1a will actually conterintuitively lower serotonergic tone.
In addition, stimulation of the 5ht1a receptor has been shown in the literature to :
3. Cbd is a “negative allosteric modulator” of the cb1 receptor, possible supplement for someone looking to reduce cb1 tone (Although I read it can inhibit FAAH, the enzyme that breaks down endogenous cannabinoids , thus increasing endogenous cannabinoids such as 2-ag, so maybe not)
4. All cannabinoid have a wide range of effects on what are known as TRP-V channels
5 Thcv works in the opposite mechanism of thc, blocking the cb1 receptor (similar to the failed drug rimonabant, expect it is not a “suicidal” “inverse agonist”. Thus, it is not dangerous like the pharma drug.
It has potential in insulin resistance and has been shown to increase glucose utilization/sucrose preference (Can’t find source at the moment)
In lowering cb1 tone, the cb1 antagonist “thc-v” as well negative allosteric modulation of the cb1 receptor (both pregnenalone and cbd are NAMs) could be of medical use.
I wonder however if pharmalogical blockade would provide an ill effects. I still don't understand what the endocannabinoid system is/does.
I would like to understand the endocannabinoid system better, as it seems to be an integral part of the human body. It is the largest receptor coupled G protein receptor in the human brain, for example. This alone makes understanding it essential for a complete understanding of biochemistry.
It has been suggested modulating (raising or lowering CB1 tone) ". According to Pal Pacher and Geroge Kunos, leading scientists with the U.S. National Institutes of Health, “[M]odulating endocannabinoid system activity may have therapeutic potential in almost all diseases affecting humans, including obesity/metabolic syndrome, diabetes and diabetic complications, neurodegenerative, inflammatory, cardiovascular, liver, gastrointestinal, skin diseases, pain, psychiatric disorders, cachexia, cancer, chemotherapy-induced nausea and vomiting among many others.”
...of course, they are coming at this with a mentality of creating pharmaceutical drugs with this statement, rather than the natural plant (which is unpatentable). This didn't work out great on their first attempt - Rimonabant: depression and suicide - PubMed
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