Reason to believe chronic vaporization of potent CB2 agonists weakens immune system

[fettered]

I'm going to put the bullshit disclaimer right here in the top of this post. I do not have a study or even want to try to prove my hypothesis true; I just want to give you the evidence that points in the direction my claim, which under any scholarly scrutiny would be dismissed right and readily since this is mostly conjecture based on reading a few relevant abstracts and personal anecdote.

A subpoint, again from the two shaky sources of information is that CB2 agonism also can have negative cognitive effects due to some of the same mechanisms related to its immunomodulatory effects.


CB2 agonism achieves immunosuppression in different types of immune cells and through many different mechanisms. (http://www.sciencedirect.com/science/article/pii/S0171298509000709)

Abstract
Cannabinoids are a group of compounds present in Cannabis plant (Cannabis sativa L.). They mediate their physiological and behavioral effects by activating specific cannabinoid receptors. With the recent discovery of the cannabinoid receptors (CB1 and CB2) and the endocannabinoid system, research in this field has expanded exponentially. Cannabinoids have been shown to act as potent immunosuppressive and anti-inflammatory agents and have been shown to mediate beneficial effects in a wide range of immune-mediated diseases such as multiple sclerosis, diabetes, septic shock, rheumatoid arthritis, and allergic asthma. Cannabinoid receptor 1 (CB1) is mainly expressed on the cells of the central nervous system as well as in the periphery. In contrast, cannabinoid receptor 2 (CB2) is predominantly expressed on immune cells. The precise mechanisms through which cannabinoids mediate immunosuppression is only now beginning to be understood and can be broadly categorized into four pathways: apoptosis, inhibition of proliferation, suppression of cytokine and chemokine production and induction of T regulatory cells (T regs). Studies from our laboratory have focused on mechanisms of apoptosis induction by natural and synthetic cannabinoids through activation of CB2 receptors. In this review, we will focus on apoptotic mechanisms of immunosuppression mediated by cannabinoids on different immune cell populations and discuss how activation of CB2 provides a novel therapeutic modality against inflammatory and autoimmune diseases as well as malignancies of the immune system, without exerting the untoward psychotropic effects.

I have to make an emotional appeal to the level of complexity the immunomodulatory effects CB2 agonists have, pair that with an appeal to absurdity regarding the huge dosages of potent CB2 agonists we vaporize/burn for their psychoactive CB1 agonist properties, and how fucking vital our immune system is.

Unless you have a myocardial infarction, an organ transplant, hepatitis, cancer, or are in the late stages of HIV infection you should not be abusing potent CB2 agonists. Even then you would be further complicating things when you have harder pressing issues to address than getting high off of internet drugs.

Win 55212-2, a cannabinoid receptor agonist, attenuates leukocyte/endothelial interactions in an experimental autoimmune encephalomyelitis model

Abstract

Multiple sclerosis (MS) is the most common of the immune demyelinating disorders of the central nervous system (C NS). Leukocyte/endothelial interactions are important steps in the progression of the disease and substances that interfere with these activities have been evaluated as potential therapeutic agents. C annabinoid receptor agonists have been shown to downregulate immune responses and there is preliminary evidence that they may slow the progress of MS. The purpo se of this investigation was to determine how cannabinoid recepto r agonists interfere with leukocyte rolling and adhesion. This was investigated in an experimental autoimmune encephalo myelitis (EAE) model using six to eight week old C 57BL/6 mice. Mouse myelin oligodendrocyte protein and pertussis toxin were used to induce EAE. WIN 55212-2, C B1 and C B2 antagonist were given. By use of in vivo intravital microscopy, leukocyte/endothelial interactio ns were evaluated via a cranial window implanted two days before. The results demonstrated that EAE increases leukocyte rolling and firm adhesion in the brain, and that this increased leukocyte/endothelial interactio n can be attenuated by administration of WIN 55212-2. Furthermore, use of the selective antagonists for the C B1 recepto r (SR 141716A) and the C B2 receptor (SR144528) in this study demonstrated that the cannabinoid’s inhibitory effects on leukocyte/endothelial interactions can be mediated by activating C B2 receptor.

CB2 cannabinoid receptor agonist, JWH-015 triggers apoptosis in immune cells: Potential role for CB2 selective ligands as immunosuppressive agents

Abstract
Cannabinoids are known to interact with CB1 and CB2 receptors expressed in the nervous and immune system, respectively and mediate a wide range of effects, including anti-inflammatory properties. However, cannabinoids that bind CB1 are also psychoactive thereby limiting their clinical use. In this study, we investigated the immunosuppressive properties of JWH-015, a synthetic CB2-selective agonist. We found that JWH-015 triggered apoptosis in thymocytes in vitro and inhibited the proliferative response of T and B cells to mitogens through induction of apoptosis. JWH-015 induced cross-talk between extrinsic and intrinsic pathways of apoptosis involving caspase-8, caspase-9, and caspase-3 as well as loss of mitochondrial membrane potential. Finally, administration of JWH-015 in vivo caused thymic atrophy, apoptosis, and decreased peripheral T cell response to mitogens. Together, this study suggests that CB2 selective agonists, devoid of psychotropic effect, may serve as novel anti-inflammatory/immunosuppressive agents.

http://en.wikipedia.org/wiki/Cytokine#Disease

Disease

Adverse effects of cytokines have been linked to many disease states and conditions ranging from major depression[12] and Alzheimer's disease[13] to cancer[14] with levels either being elevated or changed.

Anecdote:

I've had chronic bronchitis for the past four months while addicted to synthetic cannabinoids. I used a new straw and foil while I was abusing UR-144. I became lethargic, and in retrospect very schizo-something in behavior and mood, and started getting sinus infections on top of coughing up disgusting shit everyday. Then, a chronic ear infection on top of that. I was literally the walking dead, but I didn't care because I could get high whenever I wanted and didn't have to feel the physical pain of being gravely fucking ill. It was also a factor of not noticing the rapid physical deterioration because of the mental blunting I felt for up to three days when first abstaining (while using this was so bad that I don't remember entire seasons); I was covered in postules (fucking disgusting), but shrugged it off. I ate, slept, and vaped. That's what I did and was completely content with it, I literally wasn't capable of thinking outside of those three things. Libido was crushed by intense overwhelming anxiety and agitation 24/7, social interaction was impossible due to being effectively retarded, and obsession became my only thoughts.

Then one day I put 2 + 2 together and UNDERSTOOD the toll synthetic cannabinoid use was taking on me. It was the first time I had really taken the time to even consider being self-aware because of my laser-like focus on hedonism. My brain was so scrambled that I voluntarily took a few days worth of Risperdal to bring me down after discussing the concerns with my sympathetic psychiatrist. It was like the stupid went away and I could focus on healthier things. After that week I felt back to baseline and discontinued my anti-psychotic regiment. I also started got completely better infection-wise, but relapsed like a moron because I thought that I could handle it "since I'm all better". No surprise: the bronchitis came back, then the sinus infection, then my ears, and then postules. And I didn't care for a week or so because I could get high and not feel. In a moment of clarity I realized the path I was going down and disposed of my stash. Magically, and with a course of anti-biotics, I was completely better and kicking myself for being that stupid.

The mental effects potent cannabinoids have are so powerful that it will override any higher thought than "get high, eat, sleep, repeat". The consequences of this I've experienced to an extreme, learn from my mistake.

 

[sekio]

Do you personally expect there to be the same issues with plant-derived cannabinoids (CBD especially) and/or CB2 partial agonists?

 

[fettered]

Do you personally expect there to be the same issues with plant-derived cannabinoids (CBD especially) and/or CB2 partial agonists?

Refined extracts of a potent plant CB2 agonist, if it exists, would have to be a concentrated isolate since we all know butane honey oil won't mess with your ability to fight infection.

On CBD (http://www.ncbi.nlm.nih.gov/pubmed/18656454):

Abstract
Cannabidiol (CBD) is a cannabinoid compound derived from Cannabis Sativa that does not possess high affinity for either the CB1 or CB2 cannabinoid receptors. Similar to other cannabinoids, we demonstrated previously that CBD suppressed interleukin-2 (IL-2) production from phorbol ester plus calcium ionophore (PMA/Io)-activated murine splenocytes. Thus, the focus of the present studies was to further characterize the effect of CBD on immune function. CBD also suppressed IL-2 and interferon-gamma (IFN-gamma) mRNA expression, proliferation, and cell surface expression of the IL-2 receptor alpha chain, CD25. While all of these observations support the fact that CBD suppresses T cell function, we now demonstrate that CBD suppressed IL-2 and IFN-gamma production in purified splenic T cells. CBD also suppressed activator protein-1 (AP-1) and nuclear factor of activated T cells (NFAT) transcriptional activity, which are critical regulators of IL-2 and IFN-gamma. Furthermore, CBD suppressed the T cell-dependent anti-sheep red blood cell immunoglobulin M antibody forming cell (anti-sRBC IgM AFC) response. Finally, using splenocytes derived from CB1(-/-)/CB2(-/-) mice, it was determined that suppression of IL-2 and IFN-gamma and suppression of the in vitro anti-sRBC IgM AFC response occurred independently of both CB1 and CB2. However, the magnitude of the immune response to sRBC was significantly depressed in CB1(-/-)/CB2(-/-) mice. Taken together, these data suggest that CBD suppresses T cell function and that CB1 and/or CB2 play a critical role in the magnitude of the in vitro anti-sRBC IgM AFC response.

Again, more conjecture:
It seems as if CBD's immunomodulatory effects are selective for T cells and through specific mechanisms that involve CB1/CB2 indirectly; whereas CB2 immunomodulation is controlled via a variety of different mechanisms and isn't selective for any one type of immune cell.

I think the issue here with substances like UR-144, which is 83x MORE selective for CB2 over CB1 (1:83 CB1:CB2 agonism), is that CB2 receptors will be utterly saturated by the time psychoactive effects are reached. If you haven't sampled it, UR-144 is highly active at a few milligrams vaporized, so I believe that CB2 receptors will be completely occupied at dosages in the microgram range. This is complete guessing on my part based on the understanding of how drugs like mirtazapine/seroquel work. If CB2 receptors react to excessive activation by a full-agonist ligand like the CNS monoamine receptors, then there will be issues with down-regulation and what not reeking havoc on the immune system.

I have never run into those effects smoking weed or even a synthetic cannabinoid that is highly selective for CB1 (literally went through 10g+ of JWH-122 (1:2 CB1:CB2 agonism), while I had a sinus infection I attributed it to my unsanitary vaporization technique (used to use the same straw/pen over and over :/) but was fit as fuck after purchasing new straws to use each session. This seems to be unique to chronic abuse of potent and selective CB2 full-agonists.

I would be really, really interested in a table or paper on binding affinities and concentrations for the natural cannabinoids. The nail in the coffin for this thread would be evidence of a highly selective, highly potent CB2 agonist in significant quantities in cannabis. Sucks that the research suggests that I went Apocalypse Now on my immune system. Sucks even more that a drug is widely available that could be used to suppress the immune system to the point that it accepts a foreign body without a fight, even whole fucking organs. Welp.

 

[FlippingTop]

You should never be using a straw to vaporise, especially not a plastic straw. Buy a metal tooter

 

[QuasiStoned]

God that pattern of get high, eat, sleep, repeat rings true for me everytime I buy some noids. Oddly, I've noticed how much these chemicals can effect us mentally but have noticed a surprising lack of physical side effects besides extreme lethargy and somnolence. I have never gotten sick when I'm using, no acne or nothing like that. I just finished off 3 grams of 5-fur-144, 2 grams of ur-144 and 1 gram of am-2201 in a hedonistic 2 week bender. Mentally, I was in the shitter but I still felt quite healthy.

Compare this to something like a-pvp or mdpv, when I vaporize that shit my skin gets greasy, I get sores all over my face, seems hard on liver and kidneys. Makes ur-144 seem as inert as water vapor by comparison (which of course isn't true, merely comparison).

I am not attesting that these noids are safe, the aftermath has always been quite prominent for me. Coming off this most recent binge I've been extremely beside myself and experiencing undeniable withdrawal. Appetite suppression, feelings of restlessness and anxiety, and a very noticeable hot and cold flashes. Mild insomnia but when I do sleep I sweat puddles, it's really uncomfortable. It's nothing compared to opiate withdrawal and it's very brief, I'm 72 hours in and I've been scraping my tutors and smoking old foils like a crackhead so I haven't been completely abstaining but I'm feeling dramatic improvement.

These synthetic noids are obscenely potent, who knows what the chronic long term effects are. It's Russian Roulette :/

 

[Crashing]

I've experienced what i believe to be the most addicting and dangerous of substances. Those being Heroin, Crack Cocaine, MDPV, and Ketamine. After a 6ish month stint with synth cannabinoids, namely AM2201, I realized that these substances are right up there with crack and MDPV in terms of reinforcement level and addiction potential. They severely altered me psyche right under my nose and I had no idea I was acting so much out of character. The addiction was very much like crack, leaving you with overly compulsive desires to redose about every 20 minutes for your every waking moment. luckily the comedowns weren't as bad.

I have found that many users report lung problems while using these full agonist cannabinoids, and we have to remember that these substances most likely do not have the protective cancer fighting qualities provided by the inhalation of marijuana smoke. I have had a seizure on JWH-XXX before and crashed my car due to the lock up, which really sucked and led to one of my arrests.

They are very unsafe substances and probably some of the very last things (maybe right in front of inhaling gasoline) that i would personally recommend to anyone who wants to achieve an altered state of mind.

 

[QuasiStoned]

Yes they are far too rewarding given their short duration. They test my willpower in much the same way as mdpv and opiates did.

 

[AlphaMethylPhenyl]

Wow I've heard that they're addictive and dangerous but would you really put them and crack in the same category?

 

[Crashing]

Wow I've heard that they're addictive and dangerous but would you really put them and crack in the same category?

Personally, I would absolutely. For me, they have the same reinforcement complex. The only difference is that they are cheap and legal, so less problems are encountered. The withdrawal is similar, also.

 

[fettered]

Wow I've heard that they're addictive and dangerous but would you really put them and crack in the same category?

Not in the same sense as the intense pseudo-addiction you get with crack the first time smoking it, no. With regular use, though, you'll find yourself craving for "one more hit" and searching around for old foil or bags that might have a little bit left when the supply runs out. Psychosis level? Wouldn't know with crack, but with synthetic cannabis: it warps your thought process so much that introspection and being self-aware are no longer concepts you entertain or may even be capable of entertaining. I eventually go on full schizo withdrawal, agitated social interaction, panic attacks, delusions of reference (would you class them as delusions if you are 100% sure they arent real? but undeniably perceiving the phenomenon either way), paranoia, binge eating, excessive sleeping, anhedonia when not high, etc.

Cannabinoid full-agonists are fucking retarded to abuse. Maybe a one off smoke once a year kinda thing will work for some of you but the appeal is the immediate availability and abundance; if you have addictive tendencies (if you're here you probably do and if you think you don't maybe some soul searching will do you good before you decide to go down a similar path to satisfy your ego) don't fucking touch it. First time you smoke it it's like the first time you do any drug: it's usually amazing. Use it often and the nasty side effects come out. Anxiety at first, and if you think that is bad try psychosis. Knowing that youre crazy in the midst of your mind melting down is a shitty realization: hopeless, bleak, and insufferable. The regret of knowing you went too far, and the uncertainty of not knowing whether it will get better/stay the same/worsen. The shock at your condition. The shame of knowing your former loving, friendly, funny, and intelligent self is in the past and that you are pitied by those you respected for the sad state you're in. The despair over remembering the motivation and drive to pursue positive goals you once had naturally contrasted with the present inability to think clearly or only about getting high. The dissonance of being unable to recognize the mess of a person in the mirror, and knowing exactly how you got there. The grief of hurting the ones you love in the most pointless way possible.
And then the false relief as all of that falls away when you get high, and you can pretend to be the person you once loved.

Now off the cannabinoids I am a shell of who I once was: I am a bitter, hateful, argumentative, paranoid, narcissistic, and sociopath of the highest order now. Relating to people has become a task where I just fake it. I don't like people because I know they can sense my mental deficit. I can't find it in me to let myself love, and I am somehow compensating for that through manipulating people for my own personal financial gain. I've regressed from the humble student with great prospects to an egocentric piece of shit due to being jealous of how easily people can be human without trying and hating that I did it to myself.

Attending NA meetings to address the latter, as I feel my condition stems from the extreme disconnect I feel with society and the steps seem to work through spiritual fulfillment and positive integration into the real world that doesn't involve drugs.

Reading the above reads just like a page out of my opiate addiction a few years ago. That is how powerful this shit is on your mind. So yes I would put this up there with opiates and stimulants addiction-wise.. At least recovery from opiate addiction seemed viable. I feel like recovery is very possible, but the person I used to be is gone and never coming back; I'm done trying to fake it. I've been changed for the worst over shitty drugs.

I know this is darkside material, but I wanted to answer your question in the most comprehensive way possible because all I see about CB is that "ugh withdrawal is a bitch!!!!11" or that psychotic episodes are "dumb kids smoking too much and having panic attacks". I believed that withdrawals were the worst consequence and that I was somehow immune to schizo* because I had drug experience, and look where I am now: posting on an internet forum about how internet drugs took over my life, chewed me up and spit me out.