Why is cannabis non addictive, but opioids addictive?

[FrogWarrior]

NOTE: In the title, I meant to say opium not opioid

Full CB1 and CB2 agonists (the ones I know of at least) are physically addictive and can cause withdrawal symptoms. Cannabis on the other hand, seems to have minimal addictive properties and relatively non existent withdrawal symptoms. I read that full CB1/CB2 agonists can have rough withdrawals, up there with opioid or benzo withdrawals in terms of symptoms. What makes full CB1/2 agonists different from ingesting cannabis? More importantly what aspect of this difference renders the substance non addictive? And could the concept apply to other substances like opioids. So cannabis contains THC which is a "partial" agonist of CB1 and CB2 receptors. Pure THC is still addictive, so it seems unlikely that it being a partial agonist (as opposed to full) is what makes it non addictive. Using opiates as an analogy, partial mu agonists like buprenorphine are still physically addictive. People were abusing subutex (product containing only buprenorphine) to the point, that manufacturers started adding naloxone, a full opioid agonist, in order to prevent the ability to get the psychoactive effects from the drug. As far as I've heard that approach works, suboxone is not a recreational drug. Cannabis on the other hand contains CBDs, which is are partial antagonists of the CB1 receptor. Maybe thats the key. The addition of a partial antagonist. We know that taking antagonists reverse downlregulation induced by agonists. For example, flumazenil is used (experimentally at this stage) to treat benzo tolerance (for PAWS of course, not acute withdrawal which would like cause seizures). Naloxone is used to treat opioid tolerance (that has to be done under anasthesia of course). Maybe the right mix of agonism and antagonism is required to acheieve this counter addictive mechanism. Tolerance develops with cannabis, but not as extreme as with full CB agonists. I've heard of people being immune to cannabis after switching back to cannabis from a synthetic noid.

First thing I'd like to know is does CBD prevent tolerance to synthetic cannabinoids. I don't where to find CBD, so I can't perform this experiment. That would narrow things down, as it'll tell us if this anti addictive thing is specific to THC (and similar partial agonists), or applies to all cannabinoid agonists. Or it could be that cannabis contains additional anti addictive compounds that we don't yet know about, but no point complicating things too soon, maybe the key is the combination of partial agonists and antagonists. How can we explode that? The partial agonists buprenorphine isn't too hard to get hold of, what about a partial mu antagonist? I'm sure they're being developed, but are there any available yet? With opioids, things is more diversity among subtypes of receptors. Morphine binds mu, delta and to a lesser extent kappa receptors and its hard to say what role delta and kappa receptors play in physical dependence. Nalorphine is a mu antagonist, but kappa agonist. It is used to reverse opioid overdose, like naloxone but I have no idea what role the kappa agonism plays in this.

I only started researching this, so my knowledge isn't very complete, I'd appreciate if anyone can fill me in more on this subject (the interplay between partial agonists and partial antagonists.

 

[sekio]

Cannabis does produce classical tolerance and withdrawal symptoms, but they are almost always of such a minor nature that they are not worth mentioning in the same breath as opioid or benzo withdrawals. Most often cannabis is considered "addictive" in that it people find it pleasurable and hence it is habit forming, not that you're going to need to smoke a joint before you can get out of bed in the morning. Part of the reason may indeed by THC's partial agonist nature, and the fact that most cannabis is consumed in a self-limiting fashion - in general, people stop smoking weed once they get to a certain comfortable level meaning that the amount of CB1 agonism may be quite small indeed, as opposed to having total receptor activation from a synthetic. Also, weed has a 'ceiling effect' of sorts - once you get to a certain level of high you just can't get any higher. Synthetics don't.

People who consume THC in concentrates/oils/waxes can often consume far more THC in one go than in several normal joints, so the higher incidence of unpleasant w/d is not surprising. I think the real issue is dose size and frequency. Kind of like opioids. If you smoke infrequently, or even small amounts daily, you won't suffer nearly as much as someone who is doing large doses of synthetic cannabinoids all the time. Likewise, someone who takes low doses of codeine or tramadol won't feel as bad when they stop as the guy who is doing 4 daily 1 gram doses of heroin. (And of course, some poeple are more susceptible to the bad effects, some are more resilient, some overcome the effects easily, some suffer, etc.)

CBD certainly serves to modulate some of THC's effects, but it would be ineffective with superpotent synthetic cannabinoids, which bind with higher affinity to CB1 and CB2 receptors.

We know that taking antagonists reverse downlregulation induced by agonists.

This is only rarely the case. Some receptors downregulate in response to anything binding, antagonist or agonist.

People were abusing subutex (product containing only buprenorphine) to the point, that manufacturers started adding naloxone, a full opioid agonist, in order to prevent the ability to get the psychoactive effects from the drug. As far as I've heard that approach works, suboxone is not a recreational drug.

Maybe you need to do more research, people still abuse suboxone (if their tolerance is low enough) because the naloxone is not absorbed orally. (and what fraction is absorbed, is rapidly broken down - the bupe is not)

 

[FrogWarrior]

Cannabis does produce classical tolerance and withdrawal symptoms, but they are almost always of such a minor nature that they are not worth mentioning in the same breath as opioid or benzo withdrawals.

Most often cannabis is considered "addictive" in that it people find it pleasurable and hence it is habit forming, not that you're going to need to smoke a joint before you can get out of bed in the morning. Part of the reason may indeed by THC's partial agonist nature, and the fact that most cannabis is consumed in a self-limiting fashion - in general, people stop smoking weed once they get to a certain comfortable level meaning that the amount of CB1 agonism may be quite small indeed, as opposed to having total receptor activation from a synthetic. Also, weed has a 'ceiling effect' of sorts - once you get to a certain level of high you just can't get any higher. Synthetics don't.

All pretty good points. Cannabis definitely has psychologically addictive properties, but the lack of physical withdrawal is what fascinates me. I quit after about 8 years of heavy daily usage, and besides a day of depression, had not even withdrawal. Using kratom for a couple of months produced a withdrawal. Whether theres a ceiling limit or not, I never reached a point where I could no longer get higher by increasing the dose, and I've never heard of this happening to anyone else. For the whole 8 years that I smoked cannabis regularly, I was always able to get strong effects from it. Codeine on the other hand, loses its effects pretty quickly and you can end up getting withdrawal symptoms with your regular dose. That doesn't happen with cannabis. The ceiling dose of codeine does make it less addictive, but its still vastly more addictive and the withdrawals are a lot more noticeable than smoked cannabis. Different ceiling dose mechanism though, so that might not correlate.

People who consume THC in concentrates/oils/waxes can often consume far more THC in one go than in several normal joints, so the higher incidence of unpleasant w/d is not surprising. I think the real issue is dose size and frequency. Kind of like opioids. If you smoke infrequently, or even small amounts daily, you won't suffer nearly as much as someone who is doing large doses of synthetic cannabinoids all the time. Likewise, someone who takes low doses of codeine or tramadol won't feel as bad when they stop as the guy who is doing 4 daily 1 gram doses of heroin. (And of course, some poeple are more susceptible to the bad effects, some are more resilient, some overcome the effects easily, some suffer, etc.)

CBD certainly serves to modulate some of THC's effects, but it would be ineffective with superpotent synthetic cannabinoids, which bind with higher affinity to CB1 and CB2 receptors.

Good point. I don't know of anyone that had withdrawals from consumables but for now I'll take your word for it. Most people agree that codeine withdrawals aren't pleasant, and if its the first withdrawal they've ever had, they might think it was horrific. There are loads of reports of codeine withdrawals on the internet. I never got them myself, but I never used it for more than a few months in a row. Research needs to be done before we can determine how CBD would interact with synthetics.

This is only rarely the case. Some receptors downregulate in response to anything binding, antagonist or agonist.

There are more cases than that. People don't go under anaesthetic administration of opioid antagonists for nothing. It works. Inhibitory drugs (i.e. antihistamines, antipsychotics, ancholinergics etc.) generally cause upregulation of the postsynaptic receptors they're inhibiting. Theres way more to dependence than that, but thats one of significant mechanisms behind it. The degree to which that happens varies from neurotransmitter system to system of course.

Maybe you need to do more research, people still abuse suboxone (if their tolerance is low enough) because the naloxone is not absorbed orally. (and what fraction is absorbed, is rapidly broken down - the bupe is not)

Didn't know that. IV or nasal spray naloxone would work a lot better but a higher dose, and its no longer a maintenance program, its cold turkey withrawal (or worse considering the naloxone dose). From what I hear its impossible for someone with a tolerance to get high on suboxone, probably due to the lower ratio of mu receptors to ligands.

 

[endotropic]

There's a good deal of pre-clinical evidence that some of cannabis' effects are mediated by downstream activation of mu receptors (e.g. naloxone blocks THC induced dopamine efflux), and this clinical trial is looking to confirm some of that work.

Given that, I've always found it surprising that cannabis doesn't produce more of a withdrawal sydrome.

 

[TriputoryHeadicine]

First thing I'd like to know is does CBD prevent tolerance to synthetic cannabinoids. I don't where to find CBD, so I can't perform this experiment.

[source hints count as sources]. CBD has improved my quality of life trememdously.

 

[Roger&Me]

Cannabis definitely has psychologically addictive properties, but the lack of physical withdrawal is what fascinates me.

cannabis does have a pronounced withdrawal syndrome in many heavy users.

here's a highly abridged list of the current literature supporting this conjecture:

The cannabis withdrawal syndrome
By Budney Alan J; Hughes John R
From Current opinion in psychiatry(2006),19(3),233-8.

Cannabis and dependence
By Swift, Wendy; Hall, Wayne
Edited by Grotenhermen, Franjo; Russo, Ethan
From Cannabis and Cannabinoids(2002),257-268.

Review of the validity and significance of cannabis withdrawal syndrome
By Budney Alan J; Hughes John R; Moore Brent A; Vandrey Ryan
From The American journal of psychiatry(2004),161(11),1967-77.

A review of the published literature into cannabis withdrawal symptoms in human users
By Smith Neil T
From Addiction (Abingdon, England)(2002),97(6),621-32.

Withdrawal sequelae to cannabis use
By Rohr J M; Skowlund S W; Martin T E
From The International journal of the addictions(1989),24(7),627-31.

Oral delta-9-tetrahydrocannabinol suppresses cannabis withdrawal symptoms
By Budney Alan J; Vandrey Ryan G; Hughes John R; Moore Brent A; Bahrenburg Betsy
From Drug and alcohol dependence(2007),86(1),22-9.

Pharmacotherapy and psychotherapy in cannabis withdrawal and dependence
By Benyamina, Amine; Lecacheux, Marie; Blecha, Lisa; Reynaud, Michel; Lukasiewcz, Michael
From Expert Review of Neurotherapeutics(2008 ),8 (3),479-491.

Increasing treatment options for cannabis dependence: A review of potential pharmacotherapies
By Hart, Carl L.
From Drug and Alcohol Dependence(2005),80(2),147-159.

 

[Crashing]

Cannabis has a wide variety of cannabinoids. Addiction would develop rapidly under full agonization of CB1, but cannabis contains agonists, antagonists, and inverse agonists and in this way is self limiting.

Also to consider - i conducted a study with some of the synthetic cannabinoids that previously induced the classic 'spice trips of terror' in myself and combined these compounds with cannabis to find that the all the negative side effects and potentially overpowering effects of the synthetic, full ag cannabinoids, vanished completely.

 

[atara]

There isn't really any single explanation of physical (or psychological) addiction, just as there isn't a single explanation for, say, love.

Opioid receptors are responsible for a lot of stuff -- bowel movements, immune function, wakefulness, regulating anxiety, etc -- and when they're disrupted you can have big problems.

Cannabinoid receptors don't seem to be responsible for as much, but cannabinoid antagonists are still so unpleasant as to be essentially inviable as medications. It takes a pretty seriously heavy pattern of abuse to get major wd's from cannabis, and most people just don't use it that much.

 

[Hammilton]

Yeah but naloxone blocks dopamine efflux caused by many things. I'm not sure how relevant that is. Downstream stimulation of opioid receptors is common for many enjoyable things, like sex and food (I think).

 

[daveykronick]

I don't have anything interesting to add, but I just wanted to point out that people can still inject Suboxone and get high off it if they have a low enough tolerance to opiates/opiods. I have seen this many times, even with people who use heroin, but have low enough tolerance to were the Suboxone still gets them high. From what I've seen, you can inject up to around .5mg of naloxone without going into withdrawals (that would be a 2mg strip/pill, or a quarter of an 8mg strip/pill).

 

[h3lp]

This is an interesting topic.

If asked this question in terms of my personal research I can simply answer that they are two very different classes of drugs. While both have receptors in the brain the effects of the drug on the brain and body are very different from each other.

 

[Dresden]

Cannabis would be physically addictive were it not for THC's long half life. If you give rats cannabis and then give them a THC antagonist, then they will exhibit classic withdrawal symptoms, such as walking backwards.

Most opiates have a much shorter half life than THC, with the exception of methadone and maybe a few others. Opiates downregulate the endorphin system is the main reason.

 

[astudentforever]

i would check out r/leaves on reddit for those who don't think marijuana is addictive. yeah, it doesn't compare to most other addictions - but i know a lot of people who get very irritable without it.

 

[Calleja]

"CB2R localized on astrocytes or microglia could decrease dopamine levels by regulating the release of inflammatory cytokines from these cells. Alternatively, the activation of CB2R possibly located on dopaminergic terminals could also inhibit dopamine release in the NAc."
-Maldonado, R., Robledo, P., & Berrendero, F. (2013). Endocannabinoid system and drug addiction: new insights from mutant mice approaches. Current Opinion in Neurobiology, 23, 480-486. Retrieved from http://ac.els-cdn.com/S095943881300...t=1393510062_c98bd43617ceb7e7ab5894c34b8ee29a


I think the answer comes back to dopamine and the meso-cortico-limbic system. Although addiction is not as simple as release of a chemical in a region of the brain, we do know that this neurotransmitter and neural circuit do, in fact, play a significant role when it comes to reinforcement, learning of environmental cues, and formation of drug-seeking behavior. The difference between opiates and cannabis may very well depend on their downstream dopaminergic effects such as the one mentioned in the quote above. Moreover, the greater addiction potential of opiates may be explained by other long-term processes such as increased brain-derived neurotrophic factor (BDNF) in the Ventral Tegmental Are (VTA), which in turn again increases dopamine release in the meso-cortico-limbic system. I have not done enough research on how cannabis and other cannabinoids may affect dopaminergic tone but my point is that cannabis fails to activate the "addiction pathway" or at least in the same manner as opiates.

There isn't really any single explanation of physical (or psychological) addiction, just as there isn't a single explanation for, say, love.

Opioid receptors are responsible for a lot of stuff -- bowel movements, immune function, wakefulness, regulating anxiety, etc -- and when they're disrupted you can have big problems.

Cannabinoid receptors don't seem to be responsible for as much, but cannabinoid antagonists are still so unpleasant as to be essentially inviable as medications. It takes a pretty seriously heavy pattern of abuse to get major wd's from cannabis, and most people just don't use it that much.

Cannabinoid receptors also affect immune function and anxiety so I don't think that's what differentiates the addiction potential of opioids and cannabinoids.

Cannabis would be physically addictive were it not for THC's long half life. If you give rats cannabis and then give them a THC antagonist, then they will exhibit classic withdrawal symptoms, such as walking backwards.

Most opiates have a much shorter half life than THC, with the exception of methadone and maybe a few others. Opiates downregulate the endorphin system is the main reason.

I do not believe the half-life of a drug determines its addiction potential. For example, amphetamine has a half-life around 12 hours yet is unequivocally one of the most potentially addictive drugs. Although drugs that elicit a short-lasting high, like cocaine or some opiates, may lead to the user re-dosing frequently, which can lead to an addiction problem relatively more readily, pharmacokinetics is not the reason why repeated opioid use induces physical dependency and why they can be habit-forming. I think its more of when the behavioral effect of a drug has diminished, the person decides to re-dose.