Why Some Drugs Cause Physical Dependence While Others Do Not

[daddysgone]

So the title pretty much says it all. I have a decent understanding regarding the various systems involved in addiction. However, I am somewhat confused as to why some substances, when administered chronically, result in profound physical dependence after a very short time, while others do not.
Now lets be clear here and be certain to differentiate between physical and psychological dependence. As we all know, almost anything, and certainly any drug, has serious potential to result in psychological dependence. However, it seems that the chronic use of only certain drugs, will result in a true PHYSICAL dependence. The classic model and example of drug related physical dependence, is that of opioids. Chronic use of opioids, even after only several weeks, often leads to profound physical dependence, and acute withdrawal symptoms upon abrupt cessation of opioid use. I BELIEVE (not certain) that in opioid dependency, a great deal of this dependency is the changes that occur in the brains endorphin system as a result of the use of opioids, which act essentially, as exogenous endorphins. Due to the large amount of exogenous opioids being administered, the brain ceases or curtails making its own endorphins. Upon cessation of opioid use, the brain is essentially devoid or at least has greatly reduced endorphin levels, and this, in addition to some role of kappa agonists i believe, is largely responsible for the withdrawal symptoms.

However, let us briefly look at marijuana usage. Even prolonged and chronic use of marijuana does not seem to result in any sort of true physical dependency. However, like opioids, our brains produce their own endo-cannabinoids. So when we ingest large amounts of exogenous cannabinoids, why do we not experience withdrawal upon cessation of usage? Is it that despite our usage of exogenous cannabinoids, our brains continue to produce their own cannabinoids at normal levels? Or perhaps is it that our brains do curtail the production of endo cannabinoids, but low levels of cannabinoids do not cause withdrawal type symptoms.

Of course these are just 2 examples, and im aware that i have simplified addiction and withdrawal and that many many symptoms are involved. however, the question still remains for me- why do some drugs produce dependency and withdrawal upon cessation, while others do not? thanks- Dg

 

[Tsukasa]

Marijuana DOES have physical withdrawal symptoms. But sometimes it's hard for me to draw the line between physical and psychological symptoms, because often one is the cause of the other. Craving are mostly psychological, so is chemical depression, anxiety, or insomnia also considered? chemical irregularities can cause psychological symptoms like cravings, depression, anxiety, insomnia, and negative or overactive thinking or emotions can also lead to the same things, even physical pain (imagine your head being bashed with a hammer for a couple minutes and see if that doesn't give you the most massive migraine). So yea.. marijuana's physical wd symptoms may include headaches, general discomfort, insomnia, and loss of appetite, and queeziness. I've experienced it myself.

And btw, endorphins aren't the only endogenous opioids in the body, incase you didn't know. Their are others like endomorphin (mu-ligand), dynorphin (k-ligand), enkephalin (delta and mu ligand), Nociceptin (ORL ligand), Opiorphin (inhibits enkephalinase), and possibly endogenous morphine (though it's mechanism isn't known yet).

 

[Hammilton]

It seems possible that animal cells can produce morphine, it's entirely unknown if it ever actually happens outside of petri dishes.

 

[daddysgone]

Marijuana DOES have physical withdrawal symptoms. But sometimes it's hard for me to draw the line between physical and psychological symptoms, because often one is the cause of the other. Craving are mostly psychological, so is chemical depression, anxiety, or insomnia also considered? chemical irregularities can cause psychological symptoms like cravings, depression, anxiety, insomnia, and negative or overactive thinking or emotions can also lead to the same things, even physical pain (imagine your head being bashed with a hammer for a couple minutes and see if that doesn't give you the most massive migraine). So yea.. marijuana's physical wd symptoms may include headaches, general discomfort, insomnia, and loss of appetite, and queeziness. I've experienced it myself.

And btw, endorphins aren't the only endogenous opioids in the body, incase you didn't know. Their are others like endomorphin (mu-ligand), dynorphin (k-ligand), enkephalin (delta and mu ligand), Nociceptin (ORL ligand), Opiorphin (inhibits enkephalinase), and possibly endogenous morphine (though it's mechanism isn't known yet).

ok. perhaps marijuana is capable of producing some variety of minor physical dependence and withdrawal. however if this is truly what you are trying to assert, i believe you are doing some serious splitting of hairs. Conventional wisdom leans HEAVILY toward the understanding the marijuana does not cause physical dependence. The minor symptoms you listed which you attribute to physical withdrawal could very, very be the result of a psychological dependence. This it not to minimize psychological dependence in any way. indeed, psychological dependence can produce profound effects and result in fairly hellish withdrawal. However, let us not confuse the issue. I can speak from personal experience regarding marijuana and its lack of physical dependence/withdrawal upon cessation of usage. I used to be a very heavy marijuana smoker (several times a day, every day of the week, for several years). During my 4 years of heavy usage, i am certain that there were fewer then 2 weeks in total that i did not smoke. However one summer, my girlfriend and myself traveled to Brazil for a 4 week trip. I did not bring any marijuana with me, and did not smoke once for the entire 4 week trip. The ONLY symptom which I experienced which could be even loosely related to withdrawal was a slight anxiety that came and went for several days. To keep things in perspective, imagine that instead of marijuana, it was heroin which i had used several times a day, for 4 years. Im quite certain that id have more to report then some intermittent anxiety.

so look, we can go back and forth arguing whether or not marijuana can create a true PHYSICAL dependence and related withdrawal, but for the sake of this thread, i would certainly hope that we can agree that there can be zero comparison regarding the physical dependence and withdrawal when discussing marijuana and opiates, respectively.

In your other point regarding endogenous opioids other then endorphins- you are quite right. However, in this thread, Im not seeking to list and discuss all endogenous opioids found in the brain (though it is possible that these other ligands you mention may be involved in the answer to my question here). Rather, Im hoping to gain a better understanding of why the chronic use of some drugs, very quickly lead to profound and acute PHYSICAL dependence and associated withdrawal, while others appear to not.I find this issue especially confusing when considering that both substances in the example we are discussing (opioids and marijuana) flood the brain with exogenous "analogs" of substances found within our brain.

so any other thoughts? thanks-DG

 

[AlphaMethylPhenyl]

why question mjs perfection?

 

[Hammilton]

Likely a large part of the reason dependence isn't seen with THC is because it's a partial agonist. Full agonists produce much more pronounced symptoms.

 

[pofacedhoe]

thc does not produce a pyhsical addiction. ssri's however are another story

 

[Hammilton]

Please, don't use the term "physical addiction" because it expands the definition of addiction to include things that aren't addiction- physical dependence. Using the term addiction to describe dependence only confuses and evolves the language in a way that makes it much less useful.

If THC produces any sort of physical dependence, it's very mild and only in very high dose users. A reliance on the drug that mirrors addiction in some ways but doesn't engender the full 'what' of addiction. Many users use it at bed to get to sleep and find difficulty sleeping if they don't get high first. That's the main sort of psychological reliance that I can think of right now, and probably the most common.

 

[Jamshyd]

why question mjs perfection?

Um, perhaps because it is as far from perfect as you can get for some people?

There is nothing perfect about a drug that has only one consistent effect: making your heart feel like it's about to explode. Everything else about it is totally unpredictable - it might make me stimulated, it might put me to sleep, it might make me feel like the most stupid person on the face of the earth... etc.

Weed is a drug I treat the same way I treat psychedelics - sparingly, and very cynically.

 

[shibireru]

It's obviously because the opioid system in the brain is far more intimately involved in regulating and modulating some of the more critical of the central nervous system's vital functions. Despite the superabundance of Cannabinoid receptors in the brain, which seems to portend importance, their diminished activity does not give rise to any salient changes in physiological status. In other words, the functioning of the cannabinoid system doesn't appear to have very immediate or profound effects on the hypothalamic-pituitary-adrenal axis... or whatever. It may also be that cannabinoid receptors don't downregulate quite so readily as other receptors or that exogenous cannabinoids don't reach the cannabinoid receptors whose significant downregulation would produce marked and observable changes in physiological status / disruption of homeostasis.

Or something like that...

 

[shibireru]

Um, perhaps because it is as far from perfect as you can get for some people?

There is nothing perfect about a drug that has only one consistent effect: making your heart feel like it's about to explode. Everything else about it is totally unpredictable - it might make me stimulated, it might put me to sleep, it might make me feel like the most stupid person on the face of the earth... etc.

Weed is a drug I treat the same way I treat psychedelics - sparingly, and very cynically.

Agreed. What a pile of horse shit that junk is.

P.S. I'm adding Fentanyl to that list, too. Yet more overhyped garbage. I think the problem with Fentanyl is that it has a very high specificity for the mu-opioid receptor and almost no affinity for the delta. I'd be willing to bet that a great deal of the euphoria produced by certain opioids (e.g. hydrocodone) comes from their partial agonism of delta-opioid receptors or agonism of the same on the part of their various metabolites. Fentanyl seems to be a hypnotic, deliriant, and central nervous system depressant and little else. It might make your body feel tingly and warm in a vaguely pleasant way, but don't expect more than that. (or maybe it doesn't cross the blood brain barrier very readily and so exerts its effect predominantly upon the base of the brain, suppressing breathing and so forth without giving rise to much euphoria.)

 

[acetylcholine]

thc does not produce a pyhsical addiction. ssri's however are another story

The notion that SSRI's cause addiction is a simplistic misconception. Discontinuation syndrome is not "addiction".

 

[daddysgone]

why question mjs perfection?

IMO, weed's only positive attributes are its tendency to not cause tolerance and physical dependence. If you are one who enjoys MJ, then u are QUITE fortunate in that you have found a drug that provides you with an enjoyable experience, without the associated tolerance and physical dependence that is usually found with the chronic use of other drugs.

Ive posted on this subject once before, but it seems to me (and to many others with whom ive discussed), that marijuana is really a young mans game. What I mean by that is that during teenage and perhaps early twenties, many people fall in love in with marijuana. However, as one reaches adulthood, these same people find themselves no longer enjoying its effects, and in fact, begin to find the drug dysphoric rather then euphoric. I know that this has been the case for me. For many years i was a daily, habitual pot smoker. But around age 21, I found that the positive effects of pot were diminishing, while all the negatives (anxiety especially) were increasing. I know of many many people who have identical stories to tell regarding their marijuana usage.

at any rate, i seem to be contributing to the de-railing of my own thread, so lets try and get back on topic. One answer that someone provided that seemed to make some sense to me is that a drug like marijuana which acts at the endocannabiniod system, is it not involved in the regulation of vital systems in the body (respiration, heart rate, etc). Im not sure if this answer is indeed correct, but it does make some logical sense to me that because the endocannabinoid system is not intimately involved in vital functions, the cessation of usage does not lead to a withdrawal syndrome.
Now if someone can think of an example of a drug that acts on a different system which also does not control vital functions but DOES cause a physical dependence, then i would think that would disprove this theory.

Oh and for the record, i totally agree that we must be careful to differentiate between addiction and physical dependency. What I am interested in discussing in this thread is physical dependency and why the chronic use of some drugs causes this dependency, while the use of others, do not. DG

 

[Sturnam]

In my own words:
discontinuation syndrome (physical dependence) - withdrawals that occur when there is habitual use of a drug, and the physical symptoms that manifest when the drug is abruptly stopped.
addiction - persistent use of a drug (or activity. ex: gambling, sex) despite the negative effects it is having on one's life. specific negative criteria are defined in the newest DSM.

but speaking of which, i've been wondering about this same question as well. for some reason it seems odd to me that cocaine and amphetamine are generally classified as only being psychologically addicting. I guess maybe physical dependence has to do with the receptor systems it hits? That some are vulnerable to the changes that cause physical dependence while other do not?

as for the physical dependence being caused by 'vital' receptor systems, what about drugs that primarily affect dopamine (like cocaine, amphetamine)? I would think that dopamine would be pretty vital to living. I remember reading some study where mice engineered without dopamine receptors simply did not eat, and had to be force fed by the lab researchers.

 

[JustferFun]

The notion that SSRI's cause addiction is a simplistic misconception. Discontinuation syndrome is not "addiction".

Have you ever gone through it? Just curious. I know this thread is old, but I somehow stumbled upon it....SSRI cessation has been documented to cause changes in cerebral blood flow volume when replaced with placebo.

In addition, withdrawal can last for months, yet the FDA doesn't really seem to care. It's pure hell.

 

[JustferFun]

The notion that SSRI's cause addiction is a simplistic misconception. Discontinuation syndrome is not "addiction".

Just wanted to clarify....I'm not disagreeing with you. I agree that discontinuation isn't withdrawal per se. There's really no psychological addiction/ dependence to speak of. You can't compare SSRI discontinuation with say, heroin withdrawal. I agree with you, but I just wanted to throw in my 2 cents about "discontinuation syndrome."

There are definitely profound psychological and physiological changes going on. Different people react differently, so it's a little unpredictable. Some patients are super sensitive and they can't function, even if they taper slowly. Some of the antidepressants simply don't come in small enough dose increments....the jump from the final, smallest dose to zero is too big of a leap for a lot of people. A lot of these patients aren't very knowledgeable about any of this, so they don't necessarily know what to do, and neither do their doctors, in many cases.

Prozac, on the other hand, is easier to deal with due to it's very long half life. I've heard of some people successfully substituting Prozac in the final stages of discontinuation, but this isn't common practice. I wonder why this is still a relatively unexplored technique.

 

[Vaya]

It's obviously because the opioid system in the brain is far more intimately involved in regulating and modulating some of the more critical of the central nervous system's vital functions. Despite the superabundance of Cannabinoid receptors in the brain, which seems to portend importance, their diminished activity does not give rise to any salient changes in physiological status. In other words, the functioning of the cannabinoid system doesn't appear to have very immediate or profound effects on the hypothalamic-pituitary-adrenal axis... or whatever. It may also be that cannabinoid receptors don't downregulate quite so readily as other receptors or that exogenous cannabinoids don't reach the cannabinoid receptors whose significant downregulation would produce marked and observable changes in physiological status / disruption of homeostasis.

Or something like that...

Most interesting comment to me.

At least when comparing cannabinoid receptors to endogenous endorphins (et. al), the endorphins likely have a much more profound effect on the limbic system - one of the most central and yet generalized subcortical regions of the human brain. They are produced in the hypothalamus and pituitary glands, centralized structures of the limbic system.

This is only speculation on my part, but cocaine may not have the same physical dependence attached to it based on the fact that it facilitates dopamine in the prefrontal cortex (a cortical structure) and also in the midbrain, which mediates the pleasure/reward system primarily through the ventral tegmentum. Whilst the PFC is the most newly-developed part of the human brain, the midbrain is (evolutionarily) much older and may be less prone to attaching its dopaminergic activity to the physicality of the body than would the limbic system - which, by the way, is responsible for emotion, fear-response, encoding of long-term memory, hormone release... If this system were thrown off by neurological reorganization after heavy opiate use, it makes some sense that its deleterious effects would be vastly more wide-reaching (in a physically dependence sense).

Jesus, this makes a little less sense each time I try to re-conceptualize it. Amazing question, though - a fine point for some future research.

~ vaya