Wouldnt withdrawal of drugs with disphoric effects be pleasant?

[Renald]

Lets say you are using for a long time such a drug as GABA antagonist or opioid antagonist, which causes dysphoric symptoms. If you withdrawed such a drug, wouldnt the withdrawal be pleasant?

 

[Agoraphobiaphile]

No.

There can be an argument made for substances such as naltrexone helping to repair opiate receptors but no taking it does not make you produce more euphoria inducing neurotransmitters.

Please someone with more knowledge explain this better.

 

[Solipsis]

The brief blockade of opioid receptors between 2 a.m. and 4 a.m. that is caused by taking LDN at bedtime each night is believed to produce a prolonged up-regulation of vital elements of the immune system by causing an increase in endorphin and enkephalin production

http://www.lowdosenaltrexone.org/#How_does_LDN_work_

That aside, afaik on the one hand it stands to reason that the upregulation and downregulation part of tolerance and withdrawal can partially induce inverse effects to those produced by the drug, after all there are homeostatic effects so I don't think it is impossible... but on the other hand there is no guarantee of anything because a drug's effect may involve certain neuronal signal cascades, special pathways that may be more or less unique to the type of drug. Withdrawal probably cannot copy those signal cascades as it would rather be limited to just the involved receptor's response to the endogenous ligands. Agonism vs antagonism: agonism involving activation, antagonism merely binding and blocking the receptor but with no activation.
So maybe it would be better if it were something like a kappa agonist like salvia but with less atypical dissociative effects (on the claustrum possibly?)... maybe leaving potential dysphoric effects. Now if that were not smoked but taken via more reasonable ROA quite often, who's to say if a euphoric rebound can be had?

I hope compensation effects with a GABA antagonist are not like taking a pile of GABA because the effects of that are (apart from very brief) not all that pleasant per se. Not unpleasant either, mostly a dopey drowse sort of feeling and quite a bit of flushing in the face.

Dysphoric drugs seem harder to come by, or does it just seem that way?

Anyway, it seems like in a number of cases this plan wouldn't work like you might think but it seems too much to claim it is impossible.

Belongs in NSP forum?

 

[xbandit07x]

Okay first of all, you don't have to be a neuro scientist to know that drugs could make you dysphoric while having parts to them that are addicting underhandedly and subtly (Or not so).

Also tolerance reversal mystic from reversing neurogenesis clearly won't work out as planned, since usually every drug has many reasons simultaneously that determine the tolerance.

A drug of full dysphoria and terror doesn't exist because you'd have no reason to eat it again if It was not even addictive in any way.

But to answer your question OP, sure if somethings making you feel bad and it wasn't addicting at all because it was that bad and you remove it yeah youl be happier.

Can a mod close this thread? Seems to happen to my threads so definitely shut this one too.

 

[kleinerkiffer]

Can a mod close this thread? Seems to happen to my threads so definitely shut this one too.

Why would I close it, it's not against the rules...

OD -> N&PD

 

[serotonin2A]

I guess an example would be if someone was taking a GABA-A antagonist (which cause anxiety and other unpleasant symptoms) and then stopped. In that case, you would feel better than you did while you were taking the drug (ie, the anxiety would go away), but you wouldn't feel any better than you normally feel.

 

[Solipsis]

@bandit: The question was not if you get relatively euphoric by removing the dysphoric drug from the equation, it's if you could actually get euphoric compared to your baseline because of actual tolerance mediated effects like downregulation, receptor decoupling, that kind of thing.

That drugs could make you dysphoric is also not the point, I myself meant that not that many appear to be pretty much reliably dysphoric or at least with the chance of it that kappa agonist salvinorin A appears to have. This question is clearly theoretical and hypothetical so never mind that people wouldn't likely make a habit out of taking thoroughly dysphoric drugs.

I for one would like to hear the view of people who know more about this than me and thus much more sure about it being possible if not typical.

Yes thanks ser2a, but is that because of antagonism vs agonism differences? What about agonistic effects leading to dysphoria?

 

[OrbitalCombustion]

When dealing with agonists-antagonists opioids you run into the compromise that the substance provides less analgesic effects but maintains a lower addictive potential. Typically these types of drugs induce psychotomimetic effects which produce the effects you mentioned (i.e. apathy, anhedonia, alogia, asociality, avolition). Even THC and other cannabinoids can produce this result. Mixed kappa receptor agonist mu receptor antagonist opioid analgesics can cause dose-related psychotomimesis, for instance.

Staying on course with opioids though, take into consideration competitive agonists such as Naloxone which will occupy the receptor site but not bind to it, essentially moving out any existing opioids (e.g. heroin, morphine). The resulting scenario at the receptors site is such that no newly introduced opiates can occupy the receptor and produce any desired effects by the given substance. Keep in mind though, if the dosage is ample enough, it can make an appearance and give the user the feeling he or she is looking for. You most often see this with heroin addicts who may have been dosed Suboxone or Subutex but want to get high before they disappear from the receptor. You also have opioid antagonists that are not pure antagonists, meaning they can have partial agonist effects like limited analgesia. Although, the partial agonist quality will cause symptoms such as dysphoria due to the binding at k-opioid receptor sites.

 

[Solipsis]

How can such an opioid antagonist eventually have 'positive' effects if its efficacy is lower than that of the endogenous ligand? Taking more would only cause more antagonist to bind but not activate, or if it activates with an efficacy lower than that of e.g. endorphin? Wouldn't the net effect always be negative compared to baseline?

Sure it's not the rebound effect they are looking for that I mentioned earlier for low dose naloxone where upregulation may make the endogenous ligands (endorphins etc) relatively effective, or I think you most probably mean a mixed agonist/antagonist like buprenorphin which apparently behaves differently depending on dose (does it not?), but it is still not a typical antagonist? Correct me if I'm wrong.

And yeah I'm still interested in KOR the more selective agonists don't really sound familiar to me and I am wondering what it may be like to withdraw from a KOR agonist regimen. Seems almost ironic to do this considering the anti-addictive qualities associated with the activity.

 

[OrbitalCombustion]

How can such an opioid antagonist eventually have 'positive' effects if its efficacy is lower than that of the endogenous ligand? Taking more would only cause more antagonist to bind but not activate, or if it activates with an efficacy lower than that of e.g. endorphin? Wouldn't the net effect always be negative compared to baseline?

Sure it's not the rebound effect they are looking for that I mentioned earlier for low dose naloxone where upregulation may make the endogenous ligands (endorphins etc) relatively effective, or I think you most probably mean a mixed agonist/antagonist like buprenorphin which apparently behaves differently depending on dose (does it not?), but it is still not a typical antagonist? Correct me if I'm wrong.

And yeah I'm still interested in KOR the more selective agonists don't really sound familiar to me and I am wondering what it may be like to withdraw from a KOR agonist regimen. Seems almost ironic to do this considering the anti-addictive qualities associated with the activity.

Solipsis,

Buprenorphine has many actions on many receptors, notably the DOR receptor where it functions to actually promote a drug reward. Technically, buprenorphine is a mixed partial agonist opioid receptor modulator. It operates on five different receptor types and each binding action is responsible for various effects both as an agonist, antagonist and partial agonist. For instance, it's impact on the sigma receptor is weak at best; this leaves room for variations in its properties and main method of action.

Might be of interest to you > http://jpet.aspetjournals.org/content/321/2/544

 

[serotonin2A]

Yes thanks ser2a, but is that because of antagonism vs agonism differences? What about agonistic effects leading to dysphoria?

One problem with this question is that it is phrased to emphasize the role of a subjective sensation (dysphoria) in the adaptation, as opposed to pharmacological processes such as receptor upregulation. The brain doesn't process pleasure and pain that way -- they are processed in different brain regions. The brain doesn't become tolerant to chronic dysphoria by activating regions that process pleasure/reward, but rather by inactivating regions that process dysphoria.

In terms of opioid receptor upregulation occurring in regions that process pleasure/reward, I doubt that MOR would ever be upregulated to the degree necessary to produce constitutive activation of those pathways.

 

[OrbitalCombustion]

One problem with this question is that it is phrased to emphasize the role of a subjective sensation (dysphoria) in the adaptation, as opposed to pharmacological processes such as receptor upregulation. The brain doesn't process pleasure and pain that way -- they are processed in different brain regions. The brain doesn't become tolerant to chronic dysphoria by activating regions that process pleasure/reward, but rather by inactivating regions that process dysphoria.

In terms of opioid receptor upregulation occurring in regions that process pleasure/reward, I doubt that MOR would ever be upregulated to the degree necessary to produce constitutive activation of those pathways.

Serotonin2A,

In the example of morphine for instance, it's activation of the u-opioid receptor does result in euphoria and analgesia, but the consistency in these effects is reduced as tolerance builds; so as you said, yes it is not a completely constitutive pathway for such processes. I found a research paper detailing the specifics involved in the specific neural networks and systems that handle hedonia/anhedonia. In many instances they share the same circuits, as is the case with the Nucleus Accumbens which is a central network affected particularly by cocaine abuse. In this location alone, both pleasure/reward and anhedonia/dysphoria occupy the same neurobiological region. As with the brain in general, even though functions and units of processing are divided amongst regions, they obviously work in parallel to achieve their designed function.

From paper's abstract: Pleasure is mediated by well-developed mesocorticolimbic circuitry, and serves adaptive functions. In affective disorders anhedonia (lack of pleasure) or dysphoria (negative affect) can result from breakdowns of that hedonic system. Human neuroimaging studies indicate that surprisingly similar circuitry is activated by quite diverse pleasures, suggesting a common neural currency shared by all. Wanting for rewards is generated by a large and distributed brain system. Liking, or pleasure itself, is generated by a smaller set of hedonic hotspots within limbic circuitry. Those hotspots also can be embedded in broader anatomical patterns of valence organization, such as in a keyboard pattern of nucleus accumbens generators for desire versus dread. In contrast, some of the best known textbook candidates for pleasure generators, including classic pleasure electrodes and the mesolimbic dopamine system, may not generate pleasure after all. These emerging insights into brain pleasure mechanisms may eventually facilitate better treatments for affective disorders.

 

[serotonin2A]

Serotonin2A,

In the example of morphine for instance, it's activation of the u-opioid receptor does result in euphoria and analgesia, but the consistency in these effects is reduced as tolerance builds; so as you said, yes it is not a completely constitutive pathway for such processes. I found a research paper detailing the specifics involved in the specific neural networks and systems that handle hedonia/anhedonia. In many instances they share the same circuits, as is the case with the Nucleus Accumbens which is a central network affected particularly by cocaine abuse. In this location alone, both pleasure/reward and anhedonia/dysphoria occupy the same neurobiological region. As with the brain in general, even though functions and units of processing are divided amongst regions, they obviously work in parallel to achieve their designed function.

From paper's abstract: Pleasure is mediated by well-developed mesocorticolimbic circuitry, and serves adaptive functions. In affective disorders anhedonia (lack of pleasure) or dysphoria (negative affect) can result from breakdowns of that hedonic system. Human neuroimaging studies indicate that surprisingly similar circuitry is activated by quite diverse pleasures, suggesting a common neural currency shared by all. Wanting for rewards is generated by a large and distributed brain system. Liking, or pleasure itself, is generated by a smaller set of hedonic hotspots within limbic circuitry. Those hotspots also can be embedded in broader anatomical patterns of valence organization, such as in a keyboard pattern of nucleus accumbens generators for desire versus dread. In contrast, some of the best known textbook candidates for pleasure generators, including classic pleasure electrodes and the mesolimbic dopamine system, may not generate pleasure after all. These emerging insights into brain pleasure mechanisms may eventually facilitate better treatments for affective disorders.

I wasn't really talking about the mesolimbic system, which seems to be primarily responsible for detecting salience, and not reward per se. That system is activated by both reinforcing stimuli and craving, so I don't think it is necessarily relevant to this discussion (it isn't the system responsible for pleasure or dysphoria). For pleasure , I was more thinking of regions like orbitofrontal cortex and PFC, whereas for dysphoria I was thinking of the central nucleus of the amygdala and the bed nucleus of the stria terminalis. Neither list is comprehensive. I'm sure there are regions that are activated by both types of stimuli, which makes sense because at some point it is necessary to re-combine these subjective signals to generate a unified interoceptive perception, but there is a great deal of evidence that the actual processing of pleasurable sensations and dysphoria occurs in discrete brain regions.

 

[Cotcha Yankinov]

It seems to me that part of what's really being talked about is where along the line does neural activity get translated into consciousness that results in dysphoria/euphoria.

I do wonder if it's really possible to single out a particular region or arbitrary circuit as giving rise to dysphoria/euphoria, even if it's circuitry upstream that processes that information and hands it to these downstream neurons that then actually give rise to the conscious feeling (I'm thinking insula, but I'm sure that lots of different neurons are all telling the insula what to do).

 

[serotonin2A]

It seems to me that part of what's really being talked about is where along the line does neural activity get translated into consciousness that results in dysphoria/euphoria.

I do wonder if it's really possible to single out a particular region or arbitrary circuit as giving rise to dysphoria/euphoria, even if it's circuitry upstream that processes that information and hands it to these downstream neurons that then actually give rise to the conscious feeling (I'm thinking insula, but I'm sure that lots of different neurons are all telling the insula what to do).

That is a good point. However, locating the subpopulations of mu receptors that produce euphoria and the kappa receptors that produce dysphoria will help point us in the right direction.

 

[Weltmeister]

The guy from vice who loves being a human guinea pig has tried this out and wirtten an article about it. I know the article isnt exactly scientific but its interesting nontheless.

https://www.vice.com/en_uk/article/new-frontiers-of-sobriety-984-v16n8

 

[Cotcha Yankinov]

That is a good point. However, locating the subpopulations of mu receptors that produce euphoria and the kappa receptors that produce dysphoria will help point us in the right direction.

So maybe one scenario is that even if the the relevant MOR/KOR are a synapse or two away from the location where these conscious really feeling arise, it can help us determine how the (i.e.) insula must operate in order to produce euphoria/dysphoria, or maybe it can be garnered that activity in the cells carrying that MOR/KOR signal to the insula is essential to the conscious feeling as well, and that the insula shouldn't be viewed in isolation.

In other words, it may not be sufficient to create an "artificial input" or otherwise modulate the insula to mirror that of how it usually operates when euphoria is present. If the inputs to the insula are participating in the conscious feeling as well, then the inputs would need to not only achieve the same end result of causing insula operation correlated with euphoria, but rather the artificial inputs would need to correlate closely enough with the "natural" inputs that cause euphoria.


Serotonin, it's been argued that consciousness does affect "Newtonian biology" because we are talking about consciousness right now, but I've come up with another piece of evidence that I'd like your opinion on.

There seems to be coherence between biological states that are conducive to reproduction and subjectively pleasant feelings, and vice versa.

While this system can still be hijacked by ie drugs of abuse, it seems to me that there must have been selection pressure exerted by consciousness in order for this coherence to have arisen naturally.. I hope this makes sense.. Any thoughts on how this selection pressure would have actually been exerted?

 

[Solipsis]

OK then let's back up to something like opioid withdrawal producing dysphoria or other such withdrawals. A good question seems to be how much dysphoria as part of the withdrawal process is not contingent on other things like anxiety ramping up?
Can we say that once the honeymoon for benzos or opioids or something heavy like that is over, there isn't euphoria anymore to shield the rough edges and it becomes a hard question how much intrinsic euphoria there even is that can be led back to some tolerance & withdrawal type neurological effect connected to the mechanisms that once produced euphoria? Do those mechanisms just lead to possibly faster - or not - withdrawals, independent of any subjective feeling about them?

Are regions like the insula important to understand the relativity between the 'going up' and the 'going down' because of basically comparative processes that may find their result there? What is meant by any input correlating closely to feeling of at least some well-being?

I was under the impression that it was dopamine mostly that is associated with the reward pathways corresponding to a number of survival and reproduction systems. For example feeding and having sex being heavily implicated. I don't know what consciousness has anything to do with all this whatsoever Cotcha, it appears to be an observer anyway lagging behind a few [hundred?] milliseconds after the real major decisions are made, but taking all the credit. Of course there are more mystical definitions of consciousness, but still I am talking about how fast a human can even react.

Isn't dysphoria or euphoria just rather a different sort of coherence, euphoria extending beyond rewards to reflect the positive state of self-being and dysphoria the reflection of a lack of all that triggering many sorts of anxious alarms right off the bat?

So if we go into that sort of territory, how good can we feel about a positive state of well-being just by virtue of reflecting on just not lacking reward sensations so terribly anymore and does this mean that there is nothing more to it than the reader snapping to euphoria (and it's associated reward correlates) after there has been chronic dysphoria (and it's associated reward correlates)?

To some extent that would mean the posts about the 'just feeling very well only because you're not feeling shitty anymore' have a lot of bearing.

Talking about first- and second-hand experience, MDMA hangovers can be quite manageable - or not - depending on just accepting the symptoms, which could mean a lot for the reference for measing well-being! For other things like alcohol for example, there may be a limit to the leeway for tolerating the objective withdrawal symptoms in terms of the subjective ones. If you are just too sick, it may be just a bit much to ask to not feel shitty?

 

[Cotcha Yankinov]

I don't know what consciousness has anything to do with all this whatsoever Cotcha, it appears to be an observer anyway lagging behind a few [hundred?] milliseconds after the real major decisions are made, but taking all the credit. Of course there are more mystical definitions of consciousness, but still I am talking about how fast a human can even react.

There is this notion of consciousness being like the steam coming out of a train, in the sense that consciousness is merely a byproduct and the steam itself doesn't actually drive the train forward.

The argument I've heard for consciousness having some effect is that we're talking about it right now, while my second piece of evidence may argue that the effect is a bit more significant.

I don't think its by accident that when you hurt yourself (not conducive to survival) it feels subjectively bad, and when you do something that is good for survival (food/sex) it feels good - I think there has been some selection pressure exerted here, and that may have required a certain strength of interaction between consciousness and "Newtonian biology", in order for there to be enough coherence between "bad" things happening to biology and the resulting bad feelings in consciousness and vice versa. In other words, I think its a two way street.

I honestly can't think of another way to rationalize the correlation between things that are bad for survival and bad feelings etc without resorting to some intelligent design or simulation theory argument.

 

[Coolwhip]

I don't think it'd necessarily be impossible, but it takes a long time and high doses for one to become dependent on a drug in order to experience dysphoric withdrawal in the first place. On top of that most drugs of pleasure are acting on many systems at once, either directly or downstream, and it'd be hard to replicate the opposite of that.

Just to become "dependent" on a dysphoric drug would be difficult, dangerous, and possibly damaging(excitotoxicity)

Some people might argue tryptamine trips can be dysphoric but leave an euphoric afterglow, some for salvia. I think the closest you could easily get to would be dopamine antagonists which are primarily selective for presynaptic receptors, which(depending on selectivity) wouldn't be all that dysphoric in the first place. Or administration of flumazenil to someone with a jacked up GABA system.

Now getting an anti-depressant effect after removal, or from low dose administration, of a "dysphoric" drug, that might be something worth thinking about.