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addictive potential of neuroactive steroids

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Neuroprotection

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Joined
Apr 18, 2015
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I have read many studies and articles showing that meuroactive steroids,particularly the gabaergic type don't produce tolerance to their powerful CNS depressant affects, in both animal and human neuronal cell lines. Some neuroactive steroids like ganaxalone are already available.
I want to get your opinions, suggestions and any experiences with neuro steroids.
Thanks
 
Moved from homeless - not quite sure if this is the correct forum but couldn't think of a more suitable place for discussion.
 
Sorry for the merry go round but SO is not for drug discussion.

Sending or to Steroid Discussion, while this is not exactly their typical fare the folks over there are most likely to have some knowledge about this...

....edit: aaaaand it's been moved yet again, now to ADD.
 
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I will have to look into this matter down the road more but it what one study seems to be suggesting is that ganaxolone probably still down regulates GABA receptors (because previous administration of ganaxolone reduces efficacy of benzos) but there is no tolerance/limited tolerance to the anti convulsant effects, this limited tolerance to specifically the anti convulsant effects might have to do with more it's action as a neurosteroid than its action as a GABA agonist. So I would say there might be withdrawal potential assuming it's GABA agonism and hence GABA down regulation outpaces its GABA neurosteroid effects, however if it's neurosteroid effects cause it to make new GABA cells/more GABA (which I don't know about, I'll have to read more sometime) at a rate that outpaces the decrease in gabaergic tone related to GABA downregulation then maybe withdrawals wouldn't be so bad. It depends on how strong it's GABA agonism effects are relative to its neurosteroid effects, and what it's neurosteroid effects are too. What's your interest in ganaxolone? By chance is it related to sleep?
 
Neurosteroids

Cotcha Yankinov said:
I will have to look into this matter down the road more but it what one study seems to be suggesting is that ganaxolone probably still down regulates GABA receptors (because previous administration of ganaxolone reduces efficacy of benzos) but there is no tolerance/limited tolerance to the anti convulsant effects, this limited tolerance to specifically the anti convulsant effects might have to do with more it's action as a neurosteroid than its action as a GABA agonist. So I would say there might be withdrawal potential assuming it's GABA agonism and hence GABA down regulation outpaces its GABA neurosteroid effects, however if it's neurosteroid effects cause it to make new GABA cells/more GABA (which I don't know about, I'll have to read more sometime) at a rate that outpaces the decrease in gabaergic tone related to GABA downregulation then maybe withdrawals wouldn't be so bad. It depends on how strong it's GABA agonism effects are relative to its neurosteroid effects, and what it's neurosteroid effects are too. What's your interest in ganaxolone? By chance is it related to sleep?
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I am fascinated by the prospect of a non addictive CNS Depressant. I have never used a psychoactive drug before in the depressant class, but I heard substances like methaqualone, clomathiazole, 2 methyl2butanol and barbiturates can be very fun when used recreationally. They can also act as brain protectant and anti depressant and antipsychotic compounds. However tolerance and dependence are the two main problems Standing in the way of wide spread and long turn use.
 
Neurosteroids

Cotcha Yankinov said:
I will have to look into this matter down the road more but it what one study seems to be suggesting is that ganaxolone probably still down regulates GABA receptors (because previous administration of ganaxolone reduces efficacy of benzos) but there is no tolerance/limited tolerance to the anti convulsant effects, this limited tolerance to specifically the anti convulsant effects might have to do with more it's action as a neurosteroid than its action as a GABA agonist. So I would say there might be withdrawal potential assuming it's GABA agonism and hence GABA down regulation outpaces its GABA neurosteroid effects, however if it's neurosteroid effects cause it to make new GABA cells/more GABA (which I don't know about, I'll have to read more sometime) at a rate that outpaces the decrease in gabaergic tone related to GABA downregulation then maybe withdrawals wouldn't be so bad. It depends on how strong it's GABA agonism effects are relative to its neurosteroid effects, and what it's neurosteroid effects are too. What's your interest in ganaxolone? By chance is it related to sleep?
Click to expand...
I am fascinated by the prospect of a non addictive CNS Depressant. I have never used a psychoactive drug before in the depressant class, but I heard substances like methaqualone, clomathiazole, 2 methyl2butanol and barbiturates can be very fun when used recreationally. They can also act as brain protectant and anti depressant and antipsychotic compounds. However tolerance and dependence are the two main problems Standing in the way of wide spread and long turn use.
 
I don't think there is much hope for using GABA agonists without dependence or tolerance, there might be other drugs whose mechanism of action is not GABA agonist related and more related to neurosteroids but I think ganaxolone's recreational potential is related to its GABA agonist qualities and not its neurosteroid properties. I wonder if sodium channel inhibitors like sodium valproate have much recreational potential, it has a slight GABA effect but mainly a sodium channel effect I think, and it doesn't sound like you can withdraw or grow too dependent on it (at least like you can with benzos). Though I'm thinking the dependence on valproate is more related to its GABA properties and not its sodium channel properties.

Sodium valproate is something of a neurosteroid, in the sense that it is neuro protective and releases a lot of neurotrophic factors like BDNF
 
For a long time, I was doubtfull that a non addictive gabaA against will be developed. However after further research, I found there is still hope: Nitric oxide synthase inhibitors particularly 7 nitro indizole and the antioxident melatonin have been shown to reverce benzodiazepine tolerance and prevent tolerance to the moter impairment affects of diazepam. Also, the fact that chloride channels are the main affector of the gabaA receptor means, that sobstances may be developed that directly modulate chloride channels, bypassing receptors and thus reducing the likelihood of adaptive responses by the body. An example of such a substance is bumetinide
 
I have not heard that valproate has anny recreational unfortunately. Wouldn't it be nice if our reward systems were like the stress/fear systems, abel to become hyperactive long after an associated event has passed. In that case we could of had a disease called post enjoyment uforia disorder, I am shor it will not require treatment haha
 
Neuroprotection said:
Also, the fact that chloride channels are the main affector of the gabaA receptor means, that sobstances may be developed that directly modulate chloride channels, bypassing receptors and thus reducing the likelihood of adaptive responses by the body. An example of such a substance is bumetinide
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The GABA-A receptor is part of the chloride channel -- they are not seperate entities. Ligands have already been developed that can directly modulate GABA-A chloride channels: barbiturates, ganaxolone, picrotoxin, etc..

Bumetanide doesn't actually work directly on GABA-A chloride channels, but modulates a chloride transporter.
 
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Thanks for clearing up those misconseptions for me. Do you think bumetanide or its analogs could prevent addiction to sedatives of the gabaAergic class?
 
Supposedly there isn't tolerance development to Lunesta, though I assume there is still slight withdrawals / rebound insomnia. The studies seem to point to his being the case, with rebound anxiety and such disappearing and resuming to normal levels after 3 days of placebo after using lunesta for 45 days straight at 3mg. It has been touted as a drug you can take for life. Maybe you gain tolerance at a slow enough rate to some substances that you can take them for life, and if they are not toxic then you can keep increasing the dosage for life as well. This doesn't exactly subvert the hedonic treadmill (homeostasis) though.

If someone manages to find a way to increase the firing of brain cells without some mechanism of homeostasis kicking in then they have found the holy grail. Alternatively find a way to grow new brain cells at an incredible rate so that you can always keep stimulating them with drugs that down regulate receptors (it won't matter if the receptors are down regulated if new nerve terminals pop up that have up regulated receptors??).

I am horribly deficient in this area concerning receptor homeostasis, I wish I knew whether or not there was a way you could signal a cell to up regulate its receptors (without using a antagonist/inverse agonist) or cause a cell to fire a lot without down regulating receptors...
 
Cotcha Yankinov said:
Supposedly there isn't tolerance development to Lunesta, though I assume there is still slight withdrawals / rebound insomnia. The studies seem to point to his being the case, with rebound anxiety and such disappearing and resuming to normal levels after 3 days of placebo after using lunesta for 45 days straight at 3mg.
It has been touted as a drug you can take for life. I used to think that too, but I have since red about many cases of users, mainly sufferes, have become addicted to the drug. Although, it must be said widrawal was much less prominent (no convulsions, paranoya or dangerously high blood pressure. However, a very strong craving still existed. Maybe you gain tolerance at a slow enough rate to some substances that you can take them for life, and if they are not toxic then you can keep increasing the dosage for life as well. This doesn't exactly subvert the hedonic treadmill (homeostasis) though.

If someone manages to find a way to increase the firing of brain cells without some mechanism of homeostasis kicking in then they have found the holy grail. Alternatively find a way to grow new brain cells at an incredible rate so that you can always keep stimulating them with drugs that down regulate receptors (it won't matter if the receptors are down regulated if new nerve terminals pop up that have up regulated receptors??).

I am horribly deficient in this area concerning receptor homeostasis, I wish I knew whether or not there was a way you could signal a cell to up regulate its receptors (without using a antagonist/inverse agonist) or cause a cell to fire a lot without down regulating receptors...
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I understand what your saying, but unfortunately it is not yet possible to grow new brain cells unless gambogic amide is proven safe and affective. It would probably solve the problem of methamphetamine addiction, and other addictions, not by replacing lost receptors, but by addressing the serious cognitive and emotional problems that prevent users from functioning normally in society, as well as push them back towards compulsive heavy drug use to escape the grim reality
Its very difficult currently to prevent receptor down regulation, but there have been significant advances made in the past year or so I think. For example, scavingers of superoxide, and more importantly peroxinitrite, prevent mu receptor down regulation induced by morphine Such free radicals also cause tolerance to benzodiazepines, and substances that block their formation or remove them block and reverce tolerance onset and maintenance.
It turns out, that although many cellular processes are involved in receptor down and upregulation, peroxinitrite is a major one, which not only causes temporary down regulation, but induces receptor and cellular damage. This actuly destroys the receptor rather than just desensatise it as other homeostatic mechanisms e.g. phosphorylation or beta aristin
 
Neuroprotection said:
It turns out, that although many cellular processes are involved in receptor down and upregulation, peroxinitrite is a major one, which not only causes temporary down regulation, but induces receptor and cellular damage. This actuly destroys the receptor rather than just desensatise it as other homeostatic mechanisms e.g. phosphorylation or beta aristin
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You are vastly overstating the importance of peroxynitrite. It isn't the major pathway of receptor desensitization/downregulation. Furthermore, describing what peroxynitrite dose as "destroying receptors" is not very accurate.
 
Hey Neuroprotection, I thought the receptor cycle was pretty smooth and that receptors get recycled a lot anyways right? I think it's Risperdal that binds 5HT7 "irreversibly" but irreversible isn't long because the receptor gets recycled

These scavengers of superoxide and peroxynitrite, they've been shown to reduce receptor downregulation? Got the study handy?

Take care :)
 
Cotcha Yankinov said:
Hey Neuroprotection, I thought the receptor cycle was pretty smooth and that receptors get recycled a lot anyways right? I think it's Risperdal that binds 5HT7 "irreversibly" but irreversible isn't long because the receptor gets recycled

These scavengers of superoxide and peroxynitrite, they've been shown to reduce receptor downregulation? Got the study handy?

Take care :)
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Sorry I can't post links due to my vision problem. However you can just try googling role of superoxide and free radicals in receptor down regulation. There was one article I was reading but unfortunately I can't seem to find it anymore. It stated that free radicals and oxidative stress drastically reduced the expression and numbers of Mu opioid receptors in almost all tissues in the body but particularly in neurons. It then stated that treatment with anti-oxidants drastically up regulated the number of receptors and also increased their sensitivity by many orders of magnitude. If this turns out to be true then potent new anti-oxidants targeted to neurons may be a promising treatment option for addiction.
 
This is what I would consider to be an example of cherry picking results to support a particular view. There are studies showing that peroxide INCREASES mu receptor expression in SH-SY5Y cells. MOR mRNA expression can be reduced by reactive oxygen species, but that is a completely different effect than neuroprotection is discussing.

http://www.ncbi.nlm.nih.gov/pubmed/21308796
http://www.ncbi.nlm.nih.gov/pubmed/21684020
http://www.ncbi.nlm.nih.govpubmed/25623851

There is evidence that peroxynitrite can modulate morphine analgesic potency, but the mechanism is complicated and probably involves NMDA receptors. It is a huge overstatement to say the peroxynitrite is a major factor regulating MOR or other GPCRs.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2714174
 
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"Morphine-induced ROS are generated in a concentration- and time-dependent manner and inhibited by naloxone" Is this reduction of ROS significant in nalaxone's mechanism of action as far as reducing rewards by decreasing MOR expression? I didn't know nalaxone was an anti-oxidant, but have heard about its use in auto immune disease and had wondered about its mechanism of action.
 
^Naloxone isn't an antioxidant. Receptor activation usually induces a plurality of downstream effects, some of which are linked to side-effects and not to the desired response. Mu receptor activation may have effects on ROS but that doesn't mean that those effects have anything to do with reward.

Many types of immune cells express MOR, DOR, and KOR (T-cells, B-cells, dendritic cells, macrophages, neutrophils, and microglia). Morphine modulates immune responses, both through direct effects on adaptive and innate immunity, and also through effects on the HPA axis.
 
Do you think that morphine would aggravate an auto immune disease (and hence opiates should be avoided for symptomatic relief in MS and such), while on the other hand opiate antagonists would help suppress the immune system?
 
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