85 replies to this topic

[ta5]

I wonder how many long-term users of Ashwagandha there are, and how often people experience tolerance or withdrawal. Tolerance and withdrawal should be common if Ashwagandha is a GABA receptor agonist.

[health_nutty]

I wonder how many long-term users of Ashwagandha there are, and how often people experience tolerance or withdrawal. Tolerance and withdrawal should be common if Ashwagandha is a GABA receptor agonist.

Ashwagandha is a GABA receptor agonist. The question is how strong is it really at the recommended dose.

[Orajel]

I've been taking it daily for about 3 weeks and havent noticed any tolerance

[SuperjackDid_]

When i take so long i have more anxiety then i drop just little come down.

Take on occasional when so much stress is best suit for me right now .

Good poll.
GABA receptor agonist might really weak , tolerances might come from something else like too much testosterone .

[nootrope]

I think the GABA tolerance is real, but that is only one mechanism by which ashwagandha governs mood. For me, what I can identify as GABA like effects only last a short time--a special feeling of calmness, sometimes an odd feeling of smelling something burning as I am waking up in the morning. But ashwagandha also modulates the HPA axis, particularly lowering cortisol, and this may cause its long-term calming effect. It can also restore neural outgrowths that have been damaged during periods of stress.

[ta5]

I wonder how many long-term users of Ashwagandha there are, and how often people experience tolerance or withdrawal. Tolerance and withdrawal should be common if Ashwagandha is a GABA receptor agonist.

Ashwagandha is a GABA receptor agonist. The question is how strong is it really at the recommended dose.

I actually don't care what the mode of action is as long as it avoids tolerance. If people are taking it long term and see continued benefits, that would be great. It's pretty clear that it's modulating GABA receptors somehow. If it's primarily a GABA receptor agonist and manages to avoid tolerance and withdrawal, it's curious. This study doesn't explain how, but suggests that it happens:

Indian' class='bbc_url' title='External link' rel='nofollow external'>http://pmid.us/full:21407960']Indian J Psychiatry. 2000 Jul;42(3):295-301.
A double-blind, placebo-controlled evaluation of the anxiolytic efficacy of an ethanolic extract of withania somnifera.
Andrade C, Aswath A, Chaturvedi SK, Srinivasa M, Raguram R.
Abstract
A double-blind, placebo-controlled study was conducted to evaluate the efficacy an ethanolic extract of Aswagandha (Withania somnifera), in patients with ICD-10 anxiety disorders. The sample comprised 39 subjects, of whom 20 received the drug and 19 received placebo. The two groups were sociodemographically and clinically similar at baseline. At 2 and 6 weeks follow-up, data from approximately 85% of patients in each group were available for analysis. Statistical trends favouring the drug were observed at both time points. At 6 weeks, significantly more patients met a priori response criteria in the drug group (88.2%) as compared with the placebo group (50%). The drug was well-tolerated and did not occasion more adverse effects than did placebo. It is concluded that this ethanolic extract of Withania somnifera has useful anxiolytic potential and merits further investigation.

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The full text adds:

Essentially, this study demonstrated a trend for the anxiolytic superiority of drug over placebo at week 2, and a statistically significant superiority at week 6. The advantage for Aswagandha was observed only with Hamilton Anxiety ratings, and with responder analyses, but not with global ratings; this may have bean because the latter had a narrower rating range, and were therefore less sensitive to clinical change. Aswagandha was well tolerated, with adverse effects being comparable to those observed with placebo. At 6 weeks, abrupt withdrawal did not appear to be associated with any withdrawal phenomena. Thus, Aswagandha appeared to have several of the advantages but none of the disadvantages of conventional anxiolytic drugs such as the benzodiazepines, the tricyclic antidepressants, and buspirone. This study therefore confirmed the preliminary observations of the unpublished open study of the experimental drug in patients with anxiety disorders (Manufacturer, data on file).

Benzodiazepines produce anxiolysis within days; antidepressant drugs and buspirone reduce anxiety in approximately a fortnight. Speed of response was regrettably not addressed in this study. However, it is likely that significant response will be obtained in most patients within the first fortnight of therapy itself, as Aswagandha was near-significantly superior to placebo at this time-point. Future studies need to address the magnitude of anxiolysis during the first week to ascertain the position of Aswagandha relative to conventional anxiolytic drugs.

What might be the mechanism of action of Aswagandha? As reviewed earlier, Aswagandha has been shown to have GABA- mimetic properties (Mehta et al.,1991; Kulkami et al.,1993); since GABA agonism has been linked to anxiolysis (Stah1,1998), it is conceivable that Aswagandha contains a constituent that alleviates anxiety by modulating GABA neurotransmission.

[Orajel]

Actually, benzodiazepines produce anxiolysis within an hour or so, or 5 minutes if taken sublingually. If ashwagandha mimics the effects prodcued by benzodiazepines, then it can be expected to act fairly quickly. I noticed an effect from a dose of 1.2 grams (extract) within an hour and a half the first time I took it.

Unfortunately, benzodiazepines are very addictive, and cessation can be fatal in some instances. So it is possible that ashwagandha could produce a similar type of dependence/tolerance, but at a much slower rate. Ashwagandha, afterall, is not nearly as effective as benzodiazepines. I'll try stopping ashwagandha abruptly after 2 months of use and let you all know what happens.

[health_nutty]

That is a very interesting study. I suspect being a GABA agonist is not Ashwagandha's primary mechanism of action.

[ta5]

I think the GABA tolerance is real, but that is only one mechanism by which ashwagandha governs mood. For me, what I can identify as GABA like effects only last a short time--a special feeling of calmness, sometimes an odd feeling of smelling something burning as I am waking up in the morning. But ashwagandha also modulates the HPA axis, particularly lowering cortisol, and this may cause its long-term calming effect. It can also restore neural outgrowths that have been damaged during periods of stress.

Interesting. So, maybe the studies that show it's modulating GABA are simply looking at the secondary effects of lowered cortisol.

Eur' class='bbc_url' title='External link' rel='nofollow external'>http://pmid.us/15588732']Eur J Pharmacol. 2004 Dec 15;506(2):129-32.
3alpha,5beta-Reduced cortisol exhibits antagonist properties on cerebral cortical GABA(A) receptors.
Penland SN, Morrow AL.
The tetrahydro-reduced derivatives of progesterone and deoxycorticosterone, allopregnanolone, and tetrahydrodeoxycorticosterone are potent positive modulators of GABA(A) receptors that are elevated by hypothalamic-pituitary-adrenal axis activation in rodents. In humans, 11-deoxycortisol and cortisol are important hypothalamic-pituitary-adrenal axis steroids. We hypothesized that C(3,5) reduction of 11-deoxycortisol and cortisol generates steroids with GABA(A) receptor activity. 3alpha,5beta-Reduced cortisol dose-dependently inhibited muscimol-stimulated chloride flux and tetrahydrodeoxycorticosterone potentiation of muscimol responses. Cortisol, 11-deoxycortisol, 5alpha-dihydrocortisol, 3alpha,5alpha-reduced cortisol, 3alpha,5alpha-reduced 11-deoxycortisol, and 3alpha,5beta-reduced 11-deoxycortisol had no activity at 1 muM and weaker negative modulatory activity at 10 muM. We conclude that cortisol metabolism may produce antagonistic GABAergic activity.

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In a more recent article from 2009 by the same author I quoted before:

At least three studies have examined the efficacy of ASW in anxiety disorders. In a preliminary investigation, the safety and efficacy of an ethanolic extract of ASW were examined in 50 patients with anxiety disorders. By the end of the first month of treatment, 36 patients showed moderate to excellent improvement at a dose of 1 g/day; in about half of these cases, these statistically significant benefits developed within the first 2 weeks, itself. These 36 patients were continued on ASW for up to 18 months, after which the medication was uneventfully withdrawn. ASW remained effective and was very well tolerated (data available from the author on request). [...]

Auddy et al. (2008) described a 2-month, double-blind, randomized controlled study which examined benefits with a standardized extract of ASW in 130 subjects who received a descriptive diagnosis of chronic stress in an Ayurvedic hospital. ASW was dosed at 125, 250, or 500 mg/day; a fourth group of patients received placebo. All doses of ASW attenuated modified HAM-A scores significantly more than did placebo at the 1-month follow-up; there was further improvement at the 2-month endpoint. The benefits with ASW appeared to be dose-dependent; placebo patients improved little. Furthermore, relative to placebo, ASW significantly lowered heart rate (by 6-8%), systolic blood pressure (by 2-3%), and diastolic blood pressure (by 5-6%); there were significant reductions in serum cortisol, fasting blood sugar, serum lipid, and C-reactive protein levels, as well.

[gamesguru]

I read recently a study concerning ashwagandha in the treatment of Alzheimer's (in mice) for which the dosage of one group was 1g/kg of extracts containing 75% withanolides and 25% withanosides (thanks sdxl for pointing this out: http://www.longecity...post__p__506143). That's a pretty potent extract. I did not see any profound mention of withdrawal-like symptoms in the paper, but of course, the researchers were not intending to comment on withdrawal.
A disturbing study linking ashwagandha to anti-masculine effects: http://www.asiaandro...-682X/4/295.htm.

There are numerous studies indicating that something in ashwagandha is probably linked to "GABA-mimetic" activity...basically a GABA agonist. We think this is bad since it probably downregulates GABA receptors, which probably induces anxiogenesis in the long-term. We can thank ScienceGuy for pointing out some of these studies concerning W. somnifera and GABA receptor affinity (which point out that something in ashwagandha has GABA affinity, but which do not prove whether these same constituents are the ones able to cross the BBB, particularly the withanolides and withanosides. if they don't interact with the brain, then it's another whole set of issues we have to worry about.): http://www.longecity...ly-effectively/, as well as the other posters who inquired about W. somnifera (ashwagandha).
Given that we don't really have an answer, I guess we can justify swapping anecdotes and making speculations for now.

I haven't noticed any major withdrawal symptoms despite running out and experiencing shipping delays. I was only taking 5-20 mg mixed withanolides daily though. That's basically nothing.

Edited by dasheenster, 16 March 2012 - 11:11 AM.

[ta5]

Given that we don't really have an answer, I guess we can justify swapping anecdotes and making speculations for now.

Hence this poll.

[Nooby]

I think it's BS! That ScienceGuy has a paranoid complex.

Ashwagandha is no where near the strength of other pharmaceutical GABA-A agonists. I have taken it for years and can stop at any time and all I notice is that life isn't as smooth as it is on the herb. I simply return to my baseline state and I am a naturally nervous individual. There is no brutal withdrawal. I notice.... Nothing.

I know what GABA (A+B) withdrawal is like because I have pretty much done the lot (addiction wise)... GBL, Phenibut and alcohol.

With ash, perhaps there is a little downregulation but it isn't even measurable for me. There are so many compounds in these herbs you can't just attribute it to being a bog standard GABA-A agonist and that's that.

Don't let scaremongers scare you off ashwagandha. It's a great herb in the right dosages (too much kills my personality, but just the right amount has been life enhancing for me).

Edited by Nooby, 21 March 2012 - 10:08 AM.

[Introspecta]

I agree with Nooby. I've taken Ashwagandha for period of 3-6 months straight and never had any withdrawals. If anything I could see if someone was taking for a whole year they may have minor anxiety when stopping but I don't agree that ashwagandha downregulates the gaba system. If anything it does slightly. Science went around this whole forum telling everyone to avoid taking them, then after I argues he said for only short to medium term use. What does short to medium use mean? That could be 1 month for some drugs, and 1 year for others. Pretty broad. All these herbs are pretty weak and very rarely does anyone get withdrawals. Tolerance on the other hand I have noticed with ashwagandha, valerian and theanine.

[ta5]

I agree with Nooby.

Yeah, I'm leaning that way myself.

All these herbs are pretty weak and very rarely does anyone get withdrawals.

Just one thought on this. Others have commented on them being weak too. Maybe. But, I don't think a very low-dose benzo would act like Ashwagandha, which would be case if it was simply a weak benzo. I think, or hope, it works in a different way, where GABA agonism is not it's main mode of action or its part of a more complicated action.

[Introspecta]

Yeah Its mechanism of action is different. Ash does alot of things. It affects Gaba and Acetylcholine that I know of. Maybe it doesn't even really bind to the receptors or it doesn't bind tight like benzos do. All I know is I've never gotten withdrawals and I've used it after phenibut withdrawals and it never made it worse.

[Deckah]

Tolerance on the other hand I have noticed with ashwagandha, valerian and theanine.

How often are you taking ashwagandha? Like how many off and how many on. Says you took for 3-6 mo.

Edited by Deckah, 22 March 2012 - 06:47 PM.

[Introspecta]

daily. Usually at night. I usually use for about 2-3 months but there were a few times I kept stock and took continously for about 6 months.

[Orajel]

ashwagandha makes me sleepy. But its great for anxiety :D

[X_Danny_X]

I use it for brain cognitive function. not for the GABA agonist part.

[Galaxyshock]

I took it for months, started to have rebound anxiety and ended up having to redose about every 5 hours. Then it started overstimulating my thyroid, I would have bad insomnia feeling like my whole body is burning and had dooming depression. It took 7 weeks to get fully back to normal. I would use ashwagandha very cautiously, it's powerful shit in higher doses.

When I combined ashwagandha, rhodiola and mucuna I felt like a superman. I would do 2-split weight lifting program two hour workouts 6 days a week and had no problem recovering and increasing weights.

[ScienceGuy]

I think it's BS! That ScienceGuy has a paranoid complex...

I do??? If that's the case then it's because those aliens who are out to get me implanted it!

Seriously though folks, I think there's some confusion with regards to what is my particular opinion on ASHWAGANDHA, and as such I should clarify matters.

As I have previously pointed out in some other threads there is no question that one of ASHWAGANDHA's mechanisms of action is that of GABA RECEPTOR AGONIST. To what extent (i.e. how strong is its affinity for the GABA RECEPTORS) is at this point in time unknown.

Does this mean that ASHWAGANDHA is the spawn of the Devil and should be avoided at all costs? No it doesn't.

Does ASHWAGANDHA have numerous positive and beneficial therapeutic effects? Yes, it most certainly does.

So what does the fact it is a GABA RECEPTOR AGONIST mean? It means that should you take it at high enough dosage for prolonged periods (i.e. the medium to long-term) without breaks, then to an extent it will induce down-regulation of the GABA RECEPTORS, which can lead to TOLERANCE (common) and WITHDRAWAL upon its cessation (uncommon).

This fact does not mean that you should not take it at all. What I have previously stated, which I will reiterate here, is that, because it is a GABA RECEPTOR AGONIST, it is recommended that you take regular breaks from its usage (i.e. CYCLE ON/OFF its usage) with a sufficent washout 'OFF' period such that the status of your GABA RECEPTORS is allowed to return to baseline.

By taking regular breaks (i.e. cycling its usage ON and OFF) you will prevent down-regulation of the GABA RECEPTORS from occuring and hence the possibility of TOLERANCE and/or WITHDRAWAL, whilst still being able to enjoy its many beneficial therapeutic effects.

Put simply, you should cycle it and not take it every day for months on end without a break.

Edited by ScienceGuy, 26 June 2012 - 08:16 PM.

[gamesguru]

A good question was raised to you a few months ago ScienceGuy, which you however declined to answer. You were asked what you thought the optimal cycle frequency was, or put another way, how long one should use ashwagandha/valerian/related compounds and how long one should abstain from them before going back. If you let everything return all the way back to the baseline, what's the point of even using the drug?

[ScienceGuy]

A good question was raised to you a few months ago ScienceGuy, which you however declined to answer. You were asked what you thought the optimal cycle frequency was, or put another way, how long one should use ashwagandha/valerian/related compounds and how long one should abstain from them before going back. If you let everything return all the way back to the baseline, what's the point of even using the drug?

Hi dasheenster,

Please kindly note that I have in fact been absent from this forum for several months, and as such I have not "declined to answer" anything. I did in fact post a message regarding my taking said break from this forum on my profile's about me page. I have always endeavoured in the past to answer everyone's questions and will do so moving forward to the best of my capacity within the spare time that I have available. However, I would ask that you be a little patient with me since having been absent for a while there is quite a lot of replying in a great many threads for me to catch up on... I will do my utmost to catch up on everything but it will likely take a bit of time, so I would ask that you be kind enough to be a little patient in this regard.

RE: "You were asked what you thought the optimal cycle frequency was, or put another way, how long one should use ashwagandha/valerian/related compounds and how long one should abstain from them before going back." - To answer this question, in short because the half-lives of the respective PHYTOCHEMICALS are unknown it is impossible for me to confirm what are the definitive durations of the 'OFF' periods. However, this is something that can easily be ascertained by those taking the particular "ashwagandha/valerian/related compounds" by monitoring TOLERANCE levels as your key indicator. I would suggest starting with a 5 DAYS ON, 2 DAYS OFF regimen, and simply see whether over time any manifestation of TOLERANCE occurs; if it does then simply increase the duration of the 'OFF' period by 1 DAY and then re-assess; and so on until requisite 'OFF' period duration is established that prevents development of TOLERANCE occurring. And by nailing TOLERANCE you also will prevent the possibility of WITHDRAWAL.

RE: " If you let everything return all the way back to the baseline, what's the point of even using the drug?" - OK, firstly, please kindly note that none of the substances we are talking about here are classified as DRUGS; these are all natural HERBAL EXTRACTS and hence SUPPLEMENTS. Secondly, please kindly note that I specifically stated to allow enough time for "status of GABA RECEPTORS to return to baseline"; and not "everything". Also, I think you may not have realised the potential brevity of the 'OFF' period duration; it is better to take regular SHORT breaks than to take for prolonged periods and then have to take several months off. By following an X number of days ON, followed by Y number of days OFF cycle protocol you can benefit from sustained therapeutic effects indefinitely.

I hope that clarifies matters for you. Anything else please don't hesitate to ask.

[gamesguru]

Well, it's been your choice to leave the forum for a bit. I won't cut you any slack for becoming a bit rusty during your hiatus.

Well let's take a compound we roughly know the half life of. I know you discourage cannabis use since you believe it is anxiogenic long-term, and I have my own reasons for discouraging it, but many claim it is an effective short-term anxiolytic. Given how long the half life is (anywhere from 2-48 hours), models predict a relaxation period of 2 weeks to 6 months. In the case of THC, there are a lot of effects to which a tolerance develops, including but not limited to an opioid-mediated dopamine release in the nucleus accumbens (euphoria), as well as the CB1-mediated relaxation of the amygdala & prefrontal cortex (relaxation). In the case of valerian or ashwagandha, we understand it even more poorly than cananbis, but I would like to know if you have any reasons in support of the belief that it only matters that the GABA system should return to baseline, and other neurotransmitters/cellular mechanisms don't deserve attention. I would also like to know from where you derive the estimated relxation period of 2 days. I think it takes about 2 weeks-2 months for tolerance in all its varieties to cannabis to develop, but as far as I can tell, valarien, ash, theanine, bacopa, magnesium, ginkgo, etc, they all develop tolerance within 3-20 days. So I'm also naturally curious why you suggest a stress/disturbance/trigger period of 5 days.

Also, I'm not sure how you can say there is no information about the half lives of these compounds (which you hate to call drugs, even though that's fundamentally what they are), when I so easily stumbled upon this:

Pharmacokinetics of valerenic acid after administration of valerian in healthy subjects

Abstract
Objectives: To describe the pharmacokinetics of valerenic acid in a group of healthy adults after a single oral dose of valerian using a newly developed sensitive assay for serum concentrations of valerenic acid, a commonly used marker for qualitative and quantitative analysis of valerian root and valerian products.

Study design: Six healthy adults (22–61 years, five men, one female) received a single 600 mg dose of valerian at 08:00. Blood samples were collected for 8 h after administration. Valerenic acid was extracted from serum and measured using a LC/MS/MS method developed in our laboratory.

Results: The maximum serum concentration of valerenic acid for five of the six subjects occurred between 1 and 2 h ranging from 0.9 to 2.3 ng/mL. Valerenic acid serum concentrations were measurable for at least 5 h after the valerian dose. One subject showed a peak plasma value at 1 h and a second peak at 5 h. The elimination half-life (T1/2) for valerenic acid was 1.1 ± 0.6 h. The area under the concentration time curve (AUC) as a measure of valerenic acid exposure was variable (4.80 ± 2.96 µg/mL. h) and not correlated with subject's age or weight.

Conclusions: Assuming that valerenic acid serum concentrations correlate with the pharmacological activity of valerian, the timing of the valerenic acid peak concentration is consistent with the standard dosage recommendation to take valerian 30 min to 2 h before bedtime. Ongoing studies are evaluating the relationship between valerenic acid serum concentrations and objective measures of sleep in patients.

Edited by dasheenster, 27 June 2012 - 03:23 PM.

[ScienceGuy]

Well let's take a compound we roughly know the half life of. I know you discourage cannabis use since you believe it is anxiogenic long-term...

Yes, but that's due to the THC; whereas PURE CANNABDIOL is a different matter entirely, and I encourage its medicinal use

I would like to know if you have any reasons in support of the belief that it only matters that the GABA system should return to baseline, and other neurotransmitters/cellular mechanisms don't deserve attention...

With regards to ASHWAGANDHA (which is the topic of this thread) the reason why it specifically matters that the GABA system should return to baseline, as opposed to other neurotransmitters/cellular mechanisms, is because ASHWAGANDHA's primary mechanism of action relating to its ANXIOLYTIC effect is specifically via AGONISM of the GABA RECEPTORS; and ASHWAGANDHA WITHDRAWAL occurs specifically as a consequence of down-regulation of the GABA RECEPTORS in the same way as BENZODIAZEPINE WITHDRAWAL occurs and that of all other GABA RECEPTOR AGONISTS, when taken for prolonged periods without breaks.

I would also like to know from where you derive the estimated relxation period of 2 days.... I'm also naturally curious why you suggest a stress/disturbance/trigger period of 5 days...

Please do not misunderstand my suggestion of starting with a 5 DAYS ON, 2 DAYS OFF regimen. I am NOT stating that this is the ideal 'ON' and 'OFF' duration.

Since the half-life of the respective PHYTOCHEMICAL(S) contained within ASHWAGANDHA are at the present time unknown there is no way of properly confirming what is the ideal 'ON' and 'OFF' duration. So, in the spirit of trying to be helpful, what I have suggested is a process by which you can ascertain an appropriate 'ON' and 'OFF' duration and regimen which will prevent the manifestation of TOLERANCE, and consequently WITHDRAWAL, from occurring; wherein the 5 DAYS ON, 2 DAYS OFF is the suggested starting duration; and should be adjusted according to how you respond. I.e. If you find yourself starting to experience some TOLERANCE you should extend the duration of the OFF period, and so on until you find the 'sweet spot' wherein TOLERANCE is prevented.

Please kindly note that this is a suggestion. You do not have to follow my advice.

Also, I'm not sure how you can say there is no information about the half lives of these compounds

With regards to ASHWAGANDHA (which is the topic of this thread), as I have stated above, unfortunately the half-life of the respective PHYTOCHEMICAL(S) contained within ASHWAGANDHA are indeed at the present time unknown.

(which you hate to call drugs, even though that's fundamentally what they are)

Erm... sorry, but no they are not. DRUGS are DRUGS, HERBAL EXTRACTS are HERBAL EXTRACTS.... by definition HERBAL EXTRACTS are not DRUGS... but hey, if you want to call APPLES 'ORANGES' go right ahead; it won't make it so.

And BTW I happen to advocate usage of both; and yet favour neither. I believe that the benefits and therapeutics usage of a particular substance should be measured according to its own merit and not according to its label

Edited by ScienceGuy, 27 June 2012 - 06:41 PM.

[gamesguru]

Yes, but that's due to the THC; whereas PURE CANNABDIOL is a different matter entirely, and I encourage its medicinal use

Seeing as CBD is overpriced, and it's nearly impossible to find cannabis high in CBD and low in THC, and seeing as we don't even totally understand CBD, I don't think many people take this suggestion of yours very seriously.

With regards to ASHWAGANDHA (which is the topic of this thread) the reason why it specifically matters that the GABA system should return to baseline, as opposed to other neurotransmitters/cellular mechanisms, is because ASHWAGANDHA's primary mechanism of action relating to its ANXIOLYTIC effect is specifically via AGONISM of the GABA RECEPTORS; and ASHWAGANDHA WITHDRAWAL occurs specifically as a consequence of down-regulation of the GABA RECEPTORS in the same way as BENZODIAZEPINE WITHDRAWAL occurs and that of all other GABA RECEPTOR AGONISTS, when taken for prolonged periods without breaks.

I was not aware that it had been demonstrated that ashwagandha's primary mechanism of action was exhibited via GABA receptor agonism. I was aware of a study showing that ash at least activates GABA-A receptors in a dose-dependent manner, but I found nothing confirming that this is the PRIMARY mechanism of action.

Please do not misunderstand my suggestion of starting with a 5 DAYS ON, 2 DAYS OFF regimen. I am NOT stating that this is the ideal 'ON' and 'OFF' duration.

Since the half-life of the respective PHYTOCHEMICAL(S) contained within ASHWAGANDHA are at the present time unknown there is no way of properly confirming what is the ideal 'ON' and 'OFF' duration. So, in the spirit of trying to be helpful, what I have suggested is a process by which you can ascertain an appropriate 'ON' and 'OFF' duration and regimen which will prevent the manifestation of TOLERANCE, and consequently WITHDRAWAL, from occurring; wherein the 5 DAYS ON, 2 DAYS OFF is the suggested starting duration; and should be adjusted according to how you respond. I.e. If you find yourself starting to experience some TOLERANCE you should extend the duration of the OFF period, and so on until you find the 'sweet spot' wherein TOLERANCE is prevented.

Please kindly note that this is a suggestion. You do not have to follow my advice.

Well, I suppose at least it's an honest guess. But to clarify, this criteria appears distinct from "letting GABA system return to baseline", since we might be able to avoid a profound tolerance while still not letting equilibrium return completely. Do you think if someone experiences rebound anxiety after discontinuing ashwagandha that it's an indicator of overuse/abuse?

With regards to ASHWAGANDHA (which is the topic of this thread), as I have stated above, unfortunately the half-life of the respective PHYTOCHEMICAL(S) contained within ASHWAGANDHA are indeed at the present time unknown.

We know the half-life of WFA in mice, at the least:

Withaferin A inhibits breast cancer invasion and metastasis at sub-cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation.

Abstract
Withaferin A (WFA) is purified from the plant Withania somnifera and inhibits the vimentin cytoskeleton. Vimentin overexpression in cancer correlates with metastatic disease, induction of epithelial to mesenchymal transition and reduced patient survival. As vimentin functions in cell motility, we wanted to test the hypothesis that WFA inhibits cancer metastasis by disrupting vimentin function. These data showed that WFA had weak cytotoxic and apoptotic activity at concentrations less than or equal to 500 nM, but retained potent anti-invasive activity at these low doses. Imaging of breast cancer cell lines revealed that WFA induces perinuclear vimentin accumulation followed by rapid vimentin depolymerization. A concomitant induction of vimentin ser56 phosphorylation was observed, which is consistent with vimentin disassembly. Structure activity relationships were established using a set of chemically modified WFA analogs and showed that the predicted vimentin-binding region of WFA is necessary to induce vimentin ser56 phosphorylation and for its anti-invasive activity. Pharmacokinetic studies in mice revealed that WFA reaches peak concentrations up to 2 μM in plasma with a half-life of 1.36 hr following a single 4 mg/kg dose. In a breast cancer metastasis mouse model, WFA showed dose-dependent inhibition of metastatic lung nodules and induced vimentin ser56 phosphorylation, with minimal toxicity to lung tissue. Based upon these studies, we conclude that WFA is a potent breast cancer anti-metastatic agent and the anti-metastatic activity of WFA is, at least in part, mediated through its effects on vimentin and vimentin ser56 phosphorylation.

Erm... sorry, but no they are not. DRUGS are DRUGS, HERBAL EXTRACTS are HERBAL EXTRACTS.... by definition HERBAL EXTRACTS are not DRUGS... but hey, if you want to call APPLES 'ORANGES' go right ahead; it won't make it so.

And BTW I happen to advocate usage of both; and yet favour neither. I believe that the benefits and therapeutics usage of a particular substance should be measured according to its own merit and not according to its label

I don't care too much to go into intricate details, but herbal extracts are nothing but collections of many naturally occurring drugs,having a few drugs highly concentrated through extraction/distillation. That's right, I label fructose as a drug, just as artificially produced drugs. Of course, I don't judge its merit based on its label, that I judge based on its apparent efficacy.

[ScienceGuy]

Yes, but that's due to the THC; whereas PURE CANNABDIOL is a different matter entirely, and I encourage its medicinal use

Seeing as CBD is overpriced, and it's nearly impossible to find cannabis high in CBD and low in THC, and seeing as we don't even totally understand CBD, I don't think many people take this suggestion of yours very seriously.

What suggestion??? Please kindly note that it is in fact you who brought up the subject of CANNABIS, not I...

I was not aware that it had been demonstrated that ashwagandha's primary mechanism of action was exhibited via GABA receptor agonism. I was aware of a study showing that ash at least activates GABA-A receptors in a dose-dependent manner, but I found nothing confirming that this is the PRIMARY mechanism of action.

OK, not a problem; here's some published studies for you which indicate ASHWAGANDHA's primary mechanism of action relating to its ANXIOLYTIC effect is specifically via AGONISM of the GABA RECEPTORS (and as it happens not just GABA-A):

Environmental Health Perspectives * Volume 107, Number 10, October 1999

Ancient-Modern Concordance in Ayurvedic Plants: Some Examples

Sukh Dev

Source

University of Delhi, B.R.A. Centre for Biomedical Research, Delhi, India

EXTRACT FROM FULL TEXT:

Ashwagandha (root) is another important antiaging plant. We have investigated this plant in some detail because its extract showed high affinity for both GABAA and GABAB receptors. Receptor-binding assay-guided fractionation of the crude methanol extract resulted in a butanol fraction with retention of GABAB receptor activity [concentration that inhibits 50% (IC50) - 47 pg/mL] and an aqueous fraction that retained both GABAA (IC50 - 0.37 pg/mL) and GABAB (IC50 - 15.8 pg/mL) affinities.

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Phytother Res. 2010 Aug;24(8):1147-50.

The methanolic extract of Withania somnifera ACTS on GABAA receptors in gonadotropin releasing hormone (GnRH) neurons in mice.

Bhattarai JP, Ah Park S, Han SK.

Source
Department of Oral Physiology and BK21 program, School of Dentistry and Institute of Oral Bioscience, Chonbuk National University, Jeonju, 561-756, Republic of Korea.

Abstract
The effect of the methanol extract of Withania somnifera (mWS) on the gonadotropin releasing hormone (GnRH) neuron was examined in juvenile mice using the whole cell patch clamp technique. GnRH neurons are the fundamental regulators of the pulsatile release of GnRH needed for puberty and fertility. GnRH neurons were depolarized by bath application of the mWS (400 ng/microl) under the condition of a high Cl(-) pipette solution in current clamp mode. In voltage clamp mode, mWS induced reproducible inward currents (31.7 +/- 5.51 pA, n = 14). The mWS-induced inward currents persisted in the presence of tetrodotoxin (TTX, 0.5 microM), but were suppressed by bicuculline methiodide (BMI, 20 microM), a GABA(A) receptor antagonist. These results show that mWS affects the neuronal activities by mediating the GABA(A) receptor, which suggests that WS contains an ingredient with possible GABAmimetic activity.

Copyright © 2009 John Wiley & Sons, Ltd

PMID: 20044800

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Indian J Exp Biol. 2008 Jun;46(6):465-9.

Effect of Withania somnifera Dunal root extract against pentylenetetrazol seizure threshold in mice: possible involvement of GABAergic system.

Kulkarni SK, Akula KK, Dhir A.

Source
Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160 014, India. skpu@yahoo.com

Abstract
Withania somnifera (ashwagandha) is a widely used herb in the Ayurvedic system of medicine. The objective of the present study was to elucidate the effect of W. somnifera root extract (Ws) alone or in combination with exogenous gamma-amino butyric acid (GABA), a GABA receptor agonist or with diazepam, a GABA receptor modulator against pentylenetetrazol (PTZ, iv) seizure threshold in mice. Minimal dose of PTZ (iv, mg/kg) needed to induce different phases (myoclonic jerks, generalized clonus and tonic extension) of convulsions were recorded as an index of seizure threshold. Ws (100 or 200 mg/kg, po) increased the PTZ seizure threshold for the onset of tonic extension phase whereas a lower dose (50 mg/kg, po) did not show any effect on the seizure threshold. Co-administration of a sub-effective dose of Ws (50 mg/kg, po) with a sub-protective dose of either GABA (25 mg/kg, ip) or diazepam (0.5 mg/kg, ip) increased the seizure threshold. The results suggested that the anticonvulsant effect of W. somnifera against PTZ seizure threshold paradigm involved the GABAAergic modulation.

PMID: 18697606

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Indian J Med Res. 1991 Aug;94:312-5.

Pharmacological effects of Withania somnifera root extract on GABAA receptor complex.

Mehta AK, Binkley P, Gandhi SS, Ticku MK

Source
Department of Pharmacology, University of Texas Health Science Center.

Abstract
A methanolic extract of W. somnifera root inhibited the specific binding of [3H]GABA and [35S]TBPS, and enhanced the binding of [3H]flunitrazepam to their putative receptor sites. The extract (5 micrograms) inhibited [3H]GABA binding by 20 +/- 6 per cent whereas a concentration of 1 mg of the extract produced 100 per cent inhibition. The extract (5-100 micrograms) produced 20 +/- 4 to 91 +/- 16 per cent enhancement of [3H]flunitrazepam binding. In functional studies using 36Cl-influx assay in mammalian spinal cord neurons, W. somnifera root extract increased 36Cl-influx in the absence of GABA. This effect on 36Cl-influx was blocked by bicuculline and picrotoxin; and enhanced by diazepam. These results suggest that the W. somnifera extract contains an ingredient which has a GABA-mimetic activity.

Do you think if someone experiences rebound anxiety after discontinuing ashwagandha that it's an indicator of overuse/abuse?

Yes.

We know the half-life of WFA in mice, at the least...

Yes, however unfortunately that is not especially useful when it comes to HUMANS

...herbal extracts are nothing but collections of many naturally occurring drugs...

I know where you are coming from with regards to viewing matters that way; however, you are not correct in referring to herbal extracts as drugs, and furthermore there are very serious potential ramifications for doing so that might cause you to re-think your perspective.

Firstly, take WHITE WILLOW BARK for example; this is not a drug. However, ASPIRIN is. Another example is EPHEDRA; this also is not a drug. However, EPHEDRINE is. Do you understand the difference?

Secondly, all drugs must have a medicinal license; they cannot legally be sold without one. Whereas, herbal extracts are classified as supplements and do not require a medicinal license to be sold. If herbal extracts are classified as drugs then they would require a medicinal license to be sold, wherein due to the cost involved essentially this would mean an end to legal resale of most herbal extracts... is that what you want to happen? Assuming that you do not, I strongly urge you to re-think your perspective on whether or not herbal extracts are drugs.

That's right, I label fructose as a drug, just as artificially produced drugs.

FRUCTOSE by definition is not a drug either; and it's a bad example anyway, because the vast majority of FRUCTOSE is in fact "artificially produced"

You need to read the following:

Definition of DRUG

1 a : a substance used as a medication or in the preparation of medication

b: according to the Food, Drug, and Cosmetic Act (1) : a substance recognized in an official pharmacopoeia or formulary (2) : a substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease (3) : a substance other than food intended to affect the structure or function of the body (4) : a substance intended for use as a component of a medicine but not a device or a component, part, or accessory of a device

Of course, I don't judge its merit based on its label, that I judge based on its apparent efficacy.

Good to hear! There's too many people who pay too much attention to a substance's classification as opposed to its actual PHYSIOLOGICAL / PHARMACOLOGICAL effects

Edited by ScienceGuy, 28 June 2012 - 04:00 PM.

[gamesguru]

What suggestion??? Please kindly note that it is in fact you who brought up the subject of CANNABIS, not I...

It is true I brought up cannabis in the context of half-life, but I made no such recommendation to encourage (or discourage) the use of CBD, and/or CBD-rich and THC-less strains. I have chosen to remain mute, as I do not think the pharmacology is conclusive enough to provide practical and sound advise to those seeking a rush from drugs. Even though of all cannabinoids, CBD presently appears to me to have the greatest potential, I still think it suffers an undesirable profile of effects, which ultimately renders it unsafe and ineffective for any medical purposes. It acts as an agonist to 5-HT1A receptors (antidepressant, kind of like shrooms, which are thought to mediate their most pronounced effects through 5-HT2A agonism). It also allosterically modulates mu- and delta-opioid receptors (http://www.ncbi.nlm....pubmed/16489449). There is also a cytotoxic mechanism to CBD (http://www.ncbi.nlm....pubmed/20645411), which we have barely noticed, let alone realize or grasp or understand. These unfavorable aspects might balance out with the "anti-psychosis, anxiolytic, anti-depersonalization" effects which many people think CBD offers; see this study how it improves and worsens ketamine inducted psychopathology (http://www.ncbi.nlm....pubmed/21062637). There's no telling how these mechanisms would exhibit themselves in a long-term clinical setting, but my intuition says steer clear.

OK, not a problem; here's some published studies for you which indicate ASHWAGANDHA's primary mechanism of action relating to its ANXIOLYTIC effect is specifically via AGONISM of the GABA RECEPTORS (and as it happens not just GABA-A):

These do not prove it is its primary mechanism, through which it mediates the vast majority of its effects. It merely suffices to prove it is a mechanism, perhaps secondary or even tertiary. Even though ashwagandha was associated with reduced tribulin (http://www.ncbi.nlm....pubmed/11194174), that still doesn't vindicate your claim. I could just as easily say that caffeine is associated with increased dopamine, and therefore all its subtle improvements conferred to ADHD patients is due to its pro-dopaminergic activity. You can't predict how a drug is affecting the body just based on how it influences one factor...unless that factor reveals an exceptional amount of information about the biological state...which most factors don't So unless you've based your judgement on papers you're concealing from me, it seems to me that parading around these forums, dogmatically contending ashwagandha is primarily a GABAergic is therefore dishonest, premature, and perhaps misleading. You may derive pleasure from misinforming and corrupting people, but this kind of practice is discordant with my desire for humanity to flourish, and I shall therefore attempt to avoid it.

Yes, however unfortunately that is not especially useful when it comes to HUMANS

While we cannot make a very accurate or precise prediction, pharmacology tells us the half life in humans is usually longer, or the half-life multiplier in translating from mice to human metabolism is usually greater than one, since the rate of excretion of metabolites per unit of body weight tends to become greater as the animal becomes smaller, and vice versa. In accordance with this principle, I might guess that ashwagandha has a half-life between 2-6 hours, though this is admittedly just a guess, and not even a very good one. I should not wish to issue this as a suggestion, but seeing as you're willing to issue suggestions, I'd like to know how your suggestion of 5/2 days would change if the half-life were to change. Supposing the half-life were actually half or double what you presently suppose it is, how would that affect your 5/2 recommendation at all? For something like cannabis, someone seeking an intermediate between complete addiction and complete abstinence might use it nightly for a week, then abstain for 3 days and nights before resuming. This 10 day cycle means ashwagandha must also have a long half life, as 5+2=7 is not much less than 10, or there must be highly nonlinear relationships between the half life and the ideal relaxation frequency/duration, such that a compound with a half life of 1/2 hour ought to be used for 4 days on then 1 day off, while a compound with a 2 hour half life ought to be used 5 days on 2 off, and a compound with a half life of 8 hours ought to be used 7 days on 3 days off. I think you get what I mean by nonlinear. As there is little research on this subject, my recommendations should be taken as a grain of salt, not some immutable truth; there is still much thinking needed to be done before we are to know the answers to these questions with regard to what constitutes ideal cycling.

I know where you are coming from with regards to viewing matters that way; however, you are not correct in referring to herbal extracts as drugs, and furthermore there are very serious potential ramifications for doing so that might cause you to re-think your perspective.

Firstly, take WHITE WILLOW BARK for example; this is not a drug. However, ASPIRIN is. Another example is EPHEDRA; this also is not a drug. However, EPHEDRINE is. Do you understand the difference?

Secondly, all drugs must have a medicinal license; they cannot legally be sold without one. Whereas, herbal extracts are classified as supplements and do not require a medicinal license to be sold. If herbal extracts are classified as drugs then they would require a medicinal license to be sold, wherein due to the cost involved essentially this would mean an end to legal resale of most herbal extracts... is that what you want to happen? Assuming that you do not, I strongly urge you to re-think your perspective on whether or not herbal extracts are drugs.

FRUCTOSE by definition is not a drug either; and it's a bad example anyway, because the vast majority of FRUCTOSE is in fact "artificially produced"

You need to read the following:

Definition of DRUG

1 a : a substance used as a medication or in the preparation of medication

b: according to the Food, Drug, and Cosmetic Act (1) : a substance recognized in an official pharmacopoeia or formulary (2) : a substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease (3) : a substance other than food intended to affect the structure or function of the body (4) : a substance intended for use as a component of a medicine but not a device or a component, part, or accessory of a device

Depending on the connotation and context, a drug could be anything from a man-made chemical to a psychoactive constituent of a plant. Oxford has this: "A substance that has a physiological effect when ingested or otherwise introduced into the body, in particular." So by this definition, fructose is a drug, so is cellulose, and so is every compound, which, in connexion, constitute the totality of the plant. The plant is nothing but a set of chemicals, so too is the extract of the plant. Strictly speaking, it's an error to say a plant is a drug, but depending on how you frame the meaning of "drug", it could be correct to say all plants are just bunches of drugs, mild to potent, physical or psychoactive, but nevertheless drugs which humans could theoretically produce in the lab, in isolation, and which would theoretically have the same effect, excusing any interactions which occur in the plant.

Good to hear! There's too many people who pay too much attention to a substance's classification as opposed to its actual PHYSIOLOGICAL / PHARMACOLOGICAL effects

I suppose only dwelling in idiot circles would accustom oneself to believing there are disproportionately more people who hold ridiculous opinions than who hold reasonable ones. The most common example I can think of is the stereotypical hippy who habitually argues that weed is harmless on the grounds that it is a plant. Well sure, hemlock too is a plant, and a lethal one, as Socrates can attest to. There're also people who say weed is a drug, since it contains THC, and is therefore bad. Well, there are drugs that are harmless too, though I don't consider THC to be one of them.

Edited by dasheenster, 28 June 2012 - 08:12 PM.

[ScienceGuy]

...it seems to me that parading around these forums, dogmatically contending ashwagandha is primarily a GABAergic is therefore dishonest, premature, and perhaps misleading. You may derive pleasure from misinforming and corrupting people, but this kind of practice is discordant...

I suppose only dwelling in idiot circles would accustom oneself to believing there are disproportionately more people who hold ridiculous opinions than who hold reasonable ones...

You will learn that insulting someone does not motivate them to spend their valuable time replying to you.

Sadly, for reasons unknown, it is abundently clear that you are simply seeking to pick a fight with me via use of antagonism and taunts; which is a shame because you have raised a couple of interesting points; wrong, but interesting none the less. Furthermore, I would have enjoyed intelligently debating with you. So let's just agree to disagree shall we? You can keep calling FRUCTOSE a DRUG if you like; I won't try to convince you otherwise... Just don't be surprised after you ask your doctor to prescribe it for you when he books you in for a PSYCH CONSULT

Edited by ScienceGuy, 28 June 2012 - 08:35 PM.

[gamesguru]

There's more to it than just a dirty fight of insulting criticisms, since I'm being as sympathetic as critical. I guess you don't have answers to my questions, and you're only seeing what you want to see. Even if you take my insightful questions back to your friends and do all you can to follow them to their logical conclusion, being sure not to grace me with whatever insights you come upon, keeping them close to your chest out of a hostility, I am still sure I shall win in the sense of being more knowledgeable and less dogmatic, for if your habits continue, you will surely learn slowly. If you want to run away from my questions and justify such behavior by labeling me as "rude, uncongenial, etc", that is your choice, and indeed many people run away from such debates, yet I will not respect such a one as you who flees good debates because they become provocative and challenging. I should probably ask these questions to someone more knowledgeable and open-minded than yourself if I hope to achieve good results, as it seems you come on these forums primarily for attention, not to pass on knowledge to your fellow inquirer. The drug debate was boring, and you are completely wrong, so too are the doctors; all chemicals are drugs irrespective of whether or not they occur in plants or are synthesized in a lab. The intelligent part in my opinion was related to ashwagandha and half life and cycling, to which you supplied every dogmatic answer in your arsenal. Good luck to your in your dogmatic adventures. See, I'm not the only one who can fight fire with fire if I want =P. I am working on becoming more congenial, but given my childhood, it is very difficult to be more sympathetic than critical. Read through my posts...you'll see I'm an asshole struggling to be nice. If you don't wish to sympathize with me on this point, I won't make any additional effort to try to win your loyalty, and I' content for you to see me as how you do.

Edited by dasheenster, 29 June 2012 - 02:59 PM.