35 replies to this topic

[StevesPetMacaque]

Corticotropin releasing hormone (CRH) is the first step in a cascade leading to cortisol secretion (CRH --> ACTH --> cortisol). Many of the horrible biological and psychological effects of stress are actually due to CRH rather than cortisol itself, as CRH receptors also lie throughout the body, in particular causing mast cells to degranulate, causing worse allergic and inflammatory reactions in response to stress.

 

It turns out that CRH receptor antagonists have recently been developed. In particular, Antalarmin shows potential as an agent to blunt both the cognitive/emotional and inflammatory effects of stress.

 

Is anyone else interested in performing research involving this compound?

[kurdishfella]

oh wow, someone else interested in these as well, didn't think I would ever come across anyone else. Yes, I am very interested in them, I have asked various sites that sell nootropics to sell them. You can request compounds on some websites. Getting them from sites like https://www.axonmedc...om/product/1321 is expensive. I guess you could try get them from alibaba but don't know how expensive and if you can trust the quality or the product(cant find any on that site though). Antlarmin is a CRHR1 antagonist, it's not CRH you wanna focus on but what it binds to which is CRHR1 and CRHR2 receptors. Because even if you decreased the amount of CRH levels, but had high levels of CRHR1 protein, you would still have the same amount crhr1 receptors listening to CRH. Blocking crhr1 shows a blunted stress response.

 

valproic acid and lithium carbonate decrease crhr1 https://www.ncbi.nlm...pubmed/12606697

 

and it has been found that LMO3 gene regulates CRHR1 levels specifically in the basal amygdala https://www.ncbi.nlm...pubmed/29609111 and I think valproate might decrease LMO3 https://www.ncbi.nlm...pubmed/27188386

 

I have tried requesting sites like https://cosmicnootro...on-your-request and https://reachgenius.se/en/contact-us to sell crf1/crhr1 antagonist to no success, I guess if many people asked them it could work.

 

Also Olanzapine/zyprexa is calming for me, I find out it blocks crh release in the hippocampus https://www.ncbi.nlm...pubmed/19467289

Edited by farshad, 01 October 2019 - 09:28 AM.

[StevesPetMacaque]

I'll take at least one positive response as a success. There are a number of compounds besides this I'd be interested in having synthesized (currently the list includes CRHR1/2 antagonists, TLR4 antagonists, KOR antagonists, 5HT2B/C reverse agonists or antagonists, and Sonic Hedgehog agonists), and I finally have access to the capital to lead a group buy, so a lead on a reliable lab would work, too.

 

You are right to characterize Antalarmin as a CRHR1 receptor antagonist. At first glance I wasn't sure, because of all its peripheral effects, but they do all seem to be mediated by the same receptor type.

[BrankLucas]

Where do you guys do group buys? Are all of the people doing group buys affiliated with some sort of research institution to get access to biotech company sales or?

[StevesPetMacaque]

Need to find a commercial lab willing to do synthesis. I do not have such a connection but will be trying to find one. So far bothering people who have already run group buys isn't working.

[totflare]

Is this similar to mifepristone in that could it help reset the HPA axis?

[StevesPetMacaque]

Is this similar to mifepristone in that could it help reset the HPA axis?

 

I don't know for sure. If I had to make an educated guess, I would say probably not. Blocking CRHR1 will lower cortisol downstream, though chronic antagonism might lead to upregulation of the receptor in the long term. On the other hand, from what I understand, taking mifepristone "jolts" the body into increasing its endogenous cortisol production. Basically, Antalarmin would be useful in the early stages of an HPA crisis, to prevent the crash, rather than to reverse one that has already occurred.

 

But of course, how these things work in practice is very rarely as simple as this. Dysfunction seems to be a far more subtle story of disregulation, desensitization, and disturbed homeostasis, rather than substance X or Y is low or high.

Edited by StevesPetMacaque, 04 October 2019 - 05:21 PM.

[kurdishfella]

Can anyone figure out what the equivalent dosage for antalarmin would be for humans? 

 

this study says ''. Pharmacokinetic and dose-response studies suggested that an oral dose of 20 mg/kg was optimal for behavioral and endocrine effects.'' in primates 

https://www.ncbi.nlm...icles/PMC18561/

 

Does Primates include apes, monkeys and Humans? If yes, that would be like 2000mg a day for me because i am around 85kg. And the half life is 7.8 hours of the drug, so perhaps you need to dose twice separate times a day? Do you take the half the drug so 1000mg then the rest 1000mg later or do you take 2000mg twice which would be 4000mg a day to keep a steady level of it in your blood?

Would it be perhaps better to look for an alternative crhr1 antagonist that you need less of a dosage (so it wont be so expensive) and has longer half life so to last all day and less dose needed to save on $$?

Edited by farshad, 07 October 2019 - 01:41 PM.

[StevesPetMacaque]

 

Can anyone figure out what the equivalent dosage for antalarmin would be for humans? 

 

this study says ''. Pharmacokinetic and dose-response studies suggested that an oral dose of 20 mg/kg was optimal for behavioral and endocrine effects.'' in primates 

https://www.ncbi.nlm...icles/PMC18561/

 

Does Primates include apes, monkeys and Humans? If yes, that would be like 2000mg a day for me because i am around 85kg. And the half life is 7.8 hours of the drug, so perhaps you need to dose twice separate times a day? Do you take the half the drug so 1000mg then the rest 1000mg later or do you take 2000mg twice which would be 4000mg a day to keep a steady level of it in your blood?

Would it be perhaps better to look for an alternative crhr1 antagonist that you need less of a dosage (so it wont be so expensive) and has longer half life so to last all day and less dose needed to save on $$?

 

 

Looks like they used rhesus monkeys and macaques (    ) for this experiment. Based on the attached table, reflecting species differences in dosage per body weight, we could expect a conversion factor of up to 6 between these primates and humans. If we had, say, a 4x conversion, a dose of 5 mg/kg would be a lot more doable.

 

All this is academic speculation, still; I am not sure how long it will take to find a lab.

Attached Files

•  Conversion-of-animal-doses-to-human-equivalent-doses-HEDs-by-using-the-exponent-067.png   15.39KB   0 downloads

[gizmobrain]

I am very interested in this topic.
 
I have a relative who has chronic overactivation of the HPA-axis. Every minor stressor is amped up to 10.
 
Along with a few other things that would skew them towards overactivation, they have 2 rare mutations in their CRHR1 snp's

 

rs1876828 TT 2%

rs16940674 TT 2%

 
I noticed that a product containing Astressin-B had been produced and brought to market (https://dslaboratori...fficacy-booster) as a topical hair improvement product of all things. Good to see their is still active movement in the space, but I'm far more interested in getting to the bottom of the stress, irratibility, and low blood pressure that is zapping their life away.

Edited by gizmobrain, 13 October 2019 - 04:36 PM.

[kurdishfella]

I am very interested in this topic.
 
I have a relative who has chronic overactivation of the HPA-axis. Every minor stressor is amped up to 10.
 
Along with a few other things that would skew them towards overactivation, they have 2 rare mutations in their CRHR1 snp's

 

rs1876828 TT 2%

rs16940674 TT 2%

 
I noticed that a product containing Astressin-B had been produced and brought to market (https://dslaboratori...fficacy-booster) as a topical hair improvement product of all things. Good to see their is still active movement in the space, but I'm far more interested in getting to the bottom of the stress, irratibility, and low blood pressure that is zapping their life away.

Isn't Astressin B a peptide and those have to be injected to work? 

I checked those SNP's you shared, I don't have any mutations in them. I do have a CRHR1 mutation though, I use SelfDeCode website and I found something about CRHR1-IT1 (CRHR1 intronic transcript 1) and MGC57346-CRHR1 2.35 which I have both mutations in, also I have a mutation in LMO3 (https://en.wikipedia.org/wiki/LMO3) which has been shown to regulate CRHR1 levels in the basal amygdala. https://www.ncbi.nlm...pubmed/29609111

 

But from what I can tell, you don't want too much crhr1 in specific parts of the brain which is the amygdala (basal or central), but you also don't want too little crhr1 via the PFC which would make it difficult for you to overcome fear, So I think its about having an balance obviously but less of this protein is better than more.

 

I had made a huge thread about this were I just posted anything I could find regarding the CRH-CRHR1 system: https://www.longecit...f1-antagonists/

 

Studies, supplements that decrease CRH and drugs that decrease CRHR1. 

 

Astressin-B topically I don't think it would work that well, since it is a CRH antagonist and I mentioned that is is better to block/decrease CRHR1 levels rather than decrease CRH. From what I can tell the two easy to get drugs that are good at decreasing CRHR1 in the amygdala are valporic acid (decreases CRH in the central amygdala and CRHR1 in the basal amygdala) and lithium carbonate which decreases CRHR1 in the whole amygdala, but high dosage was used in both these. I also mentioned Olanzapine/zyprexa has a calming effect on me it inhibits CRH release in the hippocampus which  stops anxiety in its track from further reaching the amygdala, it is oversimplified. But if you have higher levels of crhr1 protein in the amygdala, you will react more to external stimuli.

 

 

Edited by farshad, 13 October 2019 - 06:45 PM.

[dalack]

I'm interested as well

[Daniel Cooper]

I'm hard pressed to think of one neurotransmitter receptor where long term agonism or antagonism doesn't result in maladaptive changes in the long run (tolerance, etc).

 

 

 

 

 

 

[StevesPetMacaque]

I'm hard pressed to think of one neurotransmitter receptor where long term agonism or antagonism doesn't result in maladaptive changes in the long run (tolerance, etc).

 

Some type of cycling would probably be warranted, yes. However, I do feel that this might still find use in reversing conditioned fear responses, for example.

[StevesPetMacaque]

Isn't Astressin B a peptide and those have to be injected to work? 
 

 

Interesting. I did a little reading on this stuff. It is a relatively small peptide, lighter than insulin. Intranasal insulin has numerous studies that demonstrate its efficacy at reaching the brain via this dosing method. Looking at Astressin-B's pharmacodynamics, with a Ki in the 1-10 nM range, an intranasal dose of order 10-100 micrograms might be effective.

 

Since it is available for topical use, some bulk supplier must carry it, and the restrictions for such compounds are usually less than for orally active drugs. This is a promising first candidate for experimentation.

[kurdishfella]

I assume LMO4 works together with LMO3 gene (which has been shown to regulate CRHR1 in the basal amygdala) and regulate amygdala via different mechanisms/ways etc.

https://www.scienced...896627315001300

Chronic Stress Induces Anxiety via an Amygdalar Intracellular Cascade that Impairs Endocannabinoid Signaling

 

Highlights

 

•

Mice with ablation of an endogenous PTP1B inhibitor LMO4 have anxiety

•

PTP1B dephosphorylates mGluR5 and impairs mGluR5-mediated eCB production

•

Glucocorticoids impair LMO4 palmitoylation and increase PTP1B activity

•

PTP1B inhibition in the amygdala restores eCBs and relieves stress-induced anxiety

 

I also have a mutation in my LMO1 gene but not LMO4 or LMO2. Not sure what LMO1 does but I think they all regulate your amygdala anxiety levels very importantly. And valproic acid decreases LMO1 also https://www.ncbi.nlm...pubmed/27188386

 

 

 

 Covered on Genetics Home Reference: neuroblastomaFrom UniProt: A chromosomal aberration involving LMO1 may be a cause of a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(11,14)(p15;q11) with TCRD.

     From NCBI Gene: This locus encodes a transcriptional regulator that contains two cysteine-rich LIM domains but lacks a DNA-binding domain. LIM domains may play a role in protein interactions; thus the encoded protein may regulate transcription by competitively binding to specific DNA-binding transcription factors. Alterations at this locus have been associated with acute lymphoblastic T-cell leukemia. Chromosomal rearrangements have been observed between this locus and at least two loci, the delta subunit of the T-cell antigen receptor gene and the LIM domain binding 1 gene. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2012] From UniProt: May be involved in gene regulation within neural lineage cells potentially by direct DNA binding or by binding to other transcription factors.

https://www.ncbi.nlm.../pubmed/9204936

 

LIM Genes Parcellate the Embryonic Amygdala and Regulate Its Development

https://www.ncbi.nlm...les/PMC6729599/

 

Lmo4 in the Basolateral Complex of the Amygdala Modulates Fear Learning

https://journals.plo...al.pone.0034559

 

 

 

 LMO4 is predominantly expressed in pyramidal projection neurons of the basolateral complex of the amygdala (BLC). Mice heterozygous for a genetrap insertion in the Lmo4 locus (Lmo4gt/+), which express 50% less Lmo4 than their wild type (WT) counterparts display enhanced freezing to both the context and the cue in which they received the aversive stimulus. 

 

 

Vorinostat decreases LMO1 https://www.ncbi.nlm...pubmed/27188386

 

Missing something that decreases LMO4

Development of the Mouse Amygdala as Revealed by Enhanced Green Fluorescent Protein Gene Transfer by Means of In Utero Electroporation

https://onlinelibrar....1002/cne.21945

Edited by farshad, 20 October 2019 - 05:34 PM.

[StevesPetMacaque]

Glucocorticoids impair LMO4 palmitoylation and increase PTP1B activity

Interesting. This might explain one mechanism by which chronic stress increases both anxiety and weight gain. Central PTP1B knockout mice are protected against obesity and diabetes.
 
Curcumin is a candidate for PTP1B inhibition; there are several others: 1, 2, 3.

 

Still looking into Astressin-B.

[TerraMessorem]

the drug is not in the market. synthesizing it seems dicey. why not dig up info on the histiry of how antalarmin was discovered, because most of these drugs are modified natural molecules. perhaps antalarmin is a modified pyrrolopyrimidine from some leaf or flower growing somewhere, and the natural product might even be better, because antalarmin didnt produce succesful eliminationsof anxiety in clinical trials. this means something is still off with the molecule, perhaps they added the butyl group to the wrong carbon.

[gizmobrain]

the drug is not in the market. synthesizing it seems dicey. why not dig up info on the histiry of how antalarmin was discovered, because most of these drugs are modified natural molecules. perhaps antalarmin is a modified pyrrolopyrimidine from some leaf or flower growing somewhere, and the natural product might even be better, because antalarmin didnt produce succesful eliminationsof anxiety in clinical trials. this means something is still off with the molecule, perhaps they added the butyl group to the wrong carbon.

 
You might be new here . Longecity group buys have led to nootropic vendors carrying products that were not formerly available. Also, there are many drugs that do not have successful clinical trials but are actually successful at treating a specific group of people. In this case, it may be that people with CRH mutations have better success.

The history of Antalarmin can be found here:
https://www.ncbi.nlm...23-0495.pdf]PDF

 

Binding of CP-154,526 to CRF Receptors. High speed
screening of compound libraries with a radioligand binding
assay had previously led to the discovery of potent nonpeptide
NK1 antagonists (36). Accordingly, a similar approach was
taken to assay compounds for their ability to inhibit binding of
radiolabeled oCRF (125I-oCRF) to the human CRF receptor
in membranes prepared from IMR32 cells, a human neuroblastoma cell line. This effort yielded a low affinity lead (800
nM) that served as a starting point for subsequent chemical
modifications (37). Directed synthesis then resulted in a series
of novel pyrrolo[2,3-d]pyrimidines (38) exemplified by CP154,526 (Fig. 1; butyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-
7H-pyrrolo[2,3-d]pyrimidin-4-yl]-ethylamine). CP-154,526
bound to CRF receptors in IMR32 cells with a Ki of 2.7 nM and
showed similar high affinity for cerebral cortical and pituitary
sites labeled by 125I-oCRF in multiple species (Table 1).
Compared with a-helical oCRF9-41, binding affinity for CP154,526 was greater regardless of the tissue source. Competition curves for all tissue preparations were monophasic, with
Hill slopes approximating 1.0. CP-154,526 also was examined
in radioligand binding assays for more than 40 other receptors,
and in no case did it compete for binding with an IC50 of less
than 1 ,uM, which demonstrates its high degree of selectivity.
In a series of preliminary studies, CRF1 and CRF2 receptors
were expressed in Chinese hamster ovary cells, and the affinity
of CP-154,526 for each receptor subtype was determined (39).
CP-154,526 competed for 125I-oCRF binding to the CRF1
receptor subtype with a K1 of 2.7 nM. In contrast, the Ki for
inhibition of binding by 125I-sauvigine to CRF2 receptors was
>10 ,uM.

 
So it started with screening against a library of compounds that had low affinity for the target receptor, then was modified until they produced a compound with higher affinity. 

[kurdishfella]

The CRHR1 gene contributes to genetic susceptibility of aggressive behavior towards others 

https://www.ncbi.nlm...pubmed/24243082

 

https://www.ncbi.nlm...les/PMC5616275/

 

https://www.research...vioral_outcomes

 

https://www.research...ale_Adolescents

 

 

Edited by farshad, 05 November 2019 - 08:11 AM.

[StevesPetMacaque]

Farshad, I thought you might enjoy this:
https://www.ncbi.nlm...pubmed/20881118
 

Hippocampal dysfunction and cognitive impairments provoked by chronic early-life stress involve excessive activation of CRH receptors.
Ivy AS, Rex CS, Chen Y, Dubé C, Maras PM, Grigoriadis DE, Gall CM, Lynch G, Baram TZ.

Abstract
Chronic stress impairs learning and memory in humans and rodents and disrupts long-term potentiation (LTP) in animal models. These effects are associated with structural changes in hippocampal neurons, including reduced dendritic arborization. Unlike the generally reversible effects of chronic stress on adult rat hippocampus, we have previously found that the effects of early-life stress endure and worsen during adulthood, yet the mechanisms for these clinically important sequelae are poorly understood. Stress promotes secretion of the neuropeptide corticotropin-releasing hormone (CRH) from hippocampal interneurons, activating receptors (CRF(1)) located on pyramidal cell dendrites. Additionally, chronic CRF(1) occupancy negatively affects dendritic arborization in mouse organotypic slice cultures, similar to the pattern observed in middle-aged, early-stressed (CES) rats. Here we found that CRH expression is augmented in hippocampus of middle-aged CES rats, and then tested whether the morphological defects and poor memory performance in these animals involve excessive activation of CRF(1) receptors. Central or peripheral administration of a CRF(1) blocker following the stress period improved memory performance of CES rats in novel-object recognition tests and in the Morris water maze. Consonant with these effects, the antagonist also prevented dendritic atrophy and LTP attenuation in CA1 Schaffer collateral synapses. Together, these data suggest that persistently elevated hippocampal CRH-CRF(1) interaction contributes importantly to the structural and cognitive impairments associated with early-life stress. Reducing CRF(1) occupancy post hoc normalized hippocampal function during middle age, thus offering potential mechanism-based therapeutic interventions for children affected by chronic stress.

(emphasis mine)

[TerraMessorem]

is there anything natural that can block CRH1, most things either lower acth or cortisol which is worse for stress because positive feed back increases Crh, so far i have jot found anything that lowers Crh, but if anyone has, it would be good to have an alternative if antarlamin doesnt go through

[TerraMessorem]

however amongst supps ive taken, the only 1 that actually reduced stress was chanca piedra. it is said to have some form of antiadrenergic effect, so it may or may not lower Crh. but on chanca piedra i felt less startled, less nervous, about 50% less, more than any other supp. although i took 500mg 3 times in that one day, instead of the maximum 1g daily stated on selfhacked.com.

[kurdishfella]

is there anything natural that can block CRH1, most things either lower acth or cortisol which is worse for stress because positive feed back increases Crh, so far i have jot found anything that lowers Crh, but if anyone has, it would be good to have an alternative if antarlamin doesnt go through

Yes, I posted about it on a different thread, a chinese formula called xiao yao san blocks crhr1/crf1 in the basal amygdala to that of antalarmin.

https://www.hindawi....m/2016/1238426/

 

Results. Chronic pretreatment with Xiaoyaosan or antalarmin significantly reversed elevated anxiety-like behavior and the upregulated level of CRF1R and BDNF in the amygdala of stressed rats. pCREB did not differ significantly among the groups. Conclusions. These results suggest that Xiaoyaosan exerts anxiolytic-like effects in behavioral tests and the effects may be related to CRF1R signaling in the amygdala.

 

and Phytocee is an unique polyherbal formulation containing W. somnifera, O. sanctum, and E. officinalis. O. sanctum was reported to improve body weight in immunosuppressed birds through enhancing the immune status[51] and displayed an anti-stress effect by directly inhibiting cortisol secretions and indirectly having an antagonist effect on CRHR1 receptor

https://www.ncbi.nlm...les/PMC5855364/

 

also Ocimum sanctum (holy basil)  herb

https://www.ncbi.nlm...pubmed/26899341

'' Further, O. sanctum and its constituents inhibited cortisol release and exhibited a significant CRHR1 receptor antagonist activity. Also, they had specific inhibitory activity towards 11β-HSD1 and COMT activity. Thus, O. sanctum was found to be effective in the management of stress effects, and anti-stress activity could be due to inhibition of cortisol release, blocking CRHR1 receptor, and inhibiting 11β-HSD1 and COMT activities.''

 

 

tianeptine kind of  does this aswell but not natural I guess

 Moreover, repeated tianeptine treatment significantly decreased CRF mRNA levels in the ventral BNST and CeA(central amygdala) of non-stressed controls as well as CMS-exposed rats. These results show that CMS induces a rather selective increase of CRF mRNA in the dBNST. In addition, these results suggest that repeated tianeptine treatment diminishes the basal activity of CRF neurons and reduces their sensitivity to stress.

https://www.research...ss-exposed_rats

Edited by farshad, 07 November 2019 - 04:15 PM.

[gintrux]

Also interested to try, if price wouldn't be crazy high.

[world33]

Quercetin
1) https://www.ncbi.nlm...pubmed/20447436

2) https://www.semantic...dc9b6ad274ebee8

Edited by world33, 06 December 2019 - 01:21 PM.

[StevesPetMacaque]

Quercetin
1) https://www.ncbi.nlm...pubmed/20447436

2) https://www.semantic...dc9b6ad274ebee8

 

Thanks for the references. Maybe that explains the anti-nootropic effects that some users report. I suspect that lowering CRH/cortisol abruptly can leave one feeling brain fogged for a while.

[world33]

Thanks for the references. Maybe that explains the anti-nootropic effects that some users report. I suspect that lowering CRH/cortisol abruptly can leave one feeling brain fogged for a while.

 
Possible. It may depends on someone's base levels of CRH -> ACTH -> Cortisol I guess. For me, that I suffer from generalized anxiety disorder (especially morning anxiety) and chronic stress, quercetin helps a lot to lower CRH and cortisol in the morning and sleep better at night. I take half teaspoon and I feel much more relaxed. For people that do not have my same condition it might not work the same way or a dosage adjustment might be needed to find the right "sweet spot".
I would love to try Antalarmin or Pexacerfont one day to see it has the same effect ...
By the way quercetin does not give me any brain fog at all. It actually helps me with daytime sleepiness....

Edited by world33, 13 December 2019 - 05:19 AM.

[Daniel Cooper]

Quercetin
1) https://www.ncbi.nlm...pubmed/20447436

2) https://www.semantic...dc9b6ad274ebee8

 

Those are very interesting studies. Thanks for posting them.

 

I arrive at a HED of about 250mg for a 77kg person.  That about right?

 

I think a confounding factor is that quercetin is metabolized much faster in the human liver compared to mice/rats.  So you might have to take a substantially larger dose to overwhelm the rapid metabolism.

 

Stress/anxiety is something I struggle with, so I'll give this a try.

[world33]

Those are very interesting studies. Thanks for posting them.
 
I arrive at a HED of about 250mg for a 77kg person.  That about right?
 
I think a confounding factor is that quercetin is metabolized much faster in the human liver compared to mice/rats.  So you might have to take a substantially larger dose to overwhelm the rapid metabolism.
 
Stress/anxiety is something I struggle with, so I'll give this a try.

 
Yeah I take half teaspoon of quercetin mixed with milk in the morning and half before bed. You can adjust the dosage if you feel it is too much (brain fog) or too little.
Quercetin has GRAS (Generally Recognized As Safe) status
Source: https://examine.com/...ents/quercetin/
 
 
I would suggest you to also try Apigenin (the active ingredient in chamomile) to reduce cortisol. You can find Apigenin from Swanson Vitamins.
 
Lastly you can consider to try some adaptogens, in particular Rhodiola Rosea extract (in the morning, possibly with the standardized content of 5% salidroside) and Ashwagandha extract (at night). Adaptogens helps to better cope with stress and reduce cortisol. Moreover Rhodiola helps with endurance and many other energy problems.
 
Sources:
 
Apigenin: https://www.ncbi.nlm...pubmed/11948020
 
Rhodiola: https://www.ncbi.nlm...pubmed/29325481 and https://www.ncbi.nlm...pubmed/25172797
 
Ashwagandha: https://www.ncbi.nlm...les/PMC3573577/