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Group buy for novel anxiolytic. Research topic.

gaba alpha glutamate

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#91 richards2324

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Posted 12 December 2016 - 10:44 PM

aloradine


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#92 Reformed-Redan

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Posted 06 April 2018 - 12:59 AM

Hey guys and gals,

 

I wanted to gather interest after a friend referenced me a non-tolerance forming and non-habit forming potent benzodiazepine called Imidazenil.

 

It has superb effects on people with anxiety and other neurological disorders like Schizophrenia, Bi-Polar, and depression.

 

It's non-sedating; but, has prominent effects on anxiety with no rebound effect. 

 

Due to it's potency I think it could be affordable for participants, and last a long time at its active doses.

 

Any thoughts or ideas appreciated.

 

As usual, I won't be handling the group buy. I've learned my lesson and don't want a repeat.



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#93 topsykretts

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Posted 06 April 2018 - 01:16 AM

I just came here to post about Imidazenil myself.  I've reached out to the owners of irc.bio to see if they could get it synthesized, and they spoke with some people and it is apparently expensive to produce.



#94 Reformed-Redan

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Posted 06 April 2018 - 11:08 PM

All things considered, benzodiazepines are initially expensive to purchase; but, since the doses are so minute, you can have a lot of the stuff for something in the ballpark of 100-200 USD. I suppose a years worth.

 

I contacted NewMind, and they're willing to synthesize it. They asked for 4-7 months until they have it in stock.

 

Otherwise I'm still interested in doing my own research and comparing costs, although the compound is quite hard to synthesize from what I have seen.

 

Any help with this matter appreciated.



#95 Reformed-Redan

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Posted 07 April 2018 - 02:33 AM

Yes, It's too cost prohibitive for a group buy from preliminary reports. Will hope newmind delivers.

 

 



#96 Reformed-Redan

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Posted 07 April 2018 - 03:09 AM

I got one quote for $3,500 for 100g. 

 

If you do the math 10g or even 20g will last a loooong time. 

 

I'm waiting for more quotes.

 

Price is $3,500 for 100g.



#97 Reformed-Redan

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Posted 08 April 2018 - 03:25 AM

Yeah, I got a response of 11350 USD for 100g. 

 

I'm afraid this might have to wait until NewMind decides to produce it.



#98 Reformed-Redan

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Posted 08 April 2018 - 04:47 AM

Ok, so I got a reasonable quotation for 4000 USD for 100g. 

 

Anyone interested in a non-addicting benzodiazepine, with no increase in tolerance and is effective long term?

 

I'm certainly down.



#99 focus83

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Posted 08 April 2018 - 04:57 PM

Count me in!! :)



#100 Reformed-Redan

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Posted 08 April 2018 - 05:12 PM

So, I'm hoping for 10 users at 400 USD each also including shipping costs and lab lab analysis. I haven't done estimates; but a ballpark estimate is 15 years of use.

 

At the potentiates I've seen for Imidazenil, it is extremely potent and has a long half life with no tolerance buildup.

 

I couldn't;t ask for a better benzodiazapine. No tolerance, no increases in doses, Does don't lose efficacy over time. What's not to ask for?


Edited by Reformed-Redan, 08 April 2018 - 05:13 PM.


#101 nicklesprout

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Posted 08 April 2018 - 07:45 PM

Benzo, any Benzo, should raise a big red flag. Any long term usage studies s showing no harm? Does it bind to BZD receptor? These are nothing to play around with. I know from experience.
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#102 Daniel Cooper

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Posted 09 April 2018 - 02:43 PM

Given the MOA of all benzodiazipines, how does one make a benzo that doesn't build tolerance and isn't habit forming.  Aren't both basically built into the way they work and the body's tendency to maintain homeostasis with respect to neurotransmitter systems?

 

I'm skeptical of these claims.

 

Remember, these are the same claims that were made of the z-drugs years ago, which were later found out to be completely untrue.

 

 

 

 


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#103 Reformed-Redan

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Posted 09 April 2018 - 05:36 PM

I can compile a list of research papers on it if anyone is interested. All information on it points at it being a non-tolerance inducing drug due to not targeting the alpha-1 sub-unit of BZ receptors, which lead to tolerance to said drugs. 

 

Please let me know if anyone is interested in me compiling the research papers on the drug. 

 

Imidazenil, a partial positive allosteric modulator of GABAA receptors, exhibits low tolerance and dependence liabilities in the rat.
Abstract

Long-term treatment of rats with full (triazolam) or selective (diazepam) allosteric modulators of gamma-aminobutyric acid type A (GABAA) receptors rapidly induced tolerance to the protective effect of these drugs against bicuculline-induced convulsion. In contrast, long-term administration of partial allosteric modulators (imidazenil and bretazenil) of GABAA receptors, in doses equipotent to those of diazepam and triazolam that induce anticonvulsant tolerance, failed to elicit such a tolerance. Furthermore, no cross-tolerance was observed between diazepam and imidazenil. Discontinuation of long-term treatment with diazepam or triazolam, but not of long-term treatment with imidazenil or bretazenil, sensitized rats to behavioral inhibition by punishment (electric shock) in a manner that was potentiated by flumazenil. Administration of a single oral dose of [14C]diazepam or [3H] imidazenil to rats treated repeatedly with the corresponding unlabeled drug or vehicle revealed that the brain concentrations of drugs and their metabolites were similar in both groups of animals. This suggests that tolerance to the full or selective allosteric modulators of GABAA receptors may be associated with changes in the efficacy of the allosteric modulation rather than with changes in drug metabolism. Imidazenil has a longer half-life than an equipotent dose of diazepam and protects rats against bicuculline-induced convulsions for a significantly longer time than diazepam or bretazenil.(ABSTRACT TRUNCATED AT 250 WORDS).

 

Chronic administration of an anticonvulsant dose of imidazenil fails to induce tolerance of GABAA receptor function in mice    
 
Abstract

The ability of an anticonvulsant dose (0.1 mg/kg i.p.) of imidazenil, a new partial agonist of benzodiazepine receptors, to antagonize the convulsions and the increase in t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding to the γ-aminobutyric acid type A (GABAA) receptor elicited by isoniazid, an inhibitor of central GABAergic function, was evaluated in mice chronically treated (3 times daily for 30 days) with the same dose of imidazenil. The challenge dose of imidazenil, administered 36 h after the last injection of the chronis treatment protocol, reduced both isoniazid-induced convulsions and the isoniazid-induced increase in [35S]TBPS binding to the same marked extent as in control mice. These results indicate that long-term treatment with a pharmacologically effective dose of imidazenil failed to induce tolerance to both the anticonvulsant effect and the positive modulatory action on GABAA receptor function of this drug in mouse brain.

 



#104 Reformed-Redan

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Posted 09 April 2018 - 05:39 PM

Anticonvulsant, anxiolytic, and non-sedating actions of imidazenil and other imidazo-benzodiazepine carboxamide derivatives.
Abstract

Recent evidence suggests that alpha1-containing GABA(A) receptors mediate the sedative, amnestic, and to some extent the anticonvulsant actions of non-selective benzodiazepine (BZ) receptor ligands, such as diazepam (DZ). Anxiolytic and in part, anticonvulsant actions of BZ ligands are mediated by alpha2-, alpha3-, and alpha5-containing GABA(A) receptors. This has resulted in increasing interest in developing BZ ligands with selective actions at GABA(A) receptors, including alpha2-, alpha3-, and alpha5-subunits, but devoid of efficacy at alpha1-containing receptors. To refine their spectrum of pharmacological actions, efforts are being made to minimize unwanted effects such as sedation, amnesia, and tolerance liabilities. A prototype for such BZ ligands is imidazenil (IMD), an imidazo-benzodiazepine carboxylic acid derivative that elicits potent anticonvulsant and anxiolytic actions at doses virtually devoid of sedative, cardio-respiratory depressant and amnestic effects, and anticonvulsant tolerance liability. To define the pharmacological profile of IMD and its derivatives, we compared the anticonflict (anxiolytic), anti-proconflict (antipanic), anti-bicuculline (BIC), and maximal electroshock seizure (MES) effects, and the suppression of locomotor activity by imidazo-benzodiazepine carboxylic acid derivatives to those of DZ and bretazenil (BTZ). We report here that IMD and one of its derivatives (RO 25-2775) possess dose-dependent anticonflict, anti-proconflict, and anti-BIC actions but failed to suppress locomotor activity. Like DZ, the other IMD derivatives (enazenil, RO 25-2776, and RO 25-2847) not only elicit dose-dependent anticonflict, anti-proconflict, anti-BIC, anti-MES effects but also suppress locomotor activity. In contrast, none of the IMD derivatives studied shows any similarity to BTZ, which elicits anticonflict, anti-proconflict actions and suppresses locomotor activity but is virtually inactive against BIC-induced tonic-clonic convulsions.

 



#105 Reformed-Redan

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Posted 09 April 2018 - 05:44 PM

Lack of anticonvulsant tolerance and benzodiazepine receptor down regulation with imidazenil in rats
First published: February 1996
   
Cited by:11
 
 
Abstract

 

  • 1

    Development of anticonvulsant tolerance and benzodiazepine (BZD) receptor down‐regulation has been reported to occur upon chronic administration of conventional BZDs. We compared the effect of chronic treatment with imidazenil, a new BZD partial agonist, and diazepam in rats.

  • 2

    After acute administration, imidazenil was more potent though less effective than diazepam in protecting from bicuculline‐induced seizure. The time‐course analysis of two peak equieffective doses of imidazenil (2.5 μmol kg−1 p.o.) and diazepam (35 μmol kg−1, p.o.) showed a longer lasting action of the former drug.

  • 3

    The anticonvulsant efficacy of diazepam (35 μmol kg−1, p.o.) was reduced in rats given chronic diazepam (35 μmol kg−1, p.o., 3 times a day for 8–15 days). No tolerance to imidazenil (2.5 μmol kg−1, p.o.) was apparent after 130‐day administration with imidazenil (2.5 μmol kg−1, p.o., 3 times a day).

  • 4

    Plasma levels of imidazenil and diazepam, assessed 30 min after administration, were not changed in chronically treated animals.

  • 5

    In rats made tolerant to diazepam, the maximum number of [3H]‐flumazenil binding sites were reduced in both cerebral cortex (−36%) and cerebellum (−42%). No changes in [3H]‐flumazenil binding were found in chronic imidazenil‐treated rats.

  • 6

    Specific [3H]‐flumazenil binding in vivo was decreased in the forebrain of chronic diazepam‐ but not of chronic imidazenil‐treated animals.

  • 7

    These data indicate that imidazenil possesses a very low tolerance potential to its anticonvulsant activity and does not affect BZD receptor density even after prolonged administration.

 



#106 focus83

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Posted 09 April 2018 - 06:11 PM

Great, thanks a lot for providing the relevant research. I will look into it more thoroughly on Thursday. Shouldn't we create a dedicated topic for this potential group buy?



#107 Daniel Cooper

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Posted 09 April 2018 - 06:41 PM

Anticonvulsant, anxiolytic, and non-sedating actions of imidazenil and other imidazo-benzodiazepine carboxamide derivatives.

Abstract

Recent evidence suggests that alpha1-containing GABA(A) receptors mediate the sedative, amnestic, and to some extent the anticonvulsant actions of non-selective benzodiazepine (BZ) receptor ligands, such as diazepam (DZ). Anxiolytic and in part, anticonvulsant actions of BZ ligands are mediated by alpha2-, alpha3-, and alpha5-containing GABA(A) receptors. This has resulted in increasing interest in developing BZ ligands with selective actions at GABA(A) receptors, including alpha2-, alpha3-, and alpha5-subunits, but devoid of efficacy at alpha1-containing receptors. To refine their spectrum of pharmacological actions, efforts are being made to minimize unwanted effects such as sedation, amnesia, and tolerance liabilities. A prototype for such BZ ligands is imidazenil (IMD), an imidazo-benzodiazepine carboxylic acid derivative that elicits potent anticonvulsant and anxiolytic actions at doses virtually devoid of sedative, cardio-respiratory depressant and amnestic effects, and anticonvulsant tolerance liability. To define the pharmacological profile of IMD and its derivatives, we compared the anticonflict (anxiolytic), anti-proconflict (antipanic), anti-bicuculline (BIC), and maximal electroshock seizure (MES) effects, and the suppression of locomotor activity by imidazo-benzodiazepine carboxylic acid derivatives to those of DZ and bretazenil (BTZ). We report here that IMD and one of its derivatives (RO 25-2775) possess dose-dependent anticonflict, anti-proconflict, and anti-BIC actions but failed to suppress locomotor activity. Like DZ, the other IMD derivatives (enazenil, RO 25-2776, and RO 25-2847) not only elicit dose-dependent anticonflict, anti-proconflict, anti-BIC, anti-MES effects but also suppress locomotor activity. In contrast, none of the IMD derivatives studied shows any similarity to BTZ, which elicits anticonflict, anti-proconflict actions and suppresses locomotor activity but is virtually inactive against BIC-induced tonic-clonic convulsions.

 

 

 

This sounds a lot like the alleged story for the z-drugs.  Zopiclone was selective for alpha1, alpha2, alpha3 and alpha5 and wasn't supposed to cause tolerance or dependence because of that selectivity.  That did not turn out to be the case.  Now, they are claiming no activity at alpha1, so maybe that makes all the difference in the world.  Then again, maybe not.  

 

I'm just suggesting that I would be very cautious and not assume that you won't have tolerance or dependance issues with this compound until proven otherwise.



#108 Daniel Cooper

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Posted 09 April 2018 - 06:46 PM

 

Lack of anticonvulsant tolerance and benzodiazepine receptor down regulation with imidazenil in rats
First published: February 1996
   
Cited by:11
 
 
Abstract

 

  • 1

    Development of anticonvulsant tolerance and benzodiazepine (BZD) receptor down‐regulation has been reported to occur upon chronic administration of conventional BZDs. We compared the effect of chronic treatment with imidazenil, a new BZD partial agonist, and diazepam in rats.

  • 2

    After acute administration, imidazenil was more potent though less effective than diazepam in protecting from bicuculline‐induced seizure. The time‐course analysis of two peak equieffective doses of imidazenil (2.5 μmol kg−1 p.o.) and diazepam (35 μmol kg−1, p.o.) showed a longer lasting action of the former drug.

  • 3

    The anticonvulsant efficacy of diazepam (35 μmol kg−1, p.o.) was reduced in rats given chronic diazepam (35 μmol kg−1, p.o., 3 times a day for 8–15 days). No tolerance to imidazenil (2.5 μmol kg−1, p.o.) was apparent after 130‐day administration with imidazenil (2.5 μmol kg−1, p.o., 3 times a day).

  • 4

    Plasma levels of imidazenil and diazepam, assessed 30 min after administration, were not changed in chronically treated animals.

  • 5

    In rats made tolerant to diazepam, the maximum number of [3H]‐flumazenil binding sites were reduced in both cerebral cortex (−36%) and cerebellum (−42%). No changes in [3H]‐flumazenil binding were found in chronic imidazenil‐treated rats.

  • 6

    Specific [3H]‐flumazenil binding in vivo was decreased in the forebrain of chronic diazepam‐ but not of chronic imidazenil‐treated animals.

  • 7

    These data indicate that imidazenil possesses a very low tolerance potential to its anticonvulsant activity and does not affect BZD receptor density even after prolonged administration.

 

 

 

So in this sturdy they dosed rats for up to 15 days and didn't see signs of tolerance.  Again, very similar to the testing that was done with the z-drugs where they didn't see tolerance issue in short term tests, but in the real world with longer term administration tolerance was a definite issue.

 

In my opinion, if the longest test you've run is just over 2 weeks, you really aren't that interested in finding issues with tolerance/dependence.  

 

 

 

 



#109 Reformed-Redan

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Posted 09 April 2018 - 06:56 PM

So in this sturdy they dosed rats for up to 15 days and didn't see signs of tolerance.  Again, very similar to the testing that was done with the z-drugs where they didn't see tolerance issue in short term tests, but in the real world with longer term administration tolerance was a definite issue.

 

In my opinion, if the longest test you've run is just over 2 weeks, you really aren't that interested in finding issues with tolerance/dependence.  

 

 

"The anticonvulsant efficacy of diazepam (35 μmol kg−1, p.o.) was reduced in rats given chronic diazepam (35 μmol kg−1, p.o., 3 times a day for 8–15 days). No tolerance to imidazenil (2.5 μmol kg−1, p.o.) was apparent after 130‐day administration with imidazenil (2.5 μmol kg−1, p.o., 3 times a day)."



#110 Reformed-Redan

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Posted 09 April 2018 - 07:51 PM

I posted all relevant information. Since, I'm averse to handling group buys, maybe someone could compile all the pertinent information in a neat format and try and initiate a group buy.

 

I'm in for 500 USD.



#111 Reformed-Redan

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Posted 09 April 2018 - 08:09 PM

Anyone interested in a 10 part group buy, please post here after acquainting yourself on the research on the compound.

 

The doses are minuscule and the half life long, so given a high upfront cost you get something that can last you a very long time.



#112 Daniel Cooper

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Posted 09 April 2018 - 08:18 PM

"The anticonvulsant efficacy of diazepam (35 μmol kg−1, p.o.) was reduced in rats given chronic diazepam (35 μmol kg−1, p.o., 3 times a day for 8–15 days). No tolerance to imidazenil (2.5 μmol kg−1, p.o.) was apparent after 130‐day administration with imidazenil (2.5 μmol kg−1, p.o., 3 times a day)."

 

 

My mistake, I read the study too quickly.

 

They apparently looked for tolerance by checking flumazenil binding.   I seem to recall that flumazenil only binds on the alpha sites at alpha1 and alpha6.  If so, this might not be a reliable means to check for tolerance for an agent that only binds alpha2, alpha3, and alpha5, no?

 

I'm just very cautious about this.  There is a decent history of benzo and benzo like drugs that were advertised as not building tolerance and dependence and those claims have always later proven not to be born out.   

 

You do have to wonder .... these tests were over 20 years ago.  A benzo with no tolerance and dependence issues has been the holy grail for a long time now.  If this drug was so promising in this regard, why was it never brought to market?


BTW - I do agree that you probably want to make this group buy it's own thread.

 

 

 


Edited by Daniel Cooper, 09 April 2018 - 08:40 PM.


#113 Reformed-Redan

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Posted 09 April 2018 - 11:49 PM

My mistake, I read the study too quickly.

 

They apparently looked for tolerance by checking flumazenil binding.   I seem to recall that flumazenil only binds on the alpha sites at alpha1 and alpha6.  If so, this might not be a reliable means to check for tolerance for an agent that only binds alpha2, alpha3, and alpha5, no?

 

I'm just very cautious about this.  There is a decent history of benzo and benzo like drugs that were advertised as not building tolerance and dependence and those claims have always later proven not to be born out.   

 

You do have to wonder .... these tests were over 20 years ago.  A benzo with no tolerance and dependence issues has been the holy grail for a long time now.  If this drug was so promising in this regard, why was it never brought to market?


BTW - I do agree that you probably want to make this group buy it's own thread.

 

Yeah, in all other tests I can present it maintained anxiolytic activity persistently for 14 days. I will leave it for you guys to decide if you want to make a group buy out of this compound.

 

I also found an Alibaba supplier that actually has this compound for sale. I sent a request and ill see what s/he says.



#114 socialpiranha

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Posted 10 April 2018 - 11:27 AM

Don't trust most people on alibaba, only trust companies who have the product listed on an external website and you can reach them by phone speak to their superiors etc trust me i've learned the hard way. I have a chemical supply company it was the only way to get business with legitimate companies, if you don't have at least a business email you will be ignored by any legitimate business on alibaba or lookchem etc. also don't trust redan, he hasn't earned any redemption



#115 Reformed-Redan

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Posted 10 April 2018 - 04:00 PM

Lol,

 

The last thing I want is for people to trust me. Do your own research on Alibaba and then convince yourselves that what I'm saying is bona fide.

 

 



#116 Reformed-Redan

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Posted 10 April 2018 - 05:45 PM

Here's their link. You can quote them yourselves"

 

https://www.alibaba.....120620a3KQrnKE



#117 ISayLonger

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Posted 23 June 2018 - 12:38 PM

Any progress on glutamate modulators?



#118 adamh

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Posted 24 June 2018 - 10:14 PM

Here's their link. You can quote them yourselves"

 

https://www.alibaba.....120620a3KQrnKE

 

They want about $14,000 per kilo but will sell 100gm sample paid in advance. They also mention free samples if you pay shipping, might have to be a company to get a free one, probably no more than a gram or less. 

 

If someone wanted to start a group buy, $1400 is a lot easier to manage than $3,500 or $5,000. There should not be much shipping cost on a small amount like that. Thats only maybe $15 a gram, should be some interest. I would go in but not for a large amount. For $15 you have over 100 doses



#119 Junipersun

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Posted 26 June 2018 - 07:00 PM

They want about $14,000 per kilo but will sell 100gm sample paid in advance. They also mention free samples if you pay shipping, might have to be a company to get a free one, probably no more than a gram or less. 

 

If someone wanted to start a group buy, $1400 is a lot easier to manage than $3,500 or $5,000. There should not be much shipping cost on a small amount like that. Thats only maybe $15 a gram, should be some interest. I would go in but not for a large amount. For $15 you have over 100 doses

 

How much do they want for the 100g sample? 



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#120 adamh

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Posted 27 June 2018 - 01:06 AM

How much do they want for the 100g sample? 

 

I don't know I didn't ask them. I just assumed 1/10 of the kilo price but could be more plus some shipping



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