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DNA damage and liver toxicity
Withanone, the main secondary metabolite of Ashwagandha extract, is classified as a toxicophore. This classification stems from its ability to form non-labile adducts with various nucleosides, amines, and DNA. These adducts can disrupt DNA function and cause mutations [1].
Studies have shown that withanone can have detrimental effects on cells:
●In mammalian cells, transfection with withanone-treated DNA led to decreased gene expression [1].
●Treating DNA with withanone followed by transformation of E. coli cells resulted in fewer colonies [1].
Furthermore, adduct formation can overwhelm the cellular protective system, especially when glutathione levels are low. Glutathione, crucial for detoxification, can become depleted, leading to apoptosis or a cytotoxic effect [1].This might explain reported cases of liver damage or failure associated with Ashwagandha use [2],[3],[4].
Anhedonia
Chronic use of ashwagandha can result in super sensitivity of the 5-HT2A postsynaptic receptors and enhanced 5-HT1A function[5]. This means increased postsynaptic 5-HT1A serotonin release, which may be attributed to desensitization of the 5-HT1A auto receptor.Considering that this effect takes 4-8 weeks to manifest, it draws close similarities with SSRIs in observable effects and mechanistic action, as noted by the researchers. While this has the potential to benefit depression and anxiety, it may also lead to anhedonic symptoms common with this mechanism of action, aligning with some anecdotes. It may also cause PSSD, symptoms, similar to SSRI's, in which you are left with no sex drive after, as one of the theories behind this is the desensitized 5ht1a auto receptor.
Sources
[1] DNA damage by Withanone as a potential cause of liver toxicity observed for herbal products of Withania somnifera (Ashwagandha)
[2] Liver Dangers of Herbal Products: A Case Report of Ashwagandha-Induced Liver Injury
[3] Ashwagandha-Associated Acute Liver Failure Requiring Liver Transplantation
[4] Liver Injury due to Ashwagandha. A Case Series from Iceland and the U.S. Drug-Induced Liver Injury Network
[5] Alterations in the sensitivity of 5th receptor subtypes following chronic ashwagandha treatment in rats
Withanone, the main secondary metabolite of Ashwagandha extract, is classified as a toxicophore. This classification stems from its ability to form non-labile adducts with various nucleosides, amines, and DNA. These adducts can disrupt DNA function and cause mutations [1].
Studies have shown that withanone can have detrimental effects on cells:
●In mammalian cells, transfection with withanone-treated DNA led to decreased gene expression [1].
●Treating DNA with withanone followed by transformation of E. coli cells resulted in fewer colonies [1].
Furthermore, adduct formation can overwhelm the cellular protective system, especially when glutathione levels are low. Glutathione, crucial for detoxification, can become depleted, leading to apoptosis or a cytotoxic effect [1].This might explain reported cases of liver damage or failure associated with Ashwagandha use [2],[3],[4].
Anhedonia
Chronic use of ashwagandha can result in super sensitivity of the 5-HT2A postsynaptic receptors and enhanced 5-HT1A function[5]. This means increased postsynaptic 5-HT1A serotonin release, which may be attributed to desensitization of the 5-HT1A auto receptor.Considering that this effect takes 4-8 weeks to manifest, it draws close similarities with SSRIs in observable effects and mechanistic action, as noted by the researchers. While this has the potential to benefit depression and anxiety, it may also lead to anhedonic symptoms common with this mechanism of action, aligning with some anecdotes. It may also cause PSSD, symptoms, similar to SSRI's, in which you are left with no sex drive after, as one of the theories behind this is the desensitized 5ht1a auto receptor.
Sources
[1] DNA damage by Withanone as a potential cause of liver toxicity observed for herbal products of Withania somnifera (Ashwagandha)
[2] Liver Dangers of Herbal Products: A Case Report of Ashwagandha-Induced Liver Injury
[3] Ashwagandha-Associated Acute Liver Failure Requiring Liver Transplantation
[4] Liver Injury due to Ashwagandha. A Case Series from Iceland and the U.S. Drug-Induced Liver Injury Network
[5] Alterations in the sensitivity of 5th receptor subtypes following chronic ashwagandha treatment in rats
