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Tuesday, July 12, 2016

Natural Kappa (K/KOR) Opioid Receptor Antagonists (Herbal Opiate/Opioid Antagonists) (Includes Where to Buy Them)

Kappa-opioid Receptors are incredibly important in terms of Dopamine-release, but as an anti-target, or anti-factor; a negative modulator of Dopamine release/activity[1] [2] [3]. Because of that research, the search is on to find natural/herbal Kappa opioid blockers/antagonists.

That search has yielded the following results.

  1. Amentoflavone [4] [5] (the most easily purchasable natural kappa antagonist). {Buy it HERE}
  2. Pawhuskin A [6] [7] - Isolated from the "Purple Prairie Clover" AKA Dalea purpurea. As of this point I have no source for it. Contact me if you have a source you'd like to add.
  3. Noribogaine. Although it occurs naturally in the Iboga plant, it is more frequently used separately to research and experiment with Addiction models. It is not a suitable substance for practical use, because it has many other properties and is nearly an impossible task to obtain on its own and the whole Iboga plant / shrub can not be consumed without giving way to its other unwanted effects. It's listed here for factual / research purposes only[8] [9].
  4. Ginkgo Biloba Extract; Ginkgo is an easily obtainable extract {Buy HERE} which has been and still is being used for memory/cognition issues [10] [11] as well as to enhance libido [12] [13] - it functions as a dopamine-promoter [14] and kappa-opioid antagonist [15] but also promotes histamine activity in the brain as well [16]; which may cause Insomnia [17].
  5. Instant Coffee: Coffee, yup that's it. Drinking Coffee will antagonize opioid receptors [18] [19] [20] [21] - although the effect is more related to MU/M/MOR than Kappa/KOR/K.


  1. So in terms of Amentoflavone, would you suspect that this may have the same effects as Forskolin, in terms of being a Thyroid Stimulant/cAMP booster?

    1. Similar, it appears Kappa-receptor negatively modulate specific aspects of the cAMP cycle and thus they may uniquely be selective in that it is primarily Mesolimbic projections.
      So Kappa-antagonism may actually be necessary for many people with Anhedonia. Also if something like "Amisulpride" or Amphetamine or both doesn't work for ones Anhedonia - then its a SURE BET that Kappa and natural dynorphin production is way out of control! I've yet to meet maybe only 2 people who don't respond to Amisulpride AND Amphetamine. Another 61 people I talked to all Agree its beyond-beyond Euphoria. :-)

      Kappa-Opioid-Ligand-cAMP Study:

      The Role of the Dynorphin/Kappa-opioid Receptor System and CREB in the Compulsive Behaviors Associated with Extended Access to Methamphetamine:

      J Pharmacol Exp Ther. 2002 May;301(2):599-604.
      Inhibition of cAMP accumulation by kappa-receptor activation in isolated iris-ciliary bodies: role of phosphodiesterase and protein kinase C.:

      Lastly, Kappa-Opioid-Induced Anhedonia may also be mediated by INHIBITION of Serotonin uptake and thus enhancement of Brain Serotonin like being on an SSRI-Antidepressant!

      Neuropharmacology. 2017 Feb;113(Pt A):281-292. doi: 10.1016/j.neuropharm.2016.10.011. Epub 2016 Oct 12.
      Modulation of serotonin transporter function by kappa-opioid receptor ligands.
      Sundaramurthy S1, Annamalai B2, Samuvel DJ3, Shippenberg TS4, Jayanthi LD1, Ramamoorthy S5.
      Author information
      Kappa opioid receptor (KOR) agonists produce dysphoria and psychotomimesis. While KOR agonists produce pro-depressant-like effects, KOR antagonists produce anti-depressant-like effects in rodent models. The cellular mechanisms and downstream effector(s) by which KOR ligands produce these effects are not clear. KOR agonists modulate serotonin (5-HT) transmission in the brain regions implicated in mood and motivation regulation. Presynaptic serotonin transporter (SERT) activity is critical in the modulation of synaptic 5-HT and, subsequently, in mood disorders. Detailing the molecular events of KOR-linked SERT regulation is important for examining the postulated role of this protein in mood disorders. In this study, we used heterologous expression systems and native tissue preparations to determine the cellular signaling cascades linked to KOR-mediated SERT regulation. KOR agonists U69,593 and U50,488 produced a time and concentration dependent KOR antagonist-reversible decrease in SERT function. KOR-mediated functional down-regulation of SERT is sensitive to CaMKII and Akt inhibition. The U69,593-evoked decrease in SERT activity is associated with a decreased transport Vmax, reduced SERT cell surface expression, and increased SERT phosphorylation. Furthermore, KOR activation enhanced SERT internalization and decreased SERT delivery to the membrane. These data demonstrate that KOR activation decreases 5-HT uptake by altering SERT trafficking mechanisms and phosphorylation status to reduce the functional availability of surface SERT.

      Clearance; Kappa opioid receptor; Phosphorylation; Serotonin; Serotonin transporter; Trafficking

      PMID: 27743931 PMCID: PMC5148672 DOI: 10.1016/j.neuropharm.2016.10.011

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