Picamilon Explained

Picamilon (also known as N-nicotinoyl-GABA, pycamilon, and pikamilon) is a drug formed by a synthetic combination of niacin and γ-aminobutyric acid (GABA). It was developed in the Soviet Union in 1969[1] and further studied in both Russia[2] and Japan as a prodrug of GABA.[3]

In Russia, picamilon is sold as a prescription drug. The rights to the drug belong to the Russian pharmaceutical company NPK ECHO ("НПК ЭХО"). It is not approved for sale in the United States and has been deemed an adulterating agent in dietary supplements,[4] with five American companies required to remove their picamilon products from the market in November 2015.[5] However, as recently as 2020, picamilon has been found in pharmaceutical dosages in over-the-counter supplements in the US.[6]

Regulation

In the United States, the Food and Drug Administration ruled in 2015 that picamilon does not fit any of the dietary ingredient categories in the Dietary Supplement Health and Education Act of 1994,[5] [7] namely that it is not a vitamin; a dietary mineral; an herb or other botanical; an amino acid; a dietary substance for use by humans to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract, or combination of any ingredient described above that had been marketed in the United States before 1994. Despite the FDA ruling, picamilon remains an ingredient in supplements marketed as nootropics in the US.[6]

Pharmacology

A Russian study from 1991 showed that picamilon permeated the blood–brain barrier in cats and increased cerebral blood flow.[8] Further work showed it crosses the blood-brain barrier in mice and rats.[9] It is believed that picamilon is hydrolyzed into GABA and niacin, similar to the way tocopheryl nicotinate (vitamin E nicotinate) is hydrolyzed.[10] GABA in the brain would activate GABA receptors, which in theory should have an anxiolytic effect.[11] The second released component, niacin, is a vasodilator.[12] [13] A 2023 assay study showed that picamilon itself is inactive against 50 biological targets, including GABA receptors, despite being a GABA analogue.[14]

Pharmacokinetics

Plasma picamilon concentrations are generally in the 500–3000 μg/L range during the first few hours after single oral doses of 50–200 mg.[15] It exhibits linear pharmacokinetics with a half-life of 1–2 hours.[15] As discussed previously, the drug undergoes hydrolysis to GABA and nicotinic acid. Urinary excretion of parent drug and the two metabolites accounts for up to 79% of a single dose.[15]

Notes and References

  1. Kopelevich VM, Gunar VI . Some approaches to the directed search for new drugs based on nicotinic acid . Pharmaceutical Chemistry Journal . 33 . 4 . 177–187 . April 1999 . 10.1007/BF02509934 . 36930437 .
  2. Mirzoian RS, Gan'shina TS . [The new cerebrovascular preparation pikamilon] . ru . Farmakologiia i Toksikologiia . 52 . 1 . 23–6 . 1989 . 2707413 .
  3. Matsuyama K, Yamashita C, Noda A, Goto S, Noda H, Ichimaru Y, Gomita Y . Evaluation of isonicotinoyl-gamma-aminobutyric acid (GABA) and nicotinoyl-GABA as pro-drugs of GABA . Chemical & Pharmaceutical Bulletin . 32 . 10 . 4089–95 . October 1984 . 6529802 . 10.1248/cpb.32.4089 . free .
  4. Avula B, Chittiboyina AG, Sagi S, Wang YH, Wang M, Khan IA, Cohen PA . Identification and quantification of vinpocetine and picamilon in dietary supplements sold in the United States . Drug Testing and Analysis . 8 . 3–4 . 334–43 . March 2016 . 26426301 . 10.1002/dta.1853 . free .
  5. Web site: FDA sends five warning letters over supplements containing picamilon . 2 December 2015 . NutraIngredients-USA.com, William Reed Business Media. 3 December 2015.
  6. Cohen PA, Avula B, Wang YH, Zakharevich I, Khan I . Five Unapproved Drugs Found in Cognitive Enhancement Supplements . Neurology. Clinical Practice . 11 . 3 . e303–e307 . June 2021 . 34484905 . 8382366 . 10.1212/CPJ.0000000000000960 .
  7. Web site: Welch C . Declaration of Dr. Cara Welch. Department of Health and Human Services. 21 October 2015.
  8. Dorofeev BF, Kholodov LE . Pikamilon pharmacokinetics in animals . ru . Farmakologiia i Toksikologiia . 54 . 2 . 66–9 . 1991 . 1884802 .
  9. Dorofeev BF, Kholodov LE . [Pikamilon pharmacokinetics in animals] . Farmakologiia I Toksikologiia . 54 . 2 . 66–69 . March 1991 . 1884802 .
  10. Duncan KR, Suzuki YJ . Vitamin E Nicotinate . Antioxidants . 6 . 1 . 20 . March 2017 . 28335380 . 10.3390/antiox6010020 . free .
  11. Shephard RA . Behavioral effects of GABA agonists in relation to anxiety and benzodiazepine action . Life Sciences . 40 . 25 . 2429–36 . June 1987 . 2884549 . 10.1016/0024-3205(87)90758-2 .
  12. Gille A, Bodor ET, Ahmed K, Offermanns S . Nicotinic acid: pharmacological effects and mechanisms of action . Annual Review of Pharmacology and Toxicology . 48 . 79–106 . 2008 . 17705685 . 10.1146/annurev.pharmtox.48.113006.094746 .
  13. Prousky J, Seely D . The treatment of migraines and tension-type headaches with intravenous and oral niacin (nicotinic acid): systematic review of the literature . Nutrition Journal . 4 . 3 . January 2005 . 15673472 . 548511 . 10.1186/1475-2891-4-3 . free .
  14. Santillo MF, Sprando RL . Picamilon, a γ-aminobutyric acid (GABA) analogue and marketed nootropic, is inactive against 50 biological targets . Basic & Clinical Pharmacology & Toxicology . 132 . 4 . 355–358 . April 2023 . 36668678 . 10.1111/bcpt.13836 .
  15. Cui W, Chen X, Zhan Y, Zhang Z, Zhang Y, Zhong D . Determination of picamilon concentration in human plasma by liquid chromatography-tandem mass spectrometry . Journal of Chromatography B . 878 . 15–16 . 1181–4 . May 2010 . 20359966 . 10.1016/j.jchromb.2010.03.013 .

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