Carvacrol oregano oil

This post was inspired by a report that oregano oil when applied to a region of foot pain provides lasting relief. Oregano oil is sold for a variety of maladies. According to PubChem carvacrol is highly toxic with a lethal dose between 50-500 mg/kg. A review out of Mexico states that there are more than one family of plants that are considered oregano. Even within a species of oregano, the terpene content of the essential oil may vary according to the growth conditions. [1] Since this is a North American site, these are the terpene profiles of Origanum vulgare from the Leyva-López 20217 publication [1]

The variable terpene content of oregano oil

USA: Carvacrol (17.9–81.8%), p-cymene (2.62–25.7%), γ-terpinene (2.5–19.4%), β-myrcene (0.58–6.06%).
Mexico: Carvacrol (34.0%), γ-terpinene (21.6%), p-cymene (9.4%), thymol (3.3%)

Following the electronic trail of references, the USA study was examining steam distillation times on the yield of terpenes. The range given in the review [1] reflects distillation times of 1.25 minutes to 6 hours. About an 80% yield was obtained by a steam distillation time of 40 minutes. [2] The yield of γ-terpinene in the 1.25 to 40 minute steam distillation process was 19.4% and ~3 % respectively. The interesting thing about oregano oil is that most of the terpenes are structurally similar.

Carvacrol for pain

Why might a a hgh carvacrol containing oregano essential oil rubbed into an offending body part alleviate pain? This is of course assuming that the analgesia comes from carvacrol.

GABA_A

Kessler et al (2014) found that many terpenes featured on this site activate various forms of GABA_A. [3] This is also true of carvacrol. In Xenopus oocytes expressing rat α1β2, 300 μM carvacrol increased Cl^– current 414 ± 142% of GABA alone. [3] In oocytes expressing human α1β2γ2 the enhancement was 224 ± 85% over GABA alone. [3]

A Brazilian group was interested in use of carvacrol for treating cancer related pain. {4] A sarcoma cell line was injected into the hind paw of male Swiss mice. Mice were treated daily with subcutaneous injections of carvacrol (12.5, 25 or 50 mg/kg),morphine (15 mg/kg) or vehicle and then submitted for behavior tests on alternate days.

**Figure 1** excerpts from reference [3] Images have been added to illustrate the methods. A2 a mechanical device to apply pressure to the tumor B2 Flinches per 10 minute time period when mouse was left alone in a box. C2 The tumor was palpated for 2 minutes. Flinches were measured for 2 minutes afterwards.

The authors of Wikipedia have written an excellent page on c-Fos with emphasis of its activation in the post synaptic neuron. Basically c-Fos and c-Jun are a dimer transcription factor called AP-1. The transcription of c-Fos itself is controlled by various activities of the post synaptic neuron. Joseph Mickel is the one to acknowledge for the image in the figure below. Note that this is a post synaptic neuron. TrpA1, another target of TrpA1, is found in the presynaptic neuron. The image is from the Pain Research Forum. Note pictured here is the presence of the GABA_A chloride channel in the post synaptic neuron.

Images showing the pathways leading to activation of c-Fos and data relating to c-Fos expression in various regions of the central nervous system of the rats.

The vehicle is the solvent (saline + cremophor 0.4% v/v) injected subcutaneously, presumably at the site of the tumor. The carvacrol induced increase in c-Fos neurons, such as the PAG, NRM and LC are part of descending inhibitory pathways of pain. [4] These pathways include opiates, cannabinoids, NSAIDs, and serotonin/norepinephrine reuptake blockers. [4]

Outlook

How GAABA_A channels modulate transcription factors like c-Fos in pathways that are so heavily controlled by G protein coupled receptors would seem to be a simple matter of enhancing the action of inhibitory interneurons. A clinical trial of oral carvacrol at 1 and 2 mg/kg/day. [5] While changes were noted in blood counts and blood chemistry parameters, all values were within reference ranges.[5] This particular study was a followup of a previous trial at the same oral dosage for one month. [6]

References

Leyva-López, N., Gutiérrez-Grijalva, E. P., Vazquez-Olivo, G., Heredia, J. B. (2017). Essential Oils of Oregano: Biological Activity beyond Their Antimicrobial Properties. Molecules (Basel, Switzerland), 22(6), 989. PMC free article
Zheljazkov, V. D., Astatkie, T., & Schlegel, V. (2012). Distillation Time Changes Oregano Essential Oil Yields and Composition but Not the Antioxidant or Antimicrobial Activities, HortScience horts, 47(6), 777-784. free article
Kessler, A., Sahin-Nadeem, H., Lummis, S. C., Weigel, I., Pischetsrieder, M., Buettner, A., & Villmann, C. (2014). GABA(A) receptor modulation by terpenoids from Sideritis extracts. Molecular nutrition & food research, 58(4), 851–862. PMC free article
Guimarães AG, Scotti L, Scotti MT, Mendonça Júnior FJ, Melo NS, Alves RS, De Lucca Júnior W, Bezerra DP, Gelain DP, Quintans Júnior LJ. Evidence for the involvement of descending pain-inhibitory mechanisms in the attenuation of cancer pain by carvacrol aided through a docking study. Life Sci. 2014 Oct 22;116(1):8-15. free article
Ghorani V, Alavinezhad A, Rajabi O, Mohammadpour AH, Boskabady MH. Safety and tolerability of carvacrol in healthy subjects: a phase I clinical study. Drug Chem Toxicol. 2021 Mar;44(2):177-189.
Ghorani, V., Boskabady, M., & Boskabady, M. H. (2019). Effect of carvacrol on pulmonary function tests, and total and differential white blood cell counts in healthy volunteers: A randomized clinical trial. Avicenna journal of phytomedicine, 9(2), 134–142. PMC free article

Carvacrol oregano oil