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The Journal of Alternative and Complementary Medicine Vol. 24, No. 11, pp. 1032-1038

Could the Olfactory System Be a Target for Homeopathic Remedies as Nanomedicines?

Florence Courtens (1), Jean-Louis Demangeat (2), and Mourad Benabdallah (3)

1 Private Practice, Orchies, France.
2 Nuclear Medicine Department, General Hospital, Haguenau, France.
3 Private Practice, Arras, France.

Abstract

Homeopathic remedies (HRs) contain odorant molecules such as flavonoids or terpenes and can lose their efficiency in presence of some competitive odors. Such similarities, along with extreme sensitivity of the olfactory system, widespread presence of olfactory receptors over all organic tissues (where they have metabolic roles besides perception of odors), and potential direct access to the brain through olfactory nerves (ONs) and trigeminal nerves, may suggest the olfactory system as target for HRs. Recent works highlighted that HRs exist in a dual form, that is, a still molecular form at low dilution and a nanoparticulate form at high dilution, and that remnants of source remedy persist in extremely high dilutions. From the literature, both odorants and nanoparticles (NPs) can enter the body through inhalation, digestive absorption, or through the skin, especially, NPs or viruses can directly reach the brain through axons of nerves. Assuming that HRs are recognized by olfactory receptors, their information could be transmitted to numerous tissues through receptor–ligand interaction, or to the brain by either activating the axon potential of ONs and trigeminal nerves or, in their nanoparticulate form, by translocating through axons of these nerves. Moreover, the nanoparticulate form may activate the immune system at multiple levels, induce systemic various biological responses through the pituitary axis and inflammation factors, or modulate gene expression at the cellular level. As immunity, inflammation, pituitary axis, and olfactory system are closely linked together, their permanent interaction triggered by olfactory receptors may thus ensure homeostasis.

Free full text:
https://www.liebertpub.com/doi/full/10.1089/acm.2018.0039

Excerpts:

"Homeopathic remedies (HRs) contain plant, animal, mineral, and metal products with specific odors such as flavonoids and terpenes in plant extracts, for example,1–5 and two well-recognized homeopaths, Hahnemann and Schmidt, asked their patients to smell HRs.6–9 Odorant molecules (OMs) and HRs share some properties: some OMs can enhance the perception of other OMs, and some odors can inhibit HRs efficiency.6–8,10,11 Too, OMs can exhibit different odors depending on the level of concentration in a manner analogous to how HRs can have inverse reaction depending on the level of dilution (hormesis).11,12 Some studies have demonstrated effects of HRs through inhalation,13–18 but HRs are generally too dilute for an odor to be consciously recognized.

"Two hypotheses explain the differential sensitivity of individuals toward OMs, and maybe toward HRs: different levels of olfactory receptors (ORs) gene expression and anatomical differences in the nasal cavity, both resulting from genetic polymorphism.19,20 Notion of competitiveness, modifications of electroencephalogram (EEG) during inhalation, and modifications of genes expression, among which those of ORs by high dilutions of Gelsemium,21 strongly suggest that ORs can be a target for HRs."

"Up to now, nobody is able to explain the way homeopathy operates and this medicine acting at infinitesimal dose became a subject of distrust and sarcasm. In contrast, nanomedicine is expanding rapidly in both allopathic and homeopathic5 fields. Recently, several groups1,22–30 have highlighted the presence of nanoparticles (NPs) in highly diluted HRs. Bellavite and coworkers described how HRs, at different levels of dilution, can influence immunity and inflammatory factors and even modulate gene expression,2,21 based on a ligand–effector type interaction, whereas Bell et al.1,28–30 suggested a systemic reaction to HRs as stressors.31,32

"Demangeat33 suggested that the two concepts would not contradict each other but rather reflect a dual character of HRs depending on their level of dilution. At low dilution, below C2–C4, HRs in a still molecular nature would act locally on cellular or intracellular receptors, whereas at high dilution, in a nanoparticulate form, they would cross cell membranes and physiological barriers as mucous membranes, lungs, blood–brain barrier5 (BBB), or would directly reach the brain through a neural pathway."

"First, Benabdallah34 and McGuigan10 suggested that the vomeronasal organ (VNO), which is very sensitive and able to induce a stereotypical behavior, could be a target for HRs...Bombyx pheromone can be detected at exposure levels of about 200 molecules per cm,3 equivalent to a homeopathic dilution between C8 and C9.35"

"Human sense of smell can detect extremely low concentrations of odorants,53,54 as low as 10^-18 g/L,55 equivalent to a C9 homeopathic dilution."

"HRs may take two forms depending on dilution levels. Low dilutions, below C2–C4, could still contain molecules in ponderable and subponderal amounts and bind specific targets as conventional remedies do, whereas high dilutions could contain the active ingredient in nanoparticulate forms that contain silica and nanobubbles, produced by shaking the remedy during the specific dynamization procedure of manufacturing. Assuming that such nanoparticulate forms of HRs possess similar properties as conventional NPs, they would exhibit much higher bioavailability, membrane permeability, and intracellular reactivity than the molecular form.106,107 Such properties drastically depend on NPs size, shape, charge surface, and lipophilicy.108,109 It has been shown by Demangeat33 that sizes of nanostructures in HRs depend of the level of dilution/dynamization. So, the structural duality may explain various and even paradoxical actions of HRs according to their dilution levels."

"Both OMs and NPs can enter the body through inhalation, digestive absorption, or across the skin.41 They can potentially directly reach all ORs located on organic tissues except those of the brain, which can be reached only through the ONs and trigeminal nerves or by crossing the BBB.31,59,110–114...As demonstrated several years ago, polio virus and other NPs can translocate from the nose to OB65,114 and then be found within microglia and in deeper brain regions.69"

"Inhaled NPs can penetrate into the lung interstitial tissue where they can be stored for years."

"NPs can induce various biological responses: inflammatory response, oxidative stress, modulation of gene expression, effects on cell cycle control, and proliferation.109"

"The olfactory system is the main gateway to reach the brain and the immune system, and ORs are widespread on all organic tissues; thus, the olfactory system could constitute a suitable explanation for central, local, and immune action of HRs. Moreover, clinical effects are observed for HRs administered through inhalation, and HRs exhibit similar properties as OMs. The complex reality of homeopathy may be explained by the specific manufacturing process of dilution/dynamization, which generates different structural properties of the remedy according to the level of dilution, especially nanoparticulate forms at high dilution. The present speculations only constitute a clue that raises many questions and prompts to further investigations, such as (1) tracking homeopathic NPs through the nerves and into the brain by animal studies, (2) studying EEG responses to various dilutions of a definite HR, (3) identifying immune responses from the NALT, or (4) directly studying the action of HRs on ORs from different tissues by in vitro studies."

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Comments: as we have discussed before, the "nanoparticulate" proposal cannot account for homeopathy.  There may be some contaminating bits of metal or silica detected by some researchers, but they arise from the manufacture, not from the original remedy, and they cannot give rise to the alleged properties of homeopathic remedies.

The authors try to make a case that the concentration of molecules in some homeopathic remedies is comparable to the concentration of pheromones or odorants that can trigger responses in insects or humans.  This comparison is not valid.  The pheromone or odorant concentrations refer to molecules or g per volume of air, and the insect antenna or human nose would be exposed to large volumes of air, so occasionally a molecule could interact.  In contrast, the homeopathic remedy is in a solid or liquid form.  If it were ingested, even if there were a few molecules per cubic centimeter, the chance that one would survive the digestive tract, be absorbed, and reach a target in the olfactory system would be negligible.

I was not familiar with administering homeopathic remedies by inhalation, so I looked up the first paper referred to by the author in the sentence "Some studies have demonstrated effects of HRs through inhalation..." (Bell et al., Homeopathy 100(4)203-11 (2011).
https://www.ncbi.nlm.nih.gov/pubmed/21962194
Here the subjects made several 2 second sniffs with a vial of the homeopathic remedy placed near the nose.  Even if the vial itself contained a few molecules of the original substance, it would seem that the probability that some of these would enter the vapor phase and reach the nose in these sniffs would be negligible.
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