Immunology and Homeopathy: The Rationale of the ‘Simile’

Introduction
The cardinal principle on which the theory of homeopathic medicine is based is that of ‘similarity’, according to which a homeopathic remedy in a healthy subject will produce certain sets of symptoms, while the same remedy will cure similar sets of symptoms in unhealthy (sick) subjects (1-3). Hahnemann’s theory withstands the test of time, and has been supported by scientific findings in an array of fields, including that of immuno-allergology, as described in previous lectures on the subject (4-7). This principle can now be integrated into a broad theory of the homeodynamics of living systems (Table 1).

Indeed, there is a need for viable hypotheses of homeopathy mechanism of action. One of the earliest systematic reviews of homeopathic clinical trials concludes: ‘… The amount of positive evidence even among the best studies came as a surprise to us. Based on this evidence we would readily accept that homeopathy can be efficacious, if only the mechanism of action were more plausible‘ (8).

Another controversial principle of homeopathy is that the strength of a remedy would be increased through its dilution, which is a process known as dynamization, or potentization. At the end of this report, we will briefly discuss this issue. In any event, there is the need to clarify a preliminary assumption: both molecular and non-molecular information (i.e. mechanic, acoustic, electromagnetic, quantum electrodynamic) operate biologically, and regulation through the ‘simile’ could work in both cases, since they are not conflicting one with the other.

The purpose of this lecture is to re-evaluate the principle of similarity through up-to-date scientific knowledge concerning many phenomena, from cell behavior to clinical practice (9-11). This will allow us to extrapolate a general working hypothesis according to which biologically active compounds (including highly diluted solutions) could have inverse or paradoxical effects, based on one or a combination of the following factors:

a.      non-linearity of response to different doses of the compound/signal,

b.     pathophysiological state of the treated organism and

c.     pharmacodynamics of the drug, particularly with regard to the rebound effects and long-term adaptation.

Non-linearity of the Dose-Response
In biological systems, non-linearity between dose and effect is the rule, rather than the exception. Even if this phenomenon does not clarify all the clinical effectiveness of homeopathy, the following controlled experimental models examine the similia principle.

Hormoligosis

The terms ‘hormoligosis’ and ‘hormesis’ refer to stimulation of biological systems by low-dose toxins and inhibitors, as shown in a number of experimental models (12-20). Early attempts to describe hormesis date back to 1877 when Schulz, while studying yeast metabolism, proved that almost all poisons have a weak stimulus effect at low doses (21,22). Together with R. Arndt, he then developed a principle, the so-called ‘Arndt-Schulz law’: ‘weak stimuli slightly increase biological responses, medium-strong stimuli markedly raise them, strong ones suppress them and very strong ones arrest them‘ (23).

In general, these hormetic effects can be documented by reverse-U dose-response plots or even more complex dose-response curves. In Fig. 1A, a typical hormetic (reverse-U shaped) curve is shown. Figure 1B shows the kinetic of low-dose and high-dose effects of inhibitors on a biological system: an overcompensatory response follows the initial decrease in activity due to inhibitor low doses. This may optimize the ability of an organism to meet challenges beyond the limits of normal (unexercised) adaptation.

Inhibition by Low Doses

A wide variety of substances exert opposing effects (inhibitory or stimulating) at low or high doses; this phenomenon is well documented in immunology. Figure 1C shows how specific antibody levels can change in mice inoculated with different antigen (bovine serum albumin) doses. At low or high antigen doses, the murine immune response is depressed (immune-tolerance), while there is a positive antibody-production response at intermediate doses.

Various factors contribute to the result, in conjunction with specific lymphocyte subset activation, different receptor sensitivities and the role of the tissue environment on the cell activation/suppression. At least two different mechanisms are responsible for T-cell auto-reactivity: high concentration of self-antigens causes cell depletion, while low doses cause a specific inhibition, known as bystander suppression. This low-dose regulation could be used to explain the effects of some homeopathic medicines (24). However, even with much scientific evidence, the concept of hormetic dose-response relationship is not integrated by mainstream schools of thought in toxicology (25).

Inverse Effects in a Leukocyte Model

The activation of human neutrophils shows a dose-dependence on bacterial peptides (Fig. 1D) (26,27). High doses (10^-6-10^-7 M) of bacterial peptides formyl-Methionyl-Leucyl-Phenylalanine (fMLP) were able to induce a marked increase in adhesiveness of human leukocytes, whereas 100 times lower doses (10^-8-10^-9 M) inhibited and reversed the adhesion induced by bacterial endotoxin (LPS) (28) or by migration into the inflammatory exudate (29).

This paradoxical effect of low-dose fMLP models is probably due to the ‘gating’ exerted by cyclicAMP (cAMP) at the level of intracellular signal transduction pathways (26). Figure 2 shows a schematic representation of a LPS-treated cell, with no fMLP (A), and low (B) and high (C) doses of fMLP. The latter bacterial peptide at low doses does not stimulate adhesion, whereas the intracellular cAMP increases, through activation of adenylate cyclase. cAMP is an intracellular messenger for many enzymes, including protein kinase A which, in turn, can inhibit the LPS-activated transduction machinery of adhesion (gating pathway). fMLP at high doses obtains full activation, using a different transduction pathway (represented in Fig. 2 by squares), thus by-passing the gating by cAMP.

The importance of cAMP has also been invoked in explaining other phenomena which recall the ‘simile’: interleukin-2 has opposite effects on B lymphocytes depending on intracellular cAMP levels (30); the inhibition of basophil responses by low doses (31) or high dilutions (32) of natural compounds may have a similar explanation at the level of signal transduction.

Furthermore, not only the gating theory explains the occurrence of inverse effects at a cell level: the presence of various receptors with both different affinities and different coupling capabilities to effector systems, or the induction of detoxification enzymes (gene expression and enzyme activation) should also be considered (33). Other authors (34-39) have elaborated different theories, based on the heat-shock protein system activation, or on the metabolism regulation and on toxicology. Those theories do not conflict with each other, but concern different levels of cell organization.

The Role of Pathophysiological State
The role of inflammatory processes is to control the structural integrity of organs and tissues, while the immune system controls the specific identity, or biological ‘selfness’, of molecules within the organism. Those systems are integrated with the peripheral and central nervous systems (40): mood and behavior disorders are associated with immunopathological disorders, with susceptibility to recurring infection, hypersensitivity, allergies, autoimmune diseases and diabetes. Homeopathic therapy should act by regulating the inflammatory and immune systems, both directly through molecular similarity, as seen in isopathic therapies, and indirectly through systemic interconnections, as shown in Fig. 3.

Figure 3. Typical neuroimmunoendocrine networks involved in the response to any type of stress (A) and possible dysfunction in chronic inflammatory diseases (B). 1. Cognitive functions, 2. neural networks, 3. hypothalamus, 4. locus ceruleus, 5. hypophysis, 6. sympathetic nervous system (adrenergic), 7. adrenals, 8. cardiovascular system, 9. immune system and inflammatory processes. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; IL-1, interleukin-1; IL-6, interleukin-6; TNF, tumor-necrosis factor; stimulation, inhibition.

The Response To Stress

Figure 3A shows a typical sequence of physiological mechanisms which maintain homeodynamics in the immune and endocrine systems. Psychosocial stressors activate the neuroendocrine pathways which, eventually, can lead to higher corticosteroid levels; uninterrupted strong stimulation can suppress the immune system, thus increasing susceptibility to infection (41,42). On the other hand, peripheral inflammatory cells are recruited and activated to counteract chemical or biological stress, producing molecular messages (cytokines) toward the central nervous system to build up a neuroendocrine response to stress. Increased steroid production, in conjunction with adrenergic stimulation, is important in a wide variety of adaptive responses, including regulation of inflammatory processes.

Repeated biological or physiological stress can cause internal communication failures, leading to the adaptation to a pathological state, more specifically, to chronic disease. Figure 3B depicts a typical loss of sensitivity to cytokines or to steroids. A variety of diseases are based on the lack of adaptability to environmental change through system or sub-system derangement. Immunodeficiency syndrome, atopic dermatitis, encephalomyelitis, coronary artery disease, chronic heart failure, anxiety and depression all exhibit an altered coordination or disruption of neuro-endocrine signaling. For example, glucocorticoid overproduction, combined with depression and chronic stress, cause destabilization in the glucocorticoid receptors to the feedback inhibition of the hypothalamus-pituitary-adrenal (HPA) axis and to an increase of inflammatory cytokines (43). Some chronic diseases, such as asthma, are considered as a type of pathologic adaptation of complex networks, which behave like semi-stable ‘attractors’ within the organism (11,44). This self-maintenance of disease, as organization of pathologic attractors in complex systems, can be regarded as an update to the ‘miasm’ concept of classic homeopathy (11,45-47).

The above theoretical background suggests that homeopathic medicine can regulate inflammatory and immunopathological processes as well as the neuroendocrine network and peripheral receptors. Homeopathic information mimics a pathophysiological stress, because it is able to induce symptoms of pathology, and, in the ‘already-stressed’ and inefficient organism, would re-activate a coherent response. In fact, homeopathy could have a positive effect on stress-induced behavior and on gastric and immunologic alterations in mice (48). Highly diluted histamine shows to be active on blood basophils, on skin inflammation reactions and on sleep patterns in rats (5,49).

The ‘Initial Value’ Rule

Biological responses strictly depend on the ‘starting conditions’ of any tissue or organ, and different starting conditions yield peculiar reverse responses to a drug. An example of different effects due to different cellular conditions can be found in macrophages—these cells are known to be activated, for example, by cytokines in a number of biological events including chronic inflammatory reactions, tumor defense, repair phenomena, atherosclerosis and so on. Interferons, endotoxins and tumor-necrosis factors (TNFs) increase resting macrophage functional capability, whereas they suppress previously activated macrophages (50). A related phenomenon was described by Wilder in the first decades of the past century in experimental settings (2,51,52). A typical report of Wilder’s findings is shown in Fig. 4. He recorded heart frequency and blood pressure (not shown in the figure) in dogs before and after the administration of 1 mg adrenalin.

Under normal conditions (Fig. 4, line 1) the drug causes an increase in both heart rate and blood pressure; these then plateau and finally revert to the resting state. This kinetic is due to the activation threshold of homeodynamic feedback response, conceivably due to vagus stimulation and to the inactivation of the stimulant. However, when the initial heart rate is elevated (high sympathetic tone of the test animal), the exogenous adrenaline response is different—the initial increase is less, prior to returning to the resting state (line 2). Thus, the net effect of the drug is the decrease in heart rate when compared with the initial rate. Starting with very low heart rate (vagotonic state, line 3), the response to adrenaline is higher than in normal animals, due to the system’s higher sensitivity to the drug and to a slower homeodynamic feedback threshold.

In humans, bronchial asthma is characterized by the increase of vagus activity on smooth bronchial musculature; under these conditions, adrenaline supports breathing, thanks to its dilating and relaxing effects. On the other hand, in normal subjects, adrenalin has little or no effects. In conclusion, the same treatment or similar treatments can cause different, if not opposite, effects, depending on the initial state of the system. This typical behavior has been described in different physiological systems (cardiovascular, hormonal, respiratory, nervous, etc.) and using various drugs (53,54).

More recently, a preliminary mathematical model of the action-reaction principles was developed looking at the ‘weak quantum theory’ and the ‘patient-practitioner entanglement’, based on the metaphor of a hypothetical gyroscope as physical representation of the vital force (55). Briefly, increase or decrease in the rate of spin of a hypothetical gyroscope (namely the ‘vital force’) was described in terms of quantized ‘shift operators’ constructed mathematically from the ‘complementarity’ of a remedy’s primary and secondary symptoms. Therefore, the vital force was studied as a ‘wave function’ able to illustrate the biphasal action of remedies encapsulated in the Arndt-Schulz law, Wilder’s law of initial value and some of the results of homeopathic provings.

Rebound Effects and Paradoxical Pharmacology
Inverse drug effects are evident by changing their schedule or treatment duration, or the observation period of the therapy: short treatment can be stimulating, whereas longer treatment can be inhibitory (or opposite, based on the experimental model). This area includes the so-called ‘paradoxical pharmacology’ (56): chronic and acute treatments produce opposite effects, similar to those of a single physical exercise, which will increase blood pressure, whereas ongoing training will regulate it. Obvious evidence of these phenomena is observed in receptor-mediated events and in heart failure progression: the time-course of ß-blocker treatment during heart failure can be described as an immediate worsening of the patient, whose condition then improves, with a net result of a decrease in death by heart failure in the long term. This paradox can be described in terms of beta-receptor protection from overexposure, which is a phenomenon generally associated with desensitization and decreased signaling.

In addition to analgesia, opioids cause hyperalgesic effects, depending on whether treatment is acute or chronic, which have many clinical implications (57). Antiepileptic drugs can frequently aggravate epilepsy by way of an inverse pharmacodynamic effect (58). The same secondary reaction of the organism can be described for hundreds of modern drugs, including antiinflammatory agents (59), and can be referred to as the rebound effect. The drug’s primary effect forces the organism toward a reaction against its own upsets by way of a vital (paradoxical, secondary or compensating) reaction.

If acute and chronic responses are often opposite in nature, and if the drug’s counter-indications are based on its acute effects, it is possible to find scientific input to study paradoxical pharmacology—the list of drug contra-indications, since ‘the opposite of contraindicated is indicated …’ (56). A rapid initial decline may produce long-term beneficial effects (60,61). Therefore, paradoxical and rebound effects could be considered curative, thus allowing a connection between homeopathic ‘simile’ and traditional pharmacology (62).

General Model of the ‘Simile‘
Having analyzed a few possible applications of the ‘similarity’ in biological systems, we will now describe a general model of this core principle of homeopathy. In previous studies (10,11,27,63), the concept of ‘regulation of stressed homeodynamic networks‘ was introduced, based on how the networks react to stress, and on the possible role of homeopathic self-recovery regulation. Here we summarize and update this conceptual model, which can help rationalize the basic mechanisms of homeopathic simile on different levels of biological organization (molecular, cellular, organic and systemic).

Homeodynamics of Biological Systems

The concept of homeostasis (more correctly referred to as ‘homeodynamics’), introduced by physiologist W. B. Cannon (64), refers to those activities which tend to maintain the variables of a vital system constant, or within acceptable limits. Hahnemann himself based his medical system on the action and reaction principle. In paragraph 3 of the ‘Organon’, he describes this fundamental principle: ‘Every agent that acts upon vitality, every medicine, deranges more or less the vital force, and causes a certain alteration in the health of the individual for a longer or a shorter period. This is termed primary action. To its action our vital force endeavours to oppose its own energy. This resistant action is a property, it is indeed an automatic action of our life-preserving power, which goes by the name of secondary action or counteraction‘.

The Feed-back is the Core of Homeodynamics

To illustrate homeodynamic concepts, it is best to refer to the simple model in Fig. 5A. We will consider the variable A-A’ in a state of imbalance and in reversible conditions due to the actions of two operator or effector mechanisms, which can move A towards A’ and vice versa. We refer to A as the normal condition and A’ as a far-from-equilibrium (stressed, or diseased) condition. No homeodynamic variable can properly function without a form of control, represented by one or more regulatory systems which receive information from A’ in the form of signal ‘a’, which is associated with its specific state (for example, an enzyme reaction product proportional to how much of A’ is present or to how much of A’ is functioning). Having received the ‘a’ signals (for which it has specific receptors), the control system is activated and produces the ‘r’ signal, which inhibits the A-A’ conversion, or activates the A’-A conversion. Figure 5A illustrates that the signals are considered capable of affecting other systems or other effector mechanisms, in the same way as the regulatory system can have different receptors which bind different active signals. Therefore, all homeodynamic systems are included in a broad network built on multiple elements. The model in this figure is simplified; in fact, it only shows the central feed-back structure of the complex biological homeodynamics.

The Reaction Phase

When a perturbing factor comes into play, the balance shifts to A’ (Fig. 5B) and an increase of the ‘a’ signal occurs. The regulatory system, in turn, enhances its own activity, thus producing a higher quantity of the ‘r’ signal. For example, if ‘a’ is a signal molecule (e.g. interleukin-1, cytokines, interferons) released from inflammatory exudate, the immune system produces more ‘r’ signal (e.g. antibodies, interleukin-2), thus bringing the effector system (phagocytes or complement) back to its normal homeodynamic, by eliminating A’ excess and re-establishing A condition (healing). In the initial phase of disease, the system reacts logically and efficiently in the direction of balance and health. Of course, if ‘a’ signal was an inhibitor, the A-A’ perturbation would be followed by decrease of regulatory system’s function (not described in the figure).

As shown in Fig. 5B, symptoms will appear when physiologic systems are under stress, far from the equilibrium. Symptoms are associated with endogenous regulatory system activation (or inhibition), more than with the direct damage due to the stressor/pathogenic factor. In infectious diseases, for example, fever, fatigue, loss of appetite, tachycardia and skin rashes are the product of the organism’s reaction, primarily due to molecular signals, such as complement factors, kinins, interleukin-6, adrenalin and TNF.

Generally speaking, the initial response of a regulatory system is associated with the priming of its own sensitivity with respect to the signal, represented in Fig. 5B as an increase in the number of surface receptors within the system. This pre-activation was described by us in leukocytes as ‘homologous priming’ (65) and may also involve increase of receptor sensitivity or of signal transduction. However, priming is usually not specific, owing to the increase of sensitivity also to other stimuli (heterologous priming), here represented as the exposure of new receptors by the regulatory system for substances other than ‘a’. This event is functional to adapting to new environmental conditions and to reinforcing network communications. For example, when a cell, such as a lymphocyte (a primary component of host defenses), becomes stimulated by a cytokine or another specific antigen, it becomes ‘primed’ to express a higher number of receptors to more compounds. Other examples of priming are bronchial reactivity in asthmatics following antigenic stimulation, liver induction of detoxifying enzymes following alcohol or drug ingestion, cardiac hypertrophy following physical exercise and increase of synaptic strength in neurons (memory).

Homeopathic Proving

Figure 5C shows a schematic view of homeopathic proving: in a ‘healthy’ regulating system network, an exogenous pharmacological signal could trigger many activities which mimic the reaction to stress. In accordance with homeopathic principles, because most symptoms derive from homeodynamic system activation, it should somehow be possible to reproduce their activation with a compound capable of provoking symptoms in healthy and sensitive subjects. Theoretically, symptoms similar to natural reaction can be reproduced by administering an activating (or inhibiting) substance through homologous or heterologous receptors. The resulting pattern of characteristic signs is the ‘portrait’ of a disease involving the same regulatory systems in reaction to a natural stressor.

Homeopathic Regulation

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