Morgellons Disease: A hallucinatory parasitosis due to low NO?

Morgellons Disease (MD) is a complex association of symptoms with several suggested explanations. I will add another explanation, that of low nitric oxide. I think my explanation does fit the reported symptoms somewhat better (and simultaneously) and suggests a treatment (increase NO levels). Low NO as an exacerbating factor is consistent with the symptoms and may provide at least some relief (actual and symptomatic) no matter the ultimate "cause".

The two leading explanations are Delusion of Parasitosis (DoP), and actual infestation with unknown disease organism(s) and/or unknown parasite(s). I will go into the symptoms and how the symptoms can be explained by low NO, and then suggest why low NO in particular would lead to feelings and ultimately belief that parasites are infesting the skin. I think calling it a "delusion" while technically correct (depending on the definition of delusion) may not be helpful in that symptoms which lead patient to that conclusion are quite real and not made up. I think calling it a hallucination would be more accurate and perhaps be perceived as less pejorative to those who experience it. The default conclusion that chronic itching of the skin is caused by parasites may be something that is "hard wired" in our nervous systems. An analogy would be phantom pain in a limb that has been amputated. Are people who experience phantom pain called delusional? If not, then people who experience "phantom parasites" should not be called delusional either. The "hallucination" is not in the peoples' heads, it is in their skin. It is low NO in the skin that causes the itching, low NO in the brain does lead to some clouding of thinking, and also causes fatigue and exercise intolerance.

People have many beliefs based on much less evidence than an itching and crawly feelings on the skin and are not considered "delusional" (by some at least) (think astrology, magic, ghosts, superstitions, religion). Morgellons may be thought of as a "parasitosis of the gaps", a parasitosis consistent with symptoms and all the evidence that the believer (a non expert in physiology and parasites) is aware of, the way some consider a belief in supernatural events non-delusional because they are consistent with all the evidence the believer (a non-expert in science) is aware of.

I think the mechanism is by low NO increasing the "gain" on injury detection pathways until the injury detecting pathways begin detecting injuries that are not there. They are as much phantom injuries as the phantom injuries experience in missing limbs.

Symptoms (other than presence of unknown parasites) are all consistent with low NO. Actual infestation with parasites would be expected to increase NO levels via expression of iNOS following activation of NFkB. That would be expected to increase systemic NO levels and might relieve some of the symptoms consistent with low basal NO. Intestinal worms are an effective treatment for Crohn's disease [1] and also protect against asthma in a mouse model [2]

That the presence of unknown filaments has not been resolved is quite strange to me. It is simply not possible that filaments could be looked at seriously and not identified as being parasitic in nature (if they were). Any worm-like parasite has to have characteristic internal structures. Any serious microscopic look at unknown filaments would necessarily involve potting the filaments in a suitable embedding media and taking slices so the internal structure of any filament could be observed. This would unambiguously show if the fiber was part of a worm. A fiber may remain unidentified, but if it is any type of living organism it has to have internal structures that would be unambiguous. I suppose it is possible that every case where there was an actual parasite the people investigating it have been so incompetent they didn't identify it as being parasitic in nature, but that strains credibility. It is more likely that competent investigators did identify all fibers they observed as non-parasites and diagnosed DoP, patients rejected that diagnosis and went to another health care professional who was unable or unwilling to unambiguously identify the fiber as non-parasitic.

Parasites infesting skin have been a problem for many millions of years. Organisms have evolved many different pathways to detect those parasites and to evoke compensatory responses. Itching and the urge to scratch that itch are a primary parasite reduction mechanism and are mediated through quite complex physiological pathways.[3] Essentially all organisms have this response to parasites, and some plants (such as nettles) have evolved mechanisms to specifically activate them demonstrating itching pathways must come from deep evolutionary time. Attempting to cognitively over ride such deep instinctive responses will be difficult, problematic and highly stressful. The more likely outcome is that cognition will be used to explain the symptoms by generating a plausible "cause", and this is what leads to DoP. The best solution would be to resolve the feelings of itch, which will then resolve any need to cognitively explain them.

Non-human primates spend large amounts of time grooming each other. Presumably much of this is for the removal of parasites. Human skin has much less hair, so parasites are much easier to find and remove.

The symptoms are listed on the website for Morgellons Disease, Morgellons Symptoms. I have a brief (NO explanation) following the symptom.

1. “Filaments:” (hardest to explain, Amyloid and other protein fibrils are generic symptom of proteasome inhibition [4] (and likely low ATP due to low NO too) but length scales of known materials not consistent with posted images (at least 10x scale difference). Contamination with environmental fibers most likely explanation.)

2. Movement sensations: (sequential activation of any sensation along a path on the skin will be interpreted as movement along that path. Low NO induces hypersensitivity of mast cell degranulation might make degranulation self-propagating via diffusible agents, proteases, histamine, ROS or NO.)

3. Skin lesions: (mast cell degranulation can produce lesions, scratching would exacerbate.)

4. Musculoskeletal Effects and Pain: (Pain generic symptom of ATP insufficiency as when muscles are worked to extreme exhaustion.)

5. Aerobic limitation: (low NO leads to fewer mitochondria, low aerobic ATP production rate and exercise intolerance)

6. Cognitive dysfunction: (low NO leads to low ATP, low ATP can invoke acute psychosis, NO mediates functional connectivity in neural networks (my hypothesis), low NO reduce neural network functionality, default mental state is non-cognitive low enough NO will invoke that state.)

7. Emotional effects: (Low NO invokes chronic stress and "fight or flight". Lowers the threshold for stress induced mental and physiological changes).

1. Shifting visual acuity: (light signal transduction in retina via cGMP gated channels. [5] Basal NO sets background level cGMP by basal activation sGC. NO modulates on/off response retinal cells [6]) (common effect of cocaine abuse, alcohol withdrawal, migraine see below)

2. Numerous neurological symptoms and clinical findings: (NO involved in many pathways (hundreds or thousands). Low basal NO affects all NO pathways with no threshold).

3. Gastrointestinal symptoms: (GI tract neuronal control largely via NO. [7]Dysregulated NO will impede normal function, [8]Nitroglycerine potentiates bowel peristalsis and sphincter relaxation [9]) Actual infestation with parasitic worms improves Crohn's Disease symptoms (likely mediated through NO from iNOS).

4. Acute changes in skin texture and pigment:
5. Arthralgias:

Common laboratory abnormalities: elevated cytokines, TNF-alpha, C-reactive protein, low hematocrit, elevated blood glucose, elevated insulin.
(NFkB regulates expression of many cytokines [10], NO inhibits NFkB, so low NO would lead to higher levels of cytokines. Hemoglobin is the sink for NO, NO causes activation HIFa1 which causes expression of erythropoietin increasing hematocrit. Low hematocrit is thus a compensatory response to low NO (my hypothesis). Fewer mitochondria mean more ATP via glycolysis requires increased blood sugar, increased insulin, and induces insulin resistance to allow insulin to get to tissues far from capillary.)

Aerobic limitation: (not enough ATP, not enough O2, not enough NO, not enough mitochondria, not enough glucose)

Aerobic limitation is said to be universal in Morgellons and accompanied by increased resting heart rate. Aerobic limitation is an inability to sustain aerobic production of work and is accompanied by breathlessness. The natural assumption is that breathlessness is caused by insufficient O2. However this is not always the case. For example Chronic Obstructive Pulmonary Disease (COPD) is always accompanied by breathlessness upon even modest exercise. This breathlessness is not relieved by breathing 40% O2. [11]Short burst O2 before and following exercise doesn't increase maximal exercise or reduce recovery times. [12] If breathing O2 neither increases the work that can be performed, nor decreases recovery time then a lack of O2 is not the reason for the breathlessness or the work limitation in the first place. The sensation of "breathlessness" is due to exuberant activation of the urge to breathe. There are 3 known mechanisms, low O2, high CO2 and high S-nitrosothiols. [13] For any of these to be useful in signaling the need to breathe, they must vary within their respective active ranges in the times scales important in breathing, faster than minutes. In the above paper (Stevenson and Calverley), they find that breathing with a nose clip significantly reduced aerobic work production and prolonged recovery times compared to breathing through a mask which allowed nose breathing. [14] They suggest invocation of some sort of "diving reflex", but I think NO from the nasal passages is a more plausible explanation.

The ultimate source of energy for muscle is ATP, supplied by mitochondria, glycolysis or creatinine kinase. Mitochondria are the only aerobic ATP source. Insufficient mitochondria would limit aerobic ATP production. Mitochondria have a limited lifetime and are replaced every night. What triggers mitochondria biogenesis is nitric oxide. [15] Lower NO will then lead to fewer mitochondria. Elevated blood glucose would follow from insufficient mitochondria which would necessitate an increase in the amount of ATP produced by glycolysis. It takes 20 times more glucose to produce the same ATP via glycolysis as via oxidation in mitochondria. Normally cells make ATP from glycolysis and then oxidize the lactate produced to make ATP from oxidation. If ATP from mitochondria is reduced by 5%, it will take twice as much glucose to make up for that ATP via glycolysis. Insufficient mitochondria explain the elevated glucose and elevated insulin. The only way more glucose can be delivered to cells is by increasing blood sugar. Glucose transport into cells is active, mediated by GLUT transporters which are increased by insulin. Lower mitochondria will lead to elevated blood sugar and elevated blood insulin.

Elevated TNF-alpha down regulates eNOS expression and inhibits mitochondria biogenesis. [16] Less than complete replacement of mitochondria will eventually lead to aerobic limitation due to a lack of mitochondria to produce aerobic ATP in the muscles. This may or may not be accompanied by breathlessness. Exertional weakness due to reduce mitochondria would not be correctable via oxygen breathing.

Mitochondria can produce different amounts of ATP. At rest most cellular ATP in muscle is produced by mitochondria. Aerobic ATP production can be increased 10x. This is done by increasing the mitochondrial potential, which increases the driving force for ATP production. It also increases the production of superoxide which serves to pull down the local NO level, disinhibit cytochrome c oxidase and allow O2 to be consumed to a low concentration so a larger concentration gradient develops between the blood vessel and the mitochondria so a larger O2 flux can occur down that concentration gradient. Chronic fatigue syndrome is characterized by reduced oxidative ATP production in muscle. [17] If elevated superoxide levels due to operating mitochondria at higher potentials persists during cycles of mitochondria biogenesis, the low NO produced by mitochondria superoxide is expected to reduce mitochondria biogenesis and make the low mitochondria state self-perpetuating (my hypothesis). A symptom that is consistent with this is a "hypermetabolic state", that is a basal metabolism that is higher than would be expected from lean body mass. I attribute this to fewer mitochondria and a higher mitochondria potential where there is more "slip", where the production of ATP is less efficient. It then takes more substrate and O2 to make the same ATP for basal metabolic needs. A hypermetabolic state is observed in some disorders of too few mitochondria characterized by chronic fatigue including obesity, ALS, [18] liver cirrhosis, [19] COPD. [20] Just about everything that produces a hypermetabolic state is also characterized by fatigue, but not everything that produces fatigue also produces a hypermetabolic state. Why that appears to be the case is something I am still trying to figure out. I think it depends on which tissue compartment is most affected by mitochondria depletion. Muscle can use lipid and so isn't entirely dependant on the liver and kidneys for glucose. The nervous system and immune system are, so a hypermetabolic state in them might cascade to the liver and kidneys and cause a hypermetabolic state there. It might not be just mitochondria potential, but too much lactate and glucose running through the Cori cycle increasing ATP demand in the liver and kidneys.

There is some evidence that the skin can also perform glucogenesis. [21] That might make the skin a target organ for a hypermetabolic state. That might explain why the symptoms of itching are common in both liver cirrhosis and end stage kidney failure. The liver and the kidneys are the main sites of gluconeogenesis. If they become compromised, more gluconeogenesis has to be done in other organs, including the skin (no doubt). The specific production of glucose in the skin (g/g tissue) is smaller than in the liver, but the skin is considerably larger than the liver. The skin having the capacity for gluconeogenesis is an advantage in that the skin derives O2 from the external air.

Some instances of chronic fatigue have been associated with a "trigger" by patients (n=134) including an apparent infection (72%), none (17%), surgery/trauma (9%), allergy (2%). [22] Low NO could occur due to rebound from NFkB activation or due to a hypermetabolic state. Some CFS is consistent with an immune system operating at a higher "gain". [23] Individuals with CFS have lower levels of bacterial DNA circulating in their blood than do normal controls. [24]

Infectious diseases most associated with CFS include Q-fever [25] which happens to be an intralysosomal disease. NO specifically inhibits replication of the Q-fever agent. [26]

Skin sensations

Many important immune and sensory functions in the skin are mediated via mast cells. [27] These are cells that contain a variety of chemicals stored in vesicles in the cell which are released upon activation (degranulation) by a number of different stimuli. These chemicals include histamine, leukotrienes, proteases, and cytokines such as TNF-alpha. These chemicals are responsible for many of the acute responses of skin to noxious stimuli including itching (one mechanism via the release of histamine). The itch response to nettles and the plant hairs used as itching powder is due to histamine release due to serotonin in the plant hairs. The use of SSRIs to treat the itching of primary biliary cirrhosis is well documented. [28] Presumably the SSRIs cause a desensitization of the mast cells to serotonin which reduces their activation.

For the relatively sparse distribution of mast cells in the skin to be effective, they must communicate and activation of one cell must lead to activation of adjacent cells (to some extent). To robustly "turn on" the mast cell response and produce hysteresis, there must be positive feedback where some agent released by mast cells during degranulation causes the degranulation of adjacent mast cells. There must also be inhibitory agents released (otherwise the entire skin would become activated). Activation of mast cells does cause what is called "immediate hypersensitivity". The extent of mast cell activation and then deactivation (physical and over time) will depend on the balance of activation and inhibition. Anything that tips that balance more to activation will induce hypersensitivity and inappropriate itching.

NO inhibits mast cell degranulation,[29] protease release [30] and low NO potentiates mast cell histamine release and ROS generation. [31] Low NO will then increase the release of cytokines in skin. Because NO is one of the regulators of mast cell degranulation, low NO will increase the sensitivity of mast cells to every other stimuli that causes degranulation. Mast cells generate ROS but not NO [32]. By generating ROS, mast cells decrease the NO level and so increase the sensitivity of other nearby mast cells to be triggered. This reduced NO level also sensitizes other activities including apoptosis (see below).

Skin contains xanthine dehydrogenase (XDH) and when acted upon by proteases irreversibly forms xanthine oxidase (XO) which makes superoxide which lowers NO levels still more. What deactivates XO is NO in the presence of superoxide which oxidizes the Mo-S reaction center releasing S and forming Mo=O. [33] This deactivated enzyme can be reactivated via sulfurization. Both XO and XDH reduce nitrate to nitrite and nitrite to NO. [34] I divert into XO and XDH chemistry is because of their importance in NO generation in vivo, but also because the main inhibitor of XO and XDH used pharmacologically is allopurinol, which is a leading cause of Stevens Johnson Syndrome. [35] A major mechanism of SJS seems to be some sort of hypersensitive immune reaction in the skin involving soluble fas ligand produced by peripheral blood mononuclear cells. NO involvement is plausible because hypersensitivity to allopurinol is very strongly associated with a specific allele in the Major Histocompatibility Complex, HLA-B*5801. [36] The hypersensitivity does seem to be mediated through peripheral mononuclear blood cells. SJS and the more serious Toxic Epidermal Necrolysis (TEN) can be blocked by human immunoglobulin [37] which blocks the fasL or CD95L apoptosis inducing receptor. This therapy also works in children. [38] It turns out that fas mediated apoptosis is highly regulated by NO, and exogenously applied NO specifically inhibits apoptosis mediated through the fas CD95L pathway and NOS inhibition potentiates apoptosis. [39]

I suspect that SJS and TEN are due in part to high levels of oxidative stress in the skin, sufficient to cause NO depletion which then primes cells expressing the CD95L receptor to be hypersensitive to apoptosis. Virtually all of the xenobiotic chemicals that can produce SJS or TEN are metabolized by the cytochrome P450 enzyme system which is quite uncoupled and so makes significant ROS when it metabolizes substrate. If the basal NO level is not high enough to confine that oxidative stress state to the microsome containing the P450 enzyme, then the oxidative stress state can propagate outside and perturb physiology beyond the microsome. I suspect that this is the mechanism for multiple chemical hypersensitivity. A pathologically low NO level (and NO production rate) which cannot tolerate even tiny amounts of superoxide from activation of the cytochrome P450 system by xenobiotic chemicals.

Mast cells also become hypersensitive activated by low NO and a round of positive feedback makes everything quite dicey for a while. If they release proteases which convert XDH to XO, the level of superoxide will go up and can't go down until the XO is inhibited but that takes NO. [40]

Chronic antibiotic use: Herxheimer reaction?

The use of chronic antibiotic treatment has been reported to improve symptoms associated with MD, and also for what is sometimes called Chronic Lyme Disease (also called post Lyme disease syndrome), which has some similarities to MD.

Bacterial infections are not expected to be controlled by long term antibiotic use. Either the bacteria are non-resistant and will be rapidly cleared, or they are resistant and will be unaffected, or they will develop resistance and the infection will worsen. A long term course of antibiotics is then expected either to have no effect, or to result in a worsening of symptoms as resistance develops.

Target organisms are not the only bacteria resident in the human receiving antibiotics. An adult human is reported to have more bacterial cells than human cells with a biomass of about 1.5 kg. [41] Even long term antibiotic treatment doesn't render the human gut sterile. No doubt many of these bacteria are killed by the antibiotics even when taken chronically. When bacteria are killed during antibiotic treatment, the contents of the dead bacteria spill into the infected tissues and can cause a severe immune reaction, the Jarisch-Herxheimer reaction, [42] originally found during chemotherapy for syphilis.

There are reports that antibiotics have anti-inflammatory properties. What they may be seeing is the effect of antibiotics on commensal bacteria. Either a reduction in inflammatory agents produced by those bacteria, or compensatory rebound by endogenous anti-inflammatory agents to a Jarisch-Herxheimer reaction. NO from iNOS expressed due to a Jarisch-Herxheimer reaction would be an example.

Hallucinations of extreme metabolic states: Cocaine, Alcohol Withdrawal, Migraine, Mania, Euphoric Near Death State (ENDS), Solvent Abuse, Autoerotic Asphyxiation, Drowning

Many of the hallucinatory symptoms of MD seem to be similar to those of extreme metabolic stress. I suspect because all of these states are similar in that they are characterized by low NO. I hypothesize that the reason that people somaticize when under stress is because of the physiology that stress invokes. These are adaptive responses to better cope with and survive what ever caused the stress in the first place.

If you are under stress because you are in a war zone or other dangerous or potentially injurious situation, it would be adaptive if your body was more sensitive to telling you if it was injured so you could deal with it. I suspect the mechanism to do this is by increasing the "gain" on the physiological processes that detect injury to 11. With a high enough gain, those systems will start to "detect" injuries that are not there. This is the physiology of somaticization; increase the "gain" to 11. If you are under "real" stress, such as from being chased by a bear, the "gain" goes to zero, and you completely ignore injury and pain, even those that can cause death.

At the physical endurance limit, during a near death physiological state such as is invoked when running from a bear (where to be caught is certain death) small injuries and even large injuries must be ignored and disregarded if one is to escape and survive. Evolution has configured organisms to enter a euphoric state when under near death physiologic stress. I think that is the source of the euphoria in the manic state. I think that is also the source of the euphoria of the stimulant drugs of abuse, the source of the euphoria of solvent abuse, the source of the euphoria during drowning, the source of the euphoria in autoerotic asphyxiation.

If organisms could easily enter that euphoric state they would do so and would risk death with no survival benefit. Evolution has configured organisms such that there is an aversive state between "normal" and the Euphoric Near Death State (ENDS makes a good acronym). I think that aversive state is what depression is, and is also what the physical symptoms commonly attributed to somaticization are. Aversive feelings your body is producing to try and get you to stop doing what ever it is that is invoking that physiological state.

A major factor in regulating the physiologic responses to stress is the nitric oxide level. A high stress state is a low NO state. Anything that lowers NO levels is going to invoke this state to some extent. With NO being a major regulatory signaling molecule in many stress pathways, a lower basal NO level will increase the gain on all of these pathways.

Cocaine does reduce NO production in endothelial cells. [43] In dogs, cocaine binging lowers NO production and also accelerate pacing induced cardiomyopathy. [44] Blocking nitric oxide synthase increases cardiac hypertrophy and fibrosis. [45]

Cocaine is a stimulant drug of abuse. It also causes and/or exacerbates essentially all of the degenerative diseases, as does methamphetamine abuse which also causes WMH. [46] My hypothesis is that this occurs because cocaine induces the near death metabolic state and so causes the euphoria of the "Euphoric Near Death State" (ENDS), the euphoric state that physiology induces when one is "running from a bear" and to be caught is certain death where an organism must be able to endure any injury short of death in order to survive. I discuss the details of this in my acute psychosis blog. This state induces many delusions, in particular the "runner's high", the delusion that you are not tired and can run forever. A very useful delusion when one is running from a bear and to stop to rest is to be caught and eaten. I think that depression is the generic aversive state that physiology must have between the "normal" state and the "near death metabolic state". If organisms could enter the euphoric state easily, they would, and would run themselves to death without need.

I think the somatic feelings of pain, injury and hypersensitivity to injury of the somaticized state are the somatic equivalents of "depression". The aversive state between "normal" and the ENDS.

The "near death metabolic state" is a low NO state. All organism resources are diverted to the "running from a bear" acute ATP need. Everything else is a luxury that is put off until after "the bear" has been escaped from.

So what are cocaine induced hallucinations? They are usually not associated with acute use, but more with chronic use after several days. They include:

Perceptual hallucinations typified by "cocaine bugs". Described by Freud [47] as "similar to that associated with delirium tremens: “A chronic persecution mania, characterized in my experience by the hallucination of small animals moving in the skin” (p. 172)." [48] Cocaine hallucinations are also characterized as similar to those associated with migraine.

Cocaine use is associated with white matter hyperintensities. [49] Yet women seem to be less affected (perhaps due to increased NO from estrogen). Similarly Acute alcohol withdrawal is associated with white matter hyperintensities. [50] My hypothesis is that this is due to ATP depletion in the brain due to insufficient substrate. During chronic alcohol abuse, the liver is used to oxidize alcohol to acetate and acetate is used as substrate in the brain. During alcohol withdrawal, glucose uptake by the brain increases over a period of several weeks. Presumably reduced glucose metabolism results in reduced ATP availability.

Migraines are also associated with white matter hyperintensities and (as discussed in more detail in my blog on resolution of ASD symptoms with fever). MD perhaps exhibit some of the same visual hallucinatory features as does cocaine (but perhaps milder). However these are acute hallucinatory features generated in the CNS, that are common in migraine, cocaine, alcohol withdrawal and the "light" sometimes reported by people who survive near death from drowning.

The hallucination of movement in the skin is likely generated in the skin itself, which is why it is not so much an acute hallucination of cocaine use, but one from chronic abuse. It takes a while for energy substrates and then NO in the skin to become depleted. Cocaine causes peripheral vasoconstriction, and so reduces blood flow to the skin. This can cause acute hyperthermia, but if continued chronically would likely lead to energy depletion in the skin.

The skin gets considerable O2 from the external air. [51] Substrates to be oxidized must come from the plasma which flows through the extravascular space. Cocaine induced vasoconstriction wouldn't cause immediate depletion of substrates but if consumption exceeds delivery by the now constricted vasculature eventually energy status of the skin will be compromised. Itching is a natural response by which scratching can increase local flow of lymph in the extravascular space. That will increase convective delivery of substrates. Itching in the context of infection or parasitic infestation of the skin is a way to accelerate lymph flow to lymph nodes so that antigen presenting cells can begin the process of mounting an immune response.

I think I have presented considerably evidence and reasoning that MD is plausibly related to a low NO state in the skin and in some other tissues. The treatment I would suggest to raise that NO would be via topical ammonia oxidizing bacteria. These bacteria are obligate autotrophs and so are unable to derive sustenance by metabolizing animal tissues.
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