How to Improve Histamine Levels -Including Details About MS Remyelination Drug Clemastine
dr.vanta
Clemastine had been promoted as ms remyelination drug in the news just a month ago, read the details here. Is Clemastine for MS the best option among conventional drugs?
Why I wrote this article :
Optimal levels of histamine are essential for brain health in general, and managing MS in particular. MS has been linked with histamine excess.
Antihistamine drug Clemastine may work as a ms remyelination drug, according to recent studies. Be aware that this is just an example. Other drugs that influence histamine receptors H1, H2, H3, H4 can be very helpful for MS. (will cover both pros and cons, my favorite ones and some research of these drugs for treating MS). To better understand the role of histamine and its receptors, read this article first.
Another group of drugs – mast cell stabilizers- these drugs prevent the release of histamine from mast cells, thus used successfully in allergic conditions. Did you know research suggest that mast cell stabilizers could be the next generation of drugs for MS and other neurological conditions ? Yes, they can be that powerful.
In these articles- here and here, I reviewed of natural supplements that improve histamine levels and their importance to treat MS. Not everything comes in a pill- there are other ways to optimize histamine levels,too.
Wondering why there is so little awareness about the role of histamine for MS? Well, few people write about it. It’s a complex topic and can be quite confusing. There are many questions unanswered, even in the scientific community. Let’s look at the evidence.
Summary :
A) Drugs that Influence Histamine Receptor and how they can be used in MS
B) Drugs Targeting H1Rs For MS Treatment
C) Drugs Targeting H2Rs For MS Treatment
D) Drugs Targeting H3Rs For MS Treatment
E) Drugs Targeting H4Rs For MS Treatment
F) Mast Cell Stabilizers For MS Treatment
G) My thoughts
Key point: Autoimmune diseases and allergies share more similarities than was previously thought. Similar with allergic response, T cells initiate the immune response to the target tissue ( myelin in cases of MS), but other cells (like mast cells) also play an important role [1].
A) Drugs that Influence Histamine Receptor and How They Can Be Used in MS
Drugs can either stimulate a receptor (are called agonists- example: H3 agonists) or inhibit/block a receptor (called antagonists/ inverse agonists- example: H2 antagonists or anti-histamine H2 drugs).
B) Prescription drugs targeting H1Rs for MS treatment
Why H1 antihistamine drug Clemastine is able to repair the myelin sheet ?
Clemastine -the ms myelination drug (according to the latest news) belongs to the older, first generation H1 antihistamine drugs. Clemastine has the ability to cross blood brain barrier better than the newer H1 antihistamine drugs, thus being more effective for MS or other conditions affecting the brain.
Stimulation of H1 receptors increases arousal, being involved in sleep awake cycle. Reinforces learning and memory, suppresses appetite, controls body temperature, controls the cardiovascular system, influences hormones like ACTH and b-endorphin.
H1-antihistamine like clemastine can easily cross the blood brain barrier. The pros: has anti inflammatory effects, promotes myelin repair.
The cons (clemastine side effects) : will interfere with all the processes stimulated by H1 receptors noted above- when taken during the day, H1 antihistamine drugs cause excessive sleepiness, drowsiness, fatigue, will affect the learning ; when taken at night these drugs will affect the sleep (especially REM sleep), and cause lack of coordination and attention, diminished vigilance and memory problems the next morning [3]. Other clemastine side effects include dry mouth, constipation, low blood pressure, increased heart rate, palpitations, blurred vision, double vision, painful urination, urinary retention, bone marrow suppression, wheezing and tightness in the chest [4].
Technical : As an old generation H1 antihistamine, clemastine has poor receptor sensitivity, thus will not interact only with histamine receptors, but with other receptors as well ( antimuscarinic, anti-α-adrenergic, and anti-serotonin effects). For example anticholinergic effects are responsible for clemastine side effects like dry mouth and urinary retention [5], [6].
Activation of muscarinic receptors inhibits the differentiation of oligodendrocytes therefore, the pro-myelinating effects clemastine (and benztropine) are likely via their antagonism of M1/M3 muscarinic acetylcholine receptors. These antimuscarinic effects of clemastine seem responsible for remyelination through direct effects on oligodendrocytes, without having immunosuppressive effects [7],[8]. Many antidepressants or antipsychotics also bind to the H1R [9].
C) Antihistamine H2 Drugs for MS treatment ? – Mixed results, I’d stay Away From Them
Antihistamine H2 drugs are widely used for acid reflux and peptic ulcers. They are used in some people with MS – for example those who use corticosteroids (a common side effect of corticosteroids is increased gastric acidity) or for those who have gastroesophageal reflux (GERD) associated with MS. However, by now you should be aware that antihistamine H2 drugs have many more effects in the body, influencing the brain and the immune system.
Thus, scientists looked at other potential benefits of antihistamine H2, how they can impact the brain, the autoimmune response, inflammation and neurodegeneration found in MS- are antihistamine-H2 drugs beneficial or detrimental ?
H1Rs appear to have many opposite effects when compared with H2Rs. Antihistamine-H1 show benefits for MS, while antihistamine-H2 are likely detrimental for MS.
Antihistamine H2 drugs (ie cimetidine, ranitidine) can cross the blood brain barrier, which means they gain access to the brain and can influence its function.
MS had been linked with overactive TH1 cells and underactive TH2 cells (TH= are T helper cells of the immune system) and boosting TH2 cells had been linked with MS remission. Activating H2R drugs (H2 agonists) can help boost TH2 cells, while anti-histamine H2 (H2 antagonists) drugs had been associated with increased disease severity, stimulation of the immune system and promoting inflammation and autoimmunity in EAE (the animal model of MS). These effects had not been confirmed in humans with MS, but in people with other autoimmune conditions (autoimmune hepatitis, lupus and psoriasis).
Antihistamine drugs like cimetidine appear beneficial for managing anti-viral infections like herpes zoster, herpes simplex and Epstein Barr virus (Epstein Barr virus is linked with the development of MS) [10], [11], however, I see a lot more cons than pros to recommend these drugs for MS.
Antacids drugs have a significant negative impact on the gut microbiome [13] – this is the biggest reason why I would stay away from them. I would also stay away from PPIs as long term used of them are associated with vitamin and mineral deficiency, disruption of the intestinal flora[25] and even stomach cancer [26] and increased risk of premature death, [27].
D) Both Histamine H3R Antagonists and Agonists Can Help MS
GSK239512, a potent H3R antagonist was found beneficial for managing MS. It shows a small, but positive effect on remyelination in relapsing-remitting MS (RRMS), according to a randomized, single-blind, phase II study. It is also well tolerated, insomnia being the most common side effect.
Why does GSK239512 work? The brain has the ability to regenerate myelin, and oligodendrocyte precursor cell (OPCs) play a key role in myelination. One big reason why myelination fails in MS is because this condition is associated with a decreased (OPC) differentiation. OPC differentiation is controlled by a variety of molecules and their receptors, including histamine H3Rs which are expressed by both expressed by neurons and OPCs. GSK239512 didn’t show benefits in relapse rate or EDSS (disability scale) when compared with placebo group [14].
Stimulating H3R (using histamine H3R agonists) can help MS
Immethridine dihydrobromide, a highly selective H3R agonist can reduce the symptoms of MS in animal models, according to a recent study. Treatment with immethridine lead to less inflammatory cells in the spinal cord, decreased demyelination, improved inflammatory markers like TNF-α, IFN-γ and IL-17A, improved levels of TH1 and Th17 cells (no changes in Tregs) [15].
Treatment
H4R antagonists aggravate the severity of MS (in animal models), increasing inflammation and demyelination in the spinal cord [16]. On the other hand, stimulating H4Rs has anti-inflammatory effects and a positive impact on T reg cells (T reg cells suppress potentially dangerous activities of Th cells and preventing autoimmune diseases)
Based on the current trends, we may see a combination drugs (that target multiple histamine receptors) for treating MS [17].
For example, a study conducted in EAE (animal model of MS) suggests that disrupting H1R and HR2 signals can protect against disease, while disrupting H3R and H4R would promote disease activity [18].
E) Mast Cell Stabilizers Drugs
Mast cells are potent pro inflammatory cells. They are the first responders to a microbial infection and also play a key role in allergic reactions. They contain a high amount of histamine which is released during infections and allergic reactions.
The class of drugs called “mast cell stabilizers” helps stabilize the mast cells, thus preventing the release of histamine. In other words, these mast cell stabilizers have anti-inflammatory, anti microbial, anti-allergy effects. In relation with drugs that target histamine receptors, mast cell stabilizers work like antihistamine H1 drugs. Since anti H1 drugs help to manage MS, could we assume that mast cells could also be beneficial ?
Yes, mast cell stabilizers can be very helpful. In fact, research shows that mast cell stabilizers could be the next generation of drugs for MS and other neurodegenerative and autoimmune conditions.
According to the latest studies, mast cells also play a key role in the autoimmunity in general [19], and brain inflammation/autoimmunity in particular [20],[21]
Technical: In MS and EAE, mast cells have been suggested to modulate trafficking of inflammatory cell through the BBB, and/or in peripheral lymphoid organs, where they could modulate auto-reactive T cell responses. However, studies on EAE showed conflicting results [22]. Mast cells had been identified in brain lesions of MS.
Technical: Increased levels of tryptase, a mast cell-specific protease had been found in the cerebrospinal fluid of MS patients. Furthermore, microarray analysis of MS lesions shows that transcripts encoding tryptase, histamine R1 and FcεRI are significantly raised in chronic disease. [22].
It is well known that stress has a negative impact on MS disease activity, and guess what- mast cells appear to be involved here too. Acute stress causes disruption of the blood brain barrier via activation of mast cells. Moreover, the response to stress was reversed by treatment with mast cell stabilizer drug disodium cromoglycate (study in EAE-the animal model of MS) [21].
Mast cell stabilizers for MS
As you can see above, disodium cromoglycate shows benefits in EAE- animal model of MS. Ketotifen was another drug from this group that had been found beneficial in EAE Proxicromil, cyproheptadine reserpine (all preventing the histamine release from mast cells) were also found to inhibit MS in animal models.
The MS drug dimethyl fumarate was shown to induce mast cell death, at least in vitro studies [21], [23]. Some drugs that target histamine receptors are also mast cell stabilizers -for example desloratadine [24]. A combination of desloratadine and nortriptyline (a tricyclic antidepressant) showed positive effects (decreasing relapse frequency, improving markers of inflammation/autoimmunity)
Technical: in this study, desloratadine and nortriptyline inhibits the production of IFN-γ and IL-17 produced by naive CD4(+) T cells activated in the presence of Th1/ Th17 dominance, while increasing the level of IL-4 produced by naive CD4(+) T cells activated in the presence of Th2 dominant conditions.
F) My thoughts …From all these list of drugs, which one would you choose ?
In theory, targeting the H3 receptors would be the best choice. H3Rs are found in the nervous system and they keep job is to maintain optimal levels of histamine in the body. In theory, if you support the H3Rs, you could manage excess levels of histamine (as seen in MS). That’s because the more H3Rs are triggered by histamine, the less histamine will be produced in the body. H3Rs play an important role in neurotransmission are also involved in sleep awake cycle and inflammation. The cons: 1. They can have a negative impact on other neurotransmitters (ie dopamine, norepi, serotonin) and 2.we don’t know (yet) enough about H3Rs, and we don’t have (yet) much research for using H3Rs for managing MS.
Clemastine and other Antihistamine H1Rs. There is more research on this class of drugs. The benefits of clemastine had been confirmed in several studies , including a randomised controlled trial. Many of these studies on clemastine highlight the myelin repair in the optic nerve. How well is repaired the myelin in the whole brain? They can be very helpful in cases of MS associated with histamine intolerance/mast cell activation syndrome. Biggest cons: the side effects- anti H1Rs will negatively impact the sleep, and create somnolence during day time (keep in mind that the doses used for MS are double than those used for allergies), will affect memory , and cognition, appetite and thirst, the metabolism and hormones. Can’t be used long term because chronic use of anti H1Rs and antiH2Rs lead to tolerance.
Mast cell stabilizers are indeed another great option. Histamine H4 receptors had been discovered recently, thus not enough evidence of safety or efficiency. My last choice would be any drug that targets H2 receptors.
Food for thought : vitamins like C, Bs, minerals like zinc, iodine and other nutrients and hormones are essential for myelin formation. Perhaps would be a good idea to correct first diet and nutrient deficiencies before trying Clemastine ?
How to Improve Histamine Levels Naturally With Diet, Supplements and More – Read Here : Part I and Part II
