Smith reported that 94% of the ENT surgeons in the United Kingdom prescribe betahistine to their Meniere's patients (Smith et al, 2005)
This drug (brand name Serc, chemical name betahistine), is advocated as a vestibular suppressant mainly for Meniere's disease. Curiously, Serc was approved by the US FDA about 50 years ago for roughly 5 years, but later approval was withdrawn because lack of evidence for efficacy and because the major report of effectiveness contained deficiencies and misrepresentations (Sampson, 2003). The withdrawal was upheld by a US court of appeals in 1968. Subsequently, four double-blind studies have been done reporting reduction of vertigo attacks with betahistine (Frew and Menon, 1976: Wilmot and Menon; 1976; Meyer, 1985; Mira et al, 2003). Nevertheless, these studies may have been flawed and a review suggested that it is presently still unclear if betahistine has any effect in Meniere's disease (James and Burton, 2001). Unfortunately, most of the studies of betahistine have major design failings -- such as omitting a control group, or comparing betahistine to a homeopathic preparation. A recent exception is the study of Motamed et al (2017) where betahistine was found superior to promethazine.
Betahistine was again reviewed by the FDA in June of 1999 . This link formerly had the text of the review (https://www.fda.gov/ohrms/dockets/ac/99/transcpt/3513t2.rtf). Essentially, the conclusion was that there is no evidence that Betahistine is harmful, but also little evidence that it has any therapeutic effect. It thus is similar in official status to an inert substance -- think sawdust perhaps. Betahistine has been reviewed by the "Cochrane database" (see /mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD001873/frame.html) , who concluded in 2009 that "There is insufficient evidence to say whether betahistine has any effect on Ménière's disease". Another Cochrane study from 2016 (Murdin et al), suggested that "Low quality evidence suggests that in patients suffering from vertigo from different causes there may be a positive effect of betahistine in terms of reduction in vertigo symptoms.".A study of hydrops found that betahistine had no effect (Gurkov et al, 2012). Rosenbaum and winter concluded that based on 12 trials, betahistine might be helpful, but the "certainty of evidence is low". Tinnitus is not helped by Betahistine (Wegner et al, 2018)
Our clinical judgement is that betahistine does have positive effects on vertigo, but that it is very hard to determine how great these effects are due to the immense number of poor studies and biased reviews concerning betahistine's efficacy.
A recent case report of a single patient by Strupp (2018) suggested that betahistine could be productively combined with seligiline (an MAO inhibitor) in very low doses. This strategy might allow one to use much lower doses of betahistine, and perhaps save money on betahistine prescriptions (Strupp reduced the dose by a factor of 10). Seligiline is usually covered by prescription programs in the US. One would also wonder if this combination might allow one to get the (sometimes) positive effect of betahistine to reduce weight.
Kloos et al (2022) recently reported that in animals, betahistine and selegiline increases cochlear blood flow. In fact, they noted "Cochlear microcirculation increased significantly (P < .001) in guinea pigs treated with low dose betahistine combined with selegiline by up to 58.3 ± 38.7% above baseline over a period of up to 11 minutes. In one guinea pig, the increase was 104.6%. Treatment with Selegiline alone did not affect microcirculation significantly."
At the time of this update (2021), we generally just put the order into a mail-order compounding pharmacy. Betahistine can also be easily obtained through US compounding pharmacies, with a prescription. It is difficult to see why an inert substance must be prescribed, but nevertheless, this is the situation in the US. Betahistine can be ordered at the very lowest prices from large compounding pharmacies. Generally speaking, insurance plans refuse to cover betahistine, and patients have to "self-pay". Fortunately this is far less than the "list price" of drugs that are available "off the shelf".. As of 2021, the cost in the US for Betahistine is typically about $50/month. If you are charged more, perhaps you should find a different pharmacy. In other countries, betahistine can be much less expensive.
It is sometimes challenging for a physician to order betahistine through an EMR, as it doesn't usually come up automatically.. For our "Epic" EMR, this is the way the order looks:
While there are some oddities to this order template, as one does not really dispense "60 g", this seems to work reasonably well, and the pharmacists understand that 60 means 60 capsules, not 60 grams. Perhaps Epic will someday fix their software.
For those who want the quick answer, nobody has a reasonable rationale of why betahistine should work for dizziness. Following is the longer explanation.
|H3||presynaptic||autoreceptor (reduces histamine)|
|H4||outside CNS||Inhibitory vestibular|
Although betahistine does not closely resemble histamine (see above), in the body it is a histamine agonist. There are 4 histamine receptors, namely H1-4. The rationale for its use is somewhat difficult to understand as H1 blocking antihistamines (such as meclizine, also an anticholinergic drug) are also used quite commonly to treat vertigo. Explanations commonly given are that the drug is a vasodilator, or that it acts on subreceptors of histamine. H1 and H2 are post-synaptic receptors and H3 is a pre-synaptic receptor. H4 is exitatory to the peripheral vestibular neurons (Wersinger et al, 2013). All four types of histamine receptors are found in the mouse ear as well (Takumida et al, 2016)
Betahistine is a potent H3 receptor antagonist. (Lacour and Sterkers, 2001; Lacour 2013). Stimulation of the H3 receptor reduces histamine release, so antagonism of H3 increases histamine release. H3 receptors control the synthesis and release of histamine via a Gs protein (de Waele et al, 1995). Betahistine's H4 action probably is meaningless as it is not very powerful (Desmadryl et al, 2012).
According to de Waele et al (1995), there are several lines of evidence that suggest that histamine receptors modulate the function of central vestibular neurons. One influence is via axons from the posterior hypothalamus. This may be related to wakefulness as histamine controls wakefulness. Both H1 and H2 binding sites have been detected in vestibular nuclei. These authors note that there is data suggesting both that H1 and H2 actions are excitatory on the vestibular nucleus, and that common H2 blocker drugs such as cimetidine antagonize the effect. This suggests that H2 blockers (commonly used to reduce stomach acid), at least those that cross into the brain, may have a central vestibular suppressant effect. To our knowledge, this potential use has never been exploited.
H3 antagonists appear to inhibit horizontal vestibular gain without affecting alertness. This line of reasoning does not explain at all why betahistine would be helpful. This is just one example of the large array of confusing literature about this drug.
Most antivertigo drugs are H1 blockers. Many newer allergy medications are selective peripheral H1 blockers, and many older allergy medications, including those used for dizziness such as dramamine, are peripheral and central H1 blockers. Many medications for stomach problems that block acid are H2 blockers, but these are not generally thought to affect vestibular function (see above however).
Betahistine is an H3 antagonist, according to Timmerman (1991). H3 antagonism is felt to increase H1 and H2, so the net effect of H3 antagonism is histamine (H1 and H2) agonism. Confusingly though, some authors suggest that betahistine is an H3 agonist. The neuropharmacological literature is also complex. Arrang et al (1985) found betahistine to be a partial agonist against cerebral H1 receptors, and has no effect on H3 receptors. In other words, some H3 agonists might block histamine release, but betahistine (betahistine) doesn't affect these receptors in guinea-pigs. This would suggest that either betahistine is a placebo, or that it's effects result from some mechanism other than H3. Bertlich et al (2015) suggested in a study of guinea pigs that betahistine "affects cochlear blood flow through histamnergic H3" receptors. This result is contrary to that of Arrang et al (1985). Schu et al (2014) suggested that betahistine speeded up histamine H3 receptor recovery in guinea pigs post labyrinthectomy.
Lacour (2013) suggested that Betahistine has 3 mechanisms of action: CNS -- rebalancing VN activity and arousal; vascular with increased cochlear blood flow; and peripheral labyrinth with decrease in vestibular input. With respect to "rebalancing", Chen et al (2019) also suggested that betahistine, through H1 agonism, has a "role" in vestibular compensation. One would think that were this true, H1 antagonists (such as meclizine) would block a part of the compensatory action of betahistine, should this be clinically relevant.
One would expect that any stimulant, and H1 is presumably stimulating, could help with vestibular compensation. One would think that the vestibular suppression effect, perhaps through H4, would decrease compensation. Logically, it is also difficult to see why betahistine might be useful in Meniere's disease, but not useful in other situations where CNS adaptation is needed (such as vestibular neuritis). Finally, the clinical relevance of studies like that of Chen et al (2019) done in rats, is so far not apparent.
Hui (2022) stated " Betahistine alleviates BPPV through inducing production of multiple CTRP family members and activating the ERK1/2-AKT/PPARy pathway. " This was a study of mice, who do not have BPPV, and we think more evidence is needed.
With respect to vascular effects of betahistine, it is also hard to see why betahistine should increase cochlear blood flow without also increasing blood flow in other organs (which to our knowledge is not true either). Regarding vestibular suppression, this is a reasonable conjecture.
As mentioned above, it seems contradictory that both H1 blockers (meclizine) and H1 agonists (betahistine) are advocated for vertigo. It, however, is possible that the antihistamine effects of meclizine are less important than its anticholinergic effects, so there may not be a contradiction between the H1 effects. The general thought at the present is that the effects of betahistine relate to it's effect on H3 receptors, although what exactly this effect is still rather mysterious. If betahistine is indeed an H1 agonist and an H3 antagonist, it might suppress vestibular function and enhance alertness, both valuable qualities. By this thinking, betahistine could be reasonably combined with a selective H1 blocker that does not cross into the brain (such as fexofenadine).
Is it reasonable to combine meclizine (a central H1 blocker) and betahistine (a central H1 agonist) ? Well, perhaps if you are hoping to use the central anticholinergic properties of meclizine. It would see a more logical, however, to use a pure anticholinergic agent such as scopolamine instead of meclizine. Similarly, it seems reasonable to combine betahistine with a contemporary non-sedating antihistamine, as these medications do not cross the blood brain barrier.
Immune effects ? Mollar et al (2016) suggested that there are histamine receptors in the endolymphatic sac, and that "The present data provide the first direct evidence of a molecular rationale for betahistine treatment in Menieres disease. A potential betahistine effect in Menieres disease may primarily be through the H3-receptor antagonism, leading to inhibition of vestibular neuro-transmission and central vaso-dilation. The H1-receptor localization in the ES epithelium suggests an immuno-regulatory effect. "
The author of this review has had moderate success with giving betahistine to patients who have intractable Meniere's disease, and it part of his usual regimen for intractable Meniere's (often in combination with verapamil). It comes in doses of 8, 16 and 24 mg.The usual dose is 16 mg 3-4 times per day although greater effect is obtained for doses as high as 48 mg at a time (Strupp,et al. 2008). Lacour also seems to favor the 48 mg TID dose. Strupp reported an individual taking 900 mg/day of Betahistine (2014), and using doses averaging 854 mg/day in another group of patients (Strupp et al, 2018).
With respect to a reasonable duration of trial, the author of this review generally prescribes betahistine (i.e. 16 mg BID) for a month trial, and continues if the patient finds it helpful. Lacour (2013) presents considerable data suggesting that there is both an immediate effect as well as a cumulative effect over 12 months. Nevertheless, it our impression that most people that report a positive effect can decide this with a few days. We also have encountered a very few patients who report side effects from as little as 4 mg. This is all very difficult to understand.
The author also uses Betahistine to treat severe motion intolerance (e.g. Matsnev and Sigaleva, 2007). Betahistine can be used in children (Gryczynska, Drobik-Wasiewicz et al. 2007). While claims have been made that Betahistine is associated with weight loss, these appear to be unfounded (Barak, Greenway et al. 2008). Still, recent papers suggest that betahistine may prevent weight gain in rats on an antipsychotic (Lian et al, 2014).
There are numerous puzzling aspects to betahistine and the jury is still out regarding whether or not it is an effective medication. Many studies report that betahistine cannot be distinguished from placebo. There are also some troublesome reports comparing betahistine to other medications that are almost certainly placebos, that can be interpreted in the same way. Klein et al (1998) reported that a homeopathic medication was equivalent in efficacy to betahistine. As homeopathic medications are generally felt to be placebos because of the extremely high dilutions with which they are administered, this suggests that either the Klein study was flawed, or that betahistine is also a placebo. Almost all of the literature concerning betahistine are from countries other than the United States.
So to summarize, evidence is weak for betahistine being an effective treatment of Meniere's. Our guess is that it is mildly effective, and fortunately it has very few adverse effects (see following).
Side-effects are generally minimal. The author of this review has encountered stomach upset in several, worsening asthma, headache (Barak et al, 2007), and chest tightness as side-effects. Of course, these symptoms could be found in a placebo.
Post-marketing studies conducted by the manufacturer suggest only a very small number of adverse effects (Jeck-Thole et al, 2006). In theory, stomach upset might be related to H2 agonism, as H2 blockers are used to treat gastric acidity. Against this idea is that betahistine is not a H2 agonist, but the increased release of histamine associated with h3 antagonism might stimulate H2. As mentioned above, it seems reasonable to combine betahistine with a selective H2 blocker that does not cross the blood brain barrier, or a proton pump inhibitor used for gastric acidity. Headache might also be a direct effect of histamine. On the other hand, some studies report reduction of headache by betahistine (Amelin et al, 2003). See this outside link for more information.
In its favor, betahistine does not cause drowsiness and has no effect on driving, reaction time or visual acuity (Betts et al, 1991)
Aksoy et al (2014) reported that in rats, betahistine exacerbates amikacin ototoxicity. We find this very dubious, as a histamine agonist should not interact with amikacin.
Betahistine may be associated with weight loss. The reason is that centrally acting antihistamines seem to cause weight gain (Hampton, 2007), and by the same token, histamine agonists may cause weight loss. According to a study of Barak, weight loss (averaging 4.24 kg) was confined to women below the age of 50. (Barak et al, 2008). A later trial of weight gain in patients on olanzapine, documented rather small differences (Barak et al, 2016).
According to Vlastarakos et al. (2008), Betahistine is contraindicated in pregnancy. While we agree that it is prudent to avoid use of drugs lacking rigorous data in pregnancy, the advice in this case does not appear to be supported by any adverse event data.
Betahistine may help arthritis. According to Tang et al (2016), Betahistine suppressed inflammation in mice with arthritis. We have not noticed any effect of betahistine in our patients on arthritis.
Little has been published about betahistine being incompatible with anything. If one believes in the histamine agonism mechanism, it would make little sense to take a centrally acting antihistamine medication with betahistine as the betahistine might not work. This covers a lot of ground including many conventional "dizziness" drugs. Still, if there is a balance between these drugs, one might nevertheless end up better with respect to vertigo. A person on betahistine should be able to take purely "peripheral" acting antihistamines (such as Claratin, Allegra and Zyrtec). Similarly a person on betahistine should not take antidepressants with central antihistamine side effects such as the "tryptylines". This includes Elavil and Pamelor. Practically, we have not noted any interaction problems.
According to Strupp (2018), Betahistine is metabolized rapidly, and this can be blocked with an MAO inhibitor. He reported using a very large but still smaller amounts of betahistine than he favors, when it was combined with 2.5 mg of Selegiline, twice/day. The dose averaged 205 mg/day, when combined with selegiline. In our opinion, this is a large dose, with or without selegiline. The lack of a placebo makes this uncontrolled study potentially subject to bias. Selegiline itself is not thought to be especially dangerous, and it does seem reasonable to contemplate the combination of the two medications, especially for situations where the situation is difficult (e.g. bilateral Meniere's, active on both sides). As of 2020 we have not tried this.