Galantamine and Ibudilast for ME

This blog entry will examine the rationale behind Galantamine and Ibudilast as treatments for ME both individually and in conjunction. I will also detail my experience with this treatment synthesis.
 

Galantamine

Galantamine belongs to a class of drugs known as ‘cholinesterase inhibitors.’ It is most commonly used in the treatment of Alzheimer’s disease as well as other indications involving circulation based memory impairment. Galantamine is unique as it is available as both a supplement readily accessible online as well as a prescription drug. There are a glut of possible mechanisms by which it may benefit ME patients.
 

Galantamine’s Mechanism of Action

Galantamine may benefit ME patients due to:

• Increasing acetylcholine
• Reducing DHEAS levels
• Normalising the DHEAS/cortisol ratio
• Reducing bodily inflammation
• Lowering mast cells release
• Supressing microglial activation (Microglial cells are essentially immune system cells in the brain that when overactive can cause various symptoms.)

 
ME patients responding to Galantamine most commonly note an improvement in sleep quality and length, an alleviation of cognitive impairment, a reduction in pain and dissipation of fatigue.
 

 

Studies of ME/CFS Patients Taking Galantamine

The First study examining the efficacy of Galantamine on ME/CFS patients was by Snorrason et al. in 1996. The study authors postulated that a ‘cholinergic deficit’ may be responsible for ME/CFS symptoms. As Galantamine can increase acetylcholine, the authors explored whether ME/CFS patients would improve as a result of this treatment. 49 ME/CFS patients began the study and 39 finished the Galantamine protocol. 43% of these patients reported at least a 50% improvement in the areas of ‘fatigue, pain and sleep.’ This was in contrast to just 10% of the placebo group noting an equivalent improvement. The study mentions that when symptoms did dissipate, it occurred gradually and was classified as significant only 4-8 weeks into treatment. The patients who did improve by greater than 50% didn’t relapse despite stopping the Galantamine. The major symptomatic improvement in this study centred on sleep. 60% of the ME/CFS patients taking Galantamine had a 70% of more improvement in sleep.
 
The second study was performed by Blacker et al. in 2004. This study featured 352 CFS patients taking varying amounts of Galantamine from 2.5mg to 10mg. 82 patients taking a placebo were also involved in this study. The broad Fukuda criteria were used to select ‘CFS patients.’ After 16 weeks of treatment, the CFS patients in this study failed to improve relative to the placebo group. The lack of effect from this study may have been due to the dubious CFS criteria used, the low dosage of Galantamine or indeed the lack of efficacy of the Galantamine.
 
The final Galantamine-ME/CFS study was by Turan et al. in 2009. The authors noted that many CFS symptoms such as; cognitive impairment, sleep problems, mental fatigue and HPA axis dysfunction are indicative of a ‘cholinergic deficit.’ This study focused on stress hormones such as DHEA and cortisol and their alterations in CFS patients taking Galantamine. The study contained 29 CFS patients, who were diagnosed with the Fukuda criteria as well as 20 healthy controls. The CFS patients were given 8mg of Galantamine per day for 4 weeks.
 
The patients who responded to Galantamine treatment had significantly higher pre-treatment DHEAS levels (1744ng/ml on average) and significantly higher DHEAS/cortisol ratios (146 on average). The CFS patients who didn’t respond had DHEAS levels (1122ng/ml on average) and DHEAS/cortisol ratios (128 on average)- both at similar levels to the healthy controls. After treatment with Galantamine, the CFS responders DHEAS levels dropped from 1744ng/ml to 1164ng/ml on average. The DHEAS/cortisol ratio of the CFS responders went from 146 to 121 on average. Turan et al. concluded that the various stress hormones normalising with Galantamine treatment indicated that a ‘cholinergic deficit’ may be central to CFS.
 

Side Effects

The most common side effects from Galantamine are nausea and headaches. Other frequently noted symptoms mentioned in the ME/CFS studies include; vomiting, sweating, diarrhea, confusion and hallucinations. The Blacker et al. study noted that 22.6% of ME/CFS patients taking the Galantamine withdrew from the study, although 15% of patients in the placebo group also withdrew. Unsurprisingly, this study also found that the frequency of side effects increased as the dose of Galantamine was raised. The Snorrason et al. study listed nausea as the most common side effect although stipulated that this was “dose-dependent and reversible.” The authors also stated that some patients at the lowest dosage of 5mg developed nausea. Snorrason et al. recommend that ME patients begin Galantamine treatment at very low doses and are monitored by a physician. Some non-ME users of Galantamine use this substance for its vivid dreams, although ME patients are warned not to take it close to bedtime due to the risk of it invoking nightmares.
 

Dosage

There is quite some discrepancy regarding an appropriate dosage of Galantamine in ME patients. Some patients have experienced side effects at the low amount of 2.5mg per day. As with most ME treatments, it is problematic in trying to determine a universal dose. Some patients have trialled a maximum of 4mg taken twice a day (8mg a day total) while other have ventured up to 7mg taken twice a day (14mg a day total). The ME/CFS studies used doses from 2.5mg-10mg per day. It is imperative that if a patient trials this treatment, the baseline dosage is very low and it is gradually increased if no side effects emerge.
 
Some countries class Galantamine as a supplement while other counties categorise it as a drug. It is widely available online in various formulations, some containing choline or another substance that may enhance its efficacy. Some takers of Galantamine buy choline separately to add to its effectiveness. Galantamine should be taken with food. An alternative treatment is royal jelly- a product that may be better tolerated that Galantamine and also contains acetylcholine.
 

 
 

Ibudilast

Ibudilast is a Japanese drug that has traditionally been used as a treatment for asthma and stroke. It has more recently been prescribed, with some success, to patients with multiple sclerosis and those with amphetamine, opioid or alcohol addictions.
 

Mechanism of Action

Ibudilast may benefit ME patients due to:

• Preventing the creation of inflammatory cytokines
• Inducing pro-inflammatory molecules
• Reducing neuropathic pain
• Being neuroprotective
• Reducing brain inflammation
• Stopping microglial cell activation
• Lowering the production of nitric oxide

 

Ibudilast Studies

While Ibudilast is yet to be studied on an ME patient population, several studies of relevancy have been performed. The following studies were performed on human subjects, as opposed to in vitro.
 
In progressive multiple sclerosis patients, Ibudilast has been found to have an effect on preserving brain volume as well as slowing disability progression. Trials are continuing to investigate the usefulness of Ibudilast as an MS treatment.
 
A 2016 study by Cooper et al. found Ibudilast to be a useful glial modulator and hence a treatment for opioid withdrawal.
 
A 2008 study by Inoue et al. examined the usefulness of Ibudilast in increasing blood flow in the brains of patients with cerebrovascular disease. The subjects noted a reduction in dizziness and depression. Objectively, the patients had an increase in their blood flow in the brain, specifically in the right frontal and occipital cortices.
 
A 1993 study by Fukuyama et al. examined Ibudilast’s effects on blood flow in the brains’ of stroke patients. A large initial dose of Ibudilast led to a “remarkable increase” in blood flow around the brain when measured after 30 minutes.
 
Another 1993 study, this time by Sugiyama et al. labelled Ibudilast as a ‘cerebral vasodilator.’ The authors determined that Ibudilast caused “significant changes” in the blood flow around the brain to the affected brain areas, as measured by a SPECT scan.
 

ME Etiology Theories and Ibudilast

Dr. VanElzakker wrote a 2013 paper exploring the hypothesis that infection of the vagus nerve may cause ME. He has proposed the theory that this infection of the vagus nerve subsequently activates the microglia and hence results in ME symptoms. Within the paper, Dr. VanElzakker explains that Ibudilast may be an appropriate treatment due to it being a glial inhibitor and he writes that Ibudilast has several possible mechanisms in which it may benefit ME patients.
 
Stringer et al. did a 2013 study that found Leptin levels correlating to fatigue severity in 6 ME patients throughout the 25 days of the study. Leptin is a hormone that is created by fat cells. Dr. Jarred Younger was a part of the Stringer et al. study team and has written extensively about the potential effects that Leptin has on the body in ME patients. One of his theories involves leptin lowering the threshold of the microglia hence causing ME symptoms. Similarly to Dr. VanElzakker, Dr. Younger reportedly has an interest in Ibudilast as an ME treatment.
 
Another researcher has queried weather Ibudilast will actually target the specific type of glia that is of interest to ME patients, as there are many different types of glial cells.
 
Ibudilast is overflowing with potential as a future more widespread ME treatment. As this drug becomes more researched by scientists outside of Japan for other indications, the broad nature of this treatment has become apparent. Currently, Ibudilast is being fast-tracked through FDA trials for other conditions. Future studies on ME patients would be interesting as multiple mechanisms of this treatment would be appropriate to treat many of the etiologies proposed for ME.
 

 

Side Effects and Dosage

Ibudilast is generally void of serious side effects at the therapeutic doses used. Its use in treating asthma in Japan is testament to this. The most frequent side effect in studies have been gastrointestinal, including; nausea, diarrhea and indigestion- Although the prevalence of these have been low. In a 2 year study of Ibudilast usage, patients took either 10mg three times per day or 20mg three times per day. Gastrointestinal side effects occurred in the 30mg a day group at a rate of 11.6% and at 15.2% in the 60mg per day group. In contrast, 7.8% of the placebo group felt gastrointestinal symptoms. Tolerance to these side effects built up within 2-4 days, hence it seems to be fairly rare for a patient to discontinue Ibudilast due to side effects. Hypertension is possible due to its vasodilatory properties and it may have an antiplatelet effect hence be wary if combining Ibudilast with aspirin or anticoagulants.
 
An appropriate dosage of Ibudilast for ME patients in difficult to determine. Some non-ME patients who have the goal of improving mental acuity take it at 10mg twice a day (20mg a day total) which is the same dose that asthma patients take. Studies with multiple sclerosis patients have involved dosages ranging from 30mg twice a day (60mg a day total) to 50mg twice a day (100mg a day total). This later total of 100mg a day has been referred to in a separate study as in the “high” dosage range.
 
Ibudilast is a prescription drug that is commonly used in Japan and much of the western world is only now beginning to study and embrace it. For this reason, it is currently not available in most countries. Some ME patient and non-ME patients seeking its mental acuity effects have ordered it online without a prescription. It can be moderately expensive when used at therapeutic dosages.
 
 

Galantamine and Ibudilast

When combined, Galantamine and Ibudilast may have an increased efficacy and may work in tandem to reduce cognitive impairment. Galantamine may trigger the ‘cholinergic pathway’ and Ibudilast has the potential to lower the microglial cell stimulation. Overall, Galantamine essentially targets stopping the bodily inflammation and Ibudilast focuses on eliminating the brain inflammation. Cognitive impairment is therefore potentially being treated.
 

My Experience with Galantamine and Ibudilast

On the 4^th of November 2016, I took my first dose of Galantamine at 4mg. I began to feel dizzy for the next several hours. After several days, I increased the dosage to 6mg. I then decided to add Ibudilast into the mix and commenced with a 10mg dosage. After a few days, I increased my Ibudilast dose to 10mg twice a day (20mg a day total). While on this treatment combination, I noticed a few side effects. My sleep at night seemed more disturbed than usual and I was feeling drowsier during the daytime hours. As these side effects are sometimes linked to Galantamine, I stopped this treatment and the side effects vanished. I continued taking Ibudilast for one month at 20mg a day. I didn’t notice any distinct positive or negative effects from the Ibudilast.
 

Conclusion

The Galantamine and Ibudilast treatment synthesis is experimental. If a patient does trial one or both of these treatments, it is imperative that they are monitored by a physician. Galantamine usage in ME patients has produced mixed results in studies. In isolation, it seems most likely to benefit those patients with high DHEAS levels or high DHEAS/cortisol ratios. Side effects from Galantamine seem to occur quite frequently although for the most part aren’t serious and involve transient nausea and headaches. In contrast, Ibudilast hasn’t been studied in ME patients and it is virtually untried amongst the ME patient population. It has many possible mechanisms of action in ME patients and does look like a promising drug on the horizon. Its good safety profile also enhances its allure. In the future, I plan to trial Ibudilast, on its own, at a higher dosage and hopefully reap some of its positive effects.

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