Brain Inflammation and Anxiety I am posting this in case anyone is interested in the non-standard anti-anxiety approach I used to cure my extremely high levels of anxiety (generalized anxiety disorder). This approach may well help others suffering with anxiety. This protocol may be very useful for people whose anxiety did not resolve using SSRI drugs, etc. It may also help in reducing the "wired but tired" mental state that many with chronic fatigue syndrome are all too familiar with. NOTE: If you want the quick-to-read version, go straight to the summary at the end of this post. After many years with horrible anxiety (by far the most unpleasant symptom of my CFS), I finally figured out that my anxiety was likely biochemically created by brain inflammation. As soon as I tried taking certain specific anti-inflammatory supplements, most of my anxiety vanished (within a day or so). Here is the anti-anxiety approach I took: I used the herbal extract curcumin to block the NF-κB-mediated inflammation, taking curcumin in 3 or 4 daily doses of 500 to 1000 mg. You have to take it several times a day to work: say a capsule at breakfast, one at lunch, one at supper time, and one before bed. This is because the plasma half-life of curcumin is short: 3 to 6 hours, so you need to take it 3 or 4 times a day to keep up your anti-inflammatory blockade. Another good blocker of NF-κB-mediated inflammation that can be used in place of curcumin (or in addition, if you want) is grape seed extract 500 mg daily. High doses of curcumin can occasionally slightly increase anger and irritability in some people, so keep a watch out for that; grape seed extract does not have this problem. Either of these can rapidly lower your anxiety. Other good NF-κB blockers that you can use are: ashwagandha (1000 mg), alpha lipoic acid (500 mg - though some may not be able to take this high dose), sulfasalazine (500 to 1000 mg); sulfasalazine is usually a well tolerated drug. Note than you do not want to totally block NF-κB, because it is needed for other metabolic functions. You might also want to simultaneously try a second anti-inflammatory: one that targets COX-2-mediated inflammation. This can further lower your anxiety. For this, take propolis herb, 1000 mg, on the same dosing schedule (that is, 3 or 4 times a day - not before bed, though, as propolis can keep you awake). Propolis is an potent COX-2 inhibitor. Cat's claw is another good COX-2 inhibitor, and 1000 mg of cat's claw can be used in place of propolis (or in addition, if you want). (If neither NF-κB or COX-2 inhibitors bring relief, then consider trying a 5-LOX anti-inflammatory, such as the 5-LOXIN extract of Boswellia serrata. You may also try all 3 of these together, since more than one inflammatory mechanism can be at play. ) The idea of these anti-inflammatory approaches to treating anxiety is that they block the mechanisms that create the biochemistry of anxiety in the brain in the first place. That is, they target the actual cause of anxiety, closer to the source. The Theory I suspect what is happening in the brain to create this anxiety is the chronic overstimulation of the NMDA receptors — the brain cell receptors that mediate anxiety. Dr Martin Pall has examined the state of hyperexcitement of NMDA receptors in CFS (mostly in the context of excitotoxicity and the NO/ONOO cycle). But here we are interested in the NMDA hyperexcitement–anxiety connection. The NMDA receptors are overstimulated probably because of the chronic microglial activation that is found in brain inflammation (microglia form part of the brain's immune system). Glutamate and quinolinic acid are produced as a by-product of microglial operation; glutamate will strongly activate the NMDA receptors, leading to biochemically-created anxiety. Quinolinic acid might also activate the NMDA receptors (although this study suggests not enough quinolinic acid is produced to substantially activate NMDA). In summary: inflamed brain ➤ chronic microglial activation ➤ excess glutamate production ➤ NMDA overstimulation ➤ induces anxiety state. Inhibiting NF-κB reduces microglial activation, which may be why this approach eliminates anxiety at source. Vitamin E (alpha tocopherol) also reduces microglia activation, as does the flavonoid genistein, and tetracycline antibiotics, so these can have an anti-anxiety effect when inflammation in the brain is the cause of anxiety. It may be worth adding say vitamin E and/or genistein to the anti-inflammatory protocol. Sesame seed oil also inhibits microglial activation. A lot of excellent research on brain inflammation's role in anxiety and depression has been done by Dr Gina Nick, and her protocol for treating brain inflammation uses similar supplements to those listed above. Note that brain inflammation can damage the brain through excitotoxicity, so lowering this inflammation is neuroprotective. Other Anti-Anxiety Supplements If the above anti-inflammatory approaches to treating anxiety do not work for you (or only work to a limited degree) then you may have to use additional treatments: Other anti-anxiety supplements I found useful are: inositol (10 to 15 grams daily). These supplements can be taken two or three times daily: taurine (1000 mg), L-carnitine (500 mg), picamilon (100 mg), arginine pyroglutamate (2 grams), theanine (200 mg), vitamin B1 (100 mg), vitamin B6 (50 mg), vitamin B5 (1 gram). Note that taurine inhibits NMDA receptor stimulation, by sitting on the NMDA receptors, and blocking their activation by glutamate and quinolinic acid. Some excellent anti-anxiety herbs are: ashwagandha, which is also a good NF-κB inhibitor, and Bacopa monnieri. Other useful anti-anxiety herbs are: chamomile (especially the apigenin extract of chamomile), lavender, passionflower. Holy basil can dramatically improve anxiety in some people (holy basil is potent COX-2 inhibitor, however, thus its anxiolytic mechanism may actually be as an anti-inflammatory rather than a palliative; holy basil also lowers cortisol, and high cortisol is another source of some people's anxiety states - but watch out if you have low cortisol). The antihistamines cetirizine (Zyrtec) and loratadine can reduce anxiety symptoms. Dose is 10 mg daily. Transdermal magnesium cream used twice daily is also works quite well to reduce anxiety. Transdermal magnesium is often used in autism, where there are very high levels of internal mental anxiety. Magnesium potently lowers NMDA receptor activation, by sitting on the NMDA receptors, and blocking their activation. Transdermal magnesium cream is generally very helpful in CFS, as magnesium has many useful functions, like supporting mitochondria. You can make your own cheap transdermal magnesium cream, simply using Epsom Salts mixed with some hand cream. Oral magnesium may also help, but most people reach bowel tolerance (they get diarrhea) after about 500 mg or so of oral magnesium supplements. The magnesium content of Epsom Salts (magnesium sulfate MgSO4) is 20%, so 5 grams of Epsom Salts provides 1 gram of elemental magnesium. One heaped teaspoon of Epsom Salts weights about 7 grams, just for reference. You need to use at least 1 heaped teaspoon of Epsom Salts (dissolved in little bit of water, and mixed into a hand cream) on each transdermal application. GABA and NMDA Another approach to reducing anxiety is to stimulate the GABA receptors. GABA receptors are the opposite to NMDA receptors: when you activate GABA receptors, your brain relaxes; whereas when you activate NMDA receptors, your brain goes on alert, and higher NMDA activation leads to anxiety. Therefore, to reduce anxiety, you can either lower the activation of the NMDA receptors, or increase the activation of the GABA receptors. Or both. Many anti-anxiety drugs and herbs work by increasing GABA stimulation, including the herb valerian, and benzodiazepines drugs. Benzodiazepine drugs include: clonazepam (Klonopin), alprazolam (Xanax), and diazepam (Valium). The trouble with these drugs, though, is that at high doses the GABA receptors build up tolerance, so the effect of the drug gets less with time. This also means that these GABA drugs can be additive, and so you will feel more anxiety on stopping them (ie, withdrawal symptoms, rebound). This tolerance does not occur on the NMDA receptor when you block it, so in the long term it may be better to use an NMDA blocker like magnesium, rather than a GABA stimulator like benzodiazepines. There are not that many good NMDA blockers around. Here are some NMDA antagonists: magnesium (potent), zinc, taurine, guaifenesin (possibly), huperzine A, memantine, dextromethorphan (cough medicine), amantadine (an antiviral), nitrous oxide gas (N2O), ketamine, ibogaine. But as has been recommended above, stoping the anxiety at source, by inhibiting brain inflammation, is probably by far the best approach. If you really want to wipe out your anxiety, you can take more than one approach at the same time: that is, the recommended anti-brain inflammation supplements, plus NMDA-blocking supplements like magnesium or taurine, and whatever other supplements you find helpful. If anyone has any further ideas or info on other mechanisms behind biochemically-generated anxiety, please post. Summary To try this anti-anxiety protocol, start with say grape seed extract 500 mg. Add to this 1000 mg of propolis, 3 times a day (best not to take propolis before bed - it may keep you awake). Finally, you can add vitamin E (alpha tocopherol) 400 mg twice a day. These three supplements will act to reduce brain inflammation, and thus reduce anxiety (hopefully).