TRH is a string of three amino acids. When amino acids are strung together they are called peptides. When peptides act in the nervous system, they are called neuropeptides. TRH is a neuropeptide in addition to its role in stimulating the release of thyroid-stimulating hormone.

I use thyrotropin releasing hormone (TRH) nasal spray to treat people with what I term neurosomatic disorders. These illnesses include fibromyalgia syndrome, chronic fatigue syndrome, irritable bowel syndrome, premenstrual syndrome, and a host of other disorders that are not handled properly by the brain and, as a result, the way the brain regulates the body is inappropriate.

TRH has a number of properties that would make it difficult to treat disorders such as fibromyalgia syndrome. I have been using it for several years intravenously, injecting 500 units with moderate success. At this dose, it primarily affects mood disorders and alertness but can affect all symptoms. There are usually some transient signs of arousal of the autonomic nervous system as manifested by nausea, change in blood pressure, and an urge to urinate. The effects of intravenous TRH usually last a week or two when the medication is effective.

TRH enhances norepinephrine, dopamine, and serotonin secretion. Norepinephrine is a major brain neurotransmitter that increases signal-to-noise ratio, i.e., the ability to filter out relevant from irrelevant stimuli. Many patients with neurosomatic disorders are highly distractible and function poorly in environments of stimulus overload such as malls. Their performance also deteriorates in neuropsychological testing situations when the amount of information presented is increased even if the information is in the form of helpful cues.

Dopamine also increases signal-to-noise ratio, but even more than norepinephrine, it is implicated in reward. Dopamine, acting at the level of the nucleus accumbens, a structure in the basal ganglia of the brain, makes people feel considerably better in general and increases their activity and sensations of pleasure and motivation. The interaction of dopamine with other neurotransmitters in nucleus accumbens is too complex to discuss here.

Serotonin, which stabilizes information flow in neural networks in the brain, thus constraining behavioral, affective, and cognitive output, has been found to be decreased in fibromyalgia syndrome in cerebrospinal fluid, as have norepinephrine and dopamine metabolites. TRH has nerve endings on structures in the brain stem called the dorsal raphe nuclei which secrete serotonin.

TRH is a string of three amino acids. When amino acids are strung together they are called peptides. When peptides act in the nervous system, they are called neuropeptides. TRH is a neuropeptide in addition to its role in stimulating the release of thyroid-stimulating hormone.

A physician can buy TRH in 500 unit ampules of 1 ml. Five hundred units is the usual amount that is administered during a TRH stimulation test, which is performed to measure the amount of TSH the pituitary gland will secrete in response to TRH. The neurons that secrete TRH are in the hypothalamus, right above the pituitary gland in the paraventricular nucleus, which also contains other regulatory peptides such as corticotropin-releasing hormone and gonadetropin releasing hormone.

We make a dilution of 500 units or 1 ml of TRH in 9 ml of normal saline and put it in a nasal spray bottle. Each spray delivers approximately 3 units of TRH, an amount that one would not think would have a physiologic effect if injected intravenously. However, there must be receptors for TRH somewhere in the nasopharynx or in adjacent ganglia such as the spenopalatine ganglion because patients who respond to one spray of TRH solution in each nostril report that they feel much more alert and much more energized in less than one minute. Gordon Baker, M.D., in Seattle, uses TRH nasal spray to treat multiple chemical sensitivity ("Does it help anything else?" he asked).

I have written extensively about stimulating two of the three branches of the trigeminal nerve, which conveys sensory input from the face, with pharmacologic agents. This mode of administration has an effect on brain function because the tract of the trigeminal nerve in the brain stem is an important integrator of sensory information. The solitary tract of the vagus nerve performs a similar function, but is much more difficult to access for external modulation. (Clark KB, Naritoku DK, Smith DC, Browning RA, Jensen RA, 1999) It can only be stimulated electrically with various wave forms intensities and rates. The trigeminal nerve synapses with almost all of the relevant nuclei that would be involved in having a desirable physiologic response in fibromyalgia syndrome. These include the locus ceruleus, the periaqueductal gray, the parabrachial nucleus, the dorsal raphe nucleus, and the ventral tegmental area, which secretes dopamine to the nucleus accumbens. Other important modulatory structures are involved, but I do not want to make this discussion too technical. Since trigeminal nerve function can be altered pharmacologically, electrically, and mechanically, this route allows the use of a wide range of modalities to tune brain function.

One bottle of TRH nasal spray lasts for about 45 days, and patients usually give themselves one spray in each nostril three times a day. There has not yet been a side effect in my experience, except for occasional mild allergy. I have also been using TRH ophthalmic solution, in a 1:10 dilution with artificial tears. This product works quite well also but perhaps not quite as well as TRH nasal spray. Some patients use both of them. The eyedrops act instantly when they are effective. There appear to be TRH and NMDA receptors on the cornea as has been demonstrated for substance P (Nakamura M, Ofuji K, Chikama T, Nishida T, 1997).

I have had very good success using ketamine eyedrops in varying dilutions from 1:100 down to 1:5. Some of the responses have been quite remarkable. I also make ketamine nasal spray 1:25 and 1:10 and monitor its use because of a slight potential for abuse. Ketamine is an antagonist of glutamate acting at the N-methyl-d-aspartate (NMDA) receptor. NMDA receptor antagonism is probably the most important pharmacologic aspect of treating neurosomatic disorders, and may be accomplished by many different routes with a host of agents. NMDA antagonism in the trigeminal system is possible, and should benefit the neurosomatic patient (Parada DA, Luccarini P, Woda A, 1997).

TRH nasal spray seems to be safe and effective and has the potential in certain patients to ameliorate all symptoms very rapidly. However, as I mentioned previously, it is less apt to help pain than other symptoms. Ketamine in PLO gel transdermally as well as in nasal spray and topical ophthalmic form, are better analgesics than TRH and sometimes are effective when IV ketamine is not.

Clark KB, Nartiku DK, Smith DC, Browning RA (1999), Enhanced recognition memory following vagus nerve stimulation in human subjects. Nature Neuroscience 2(1): 79-87.

Nakamura M, Ofuji K, Chikama T, Nishida T (1997). The NK1 receptor and its participation in the synergistic enhancement of corneal epithelial migration by substance P and insulin-like growth factor-1. Br J Pharmacol 1997 Feb;120(4)547-52.

Parada CA, Luccarini P, Woda A (1997). Effect of an NMDA receptor antagonist on the wind-up of neurons in the trigeminal oralis subnucleus. Brain Research 761:313-320.

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