Scientific Information

Serotonin, also known as 5 hydroxytryptamine or 5HT is found in the cells of the brain, spinal cord, intestines and in blood platelets. It is a neurotransmitter. When walls of blood vessels are damaged, serotonin is released from the platelets to constrict the blood vessel and prevent hemorrhage. Serotonin also acts as a stimulant in the intestinal tissue, causing smooth muscle to contract. In the brain, it acts as a neurotransmitter, aiding the transmission of nerve impulses between synapses. Synapses are junctions between nerve cells where nerve impulses are transferred from one neuron to another. Serotonin is very important to all body systems.

Serotonin is obtained from various dietary sources, it is also synthesized in the nervous system from tryptophan through the actions of enzymes. Note the shapes of the molecules.

It is believed that serotonin plays a major role in causing cluster headache and migraine, possibly because of a dysfunction or problem in a specific serotonin receptor cell; - there are more than one – which in normal circumstances cause blood vessels to constrict. Because of this dysfunction, various irritating factors can cause blood vessels to dilate, putting pressure on surrounding tissues and causing pain.

Low brain serotonin levels also appear to be associated with increased sensitivity to pain, and chronic pain sufferers show reduced serotonin function. Serotonin is also believed to have an effect on pain awareness by controlling the release of a pain signalling chemical known as Substance P.

More information on serotonin may be found at:

• OUCH Research Library - 5HT
• Basic Physiology of Psychoactive Drugs ~ Catherine Seeley

Deficiency of serotonin is implicated in mood disorders, appetite control, pre-menstrual syndrome, autism, eating disorders, fibromyalgia, the pain phase of migraine and CH. Some serotonin is converted by the pineal gland into melatonin, the hormone that controls sleep cycles, (circadian rhythm) and deficiency of this hormone can lead to insomnia and other sleep disorders.

What is a hormone?

It is an organic molecule synthesized in specific glands which regulates many body functions, such as appetite, circadian rhythm, and sex. Hormones act by binding to receptors outside cell walls, causing a signal to go through the membrane and initiate a “cascade” inside the cell.

What is a neurotransmitter?

Neurotransmitters are manufactured in neurons, which are nerve cells. These have three parts:

The soma, the central part which is a long protrusion which carries electrical nerve impulses resulting in a release of neurotransmitters from its tip called: dendrites.

The axon and large numbers of stringy long hair- like filaments which stick out everywhere so that they are able to catch neurotransmitters from other neurons called: dendrites.

Neurotransmitters such as serotonin are manufactured in the soma of the neuron, transported to the tip of the axon and released when the neuron fires. Dendrites from one or more other neurons in the area catch these neurotransmitters which may cause these other neurons to fire and release their neurotransmitters to be caught by still more neurons etc etc.

After a dendrite has caught a neurotransmitter molecule it breaks it down and releases the parts into the space between neurons which may or may not fire before decomposing the neurotransmitter. (This fire/not fire depends on a lot of biochemical conditions present at the time.)The broken down neurotransmitter molecule is absorbed by the soma of a neuron in the area, turned back into a functional neurotransmitter molecule, transported back to the neuron’s axon ad finitum. This is serotonin re-uptake.

Neurotransmitter receptor sites are located on neuron dendrites which can have receptors for many different neurotransmitters of which serotonin is only one.

What is a receptor cell?

Remember the kiddie toy where a barrel has shapes such as circles, triangles, squares, plusses and crosses inside it, and these shapes are fitted in to holes of the same shape on the lid? Receptor cells are similar in that they have a definite shape, and it is this shape that allows a chemical of the same shape to bind to them. Each chemical neurotransmitter molecule has its own individual shape, and the receptor cells on the dendrites of other neurons that it is to bind to will have that shape too. In this way, the right chemical signals are sent to the right places.

The serotonin molecule has a unique shape. It has a series of atoms linked to form what is called an indole ring.

Other molecules share this indole ring and are able to be accepted or blocked by the serotonin receptors. The best known accepted molecule is sumatriptan, (Imitrex, or Imigran) and as well as restricting blood vessels, it works by kidding the serotonin receptors into believing that there is the right amount of serotonin present to keep body systems functioning regularly, and attacks are aborted. It is able to correct the aberration that causes the headache, although real understanding of the mechanism by which it works, and the aberration that causes the attack, is still debatable and still being researched. Other indole ring molecules block the serotonin receptor cells from picking up further serotonin and this too, may abort and prevent headaches from occurring. Note that serotonin molecules are indole rings.

Other well known substances like LSD, and psilocilin from psilocybin, also are indole ring molecules and have been used in the past for treatment of headaches, especially migraine. It was the “War on drugs” of the late seventies that stopped research on these substances, and although results then were promising, further research has stopped. It is believed that these substances may yet have a role to play in the treatment of cluster headache.

Psilocilin from psilocybin is a hallucinogen which is closely related to LSD. Both are psychedelic drugs which have actions at multiple sites in the central nervous system. One of the sites is probably a serotonin receptor site, the 5 HT2 subtype. It is not known whether these substances work as agonists or antagonists.

Experienced neurological researchers believe that psilocilin is bound to the 5 HTP 2A synaptic receptor sites blocking the re- uptake of serotonin. This would make them antagonists. In this manner the synapses receive a slightly different signal from the psilocilin molecules than they would from serotonin molecules.

Although some psychotropic effects are noticed, these substances appear to re-set the serotonin uptake mechanism, controlled by the hypothalamus; serotonin levels return to normal and stop the headaches. In cluster headache this re-setting not only aborts the headache in progress, but appears to last beyond any lingering traces of psilocilin in the body – up to one year according to anecdotal evidence.

What is an agonist?

An agonist is a drug that shows affinity for and stimulates a receptor.

What is an antagonist?

An antagonist is a drug that has an affinity for a receptor but does not stimulate it and prevents a response from occurring.
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Related Scientific Abstracts and Findings

Clinical Data on the CGRP Antagonist BIBN4096BS for Treatment of Migraine Attacks.
CNS Drug Rev. 2005 Spring;11(1):69-76.

Edvinsson L. Department of Internal Medicine,
University Hospital, S-221 85 Lund, Sweden.
lars.edvinsson@med.lu.se.

Basal studies have shown that calcitonin gene-related peptide (CGRP) is a major sensory neuronal messenger in the trigeminovascular system, the pathway conveying intracranial pain. In migraine and cluster headache attacks, CGRP is released in parallel with the pain and successful treatment of the attacks abort both the associated pain and the CGRP release. The search for a potent small molecule CGRP antagonist has been successful and such an agent has been tested in preclinical and clinical studies. The aim of the present study was to examine current knowledge on the clinical pharmacology of systemic BIBN4096BS, which has been shown in man to abort acute migraine attacks as well or better than oral sumatriptan. BIBN4096BS is a specific and potent CGRP receptor antagonist in humans. In safety and tolerability studies the substance is well tolerated with no or only mild side effects. In acute migraine attacks the overall response was 66% with the drug and 27% with placebo. A difference as compared to placebo was seen at 30 min; the response was still rising at 4 h suggesting a long duration of action. At 24 h the pain-free rate was better than that with triptans, suggesting a lower grade of rebound and perhaps even a prophylactic possibility.

The following says that the CGRP and 5-ht2a genes tend to be expressed in the same cells, and that inflammation that leads to increased CGRP also increases 5-ht2a gene expression/receptors. All of which is consistent with the idea that a potent 5-ht2a mimic (clusterbuster) leads to tolerance and long term reduction of the very receptors it initially stimulates.
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Pain. 2002 Sep;99(1-2):133-43.

5-HT2A receptor subtype in the peripheral branch of sensory fibers is involved in the potentiation of inflammatory pain in rats.

Okamoto K, Imbe H, Morikawa Y, Itoh M, Sekimoto M, Nemoto K, Senba E.
Department of Anatomy and Neurobiology, Wakayama Medical University, 811-1
Kimiidera, Wakayama City 641-8509, Japan.

One of the major serotonin (5-HT) receptor subtypes expressed in the rat dorsal root ganglion (DRG) neurons is the 5-HT2A receptor. We have previously shown that 5-HT2A receptors in the peripheral sensory terminals are responsible for 5-HT-induced pain and hyperalgesia. In the present study, we characterized neurons expressing 5-HT2A receptors in the rat DRG neurons by means of in situ hybridization, immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR) and behavioral tests. In situ hybridization on consecutive sections revealed that 5-HT2A receptor mRNA is colocalized with calcitonin-gene related peptide (CGRP) mRNA (100/104; 96.2%) but not with c-Ret mRNA (1/115; 0.9%). Signals for 5-HT2A receptor mRNA were found in 9.4 +/- 2.2% of normal DRG (L5) neurons, most of which were small to medium in size. Four days of complete Freund's adjuvant-induced inflammation of the hindpaw doubled the incidence of 5-HT2A receptor mRNA-expressing neurons to 19.3 +/- 2.8%. The level of 5-HT2A receptor mRNA in DRGs of normal and various pathological conditions was then determined by RT-PCR. The level was up-regulated by peripheral inflammation, but not by axotomy or chronic constriction of the peripheral nerve. Systemic administration of 5-HT2A receptor antagonist (Sarpogrelate HCI) produced analgesic effects on thermal hyperalgesia caused by peripheral inflammation, but failed to attenuate thermal hyperalgesia in chronic constriction injury model. These findings suggest that 5-HT2A receptors are mainly expressed in CGRP-synthesizing small DRG neurons and may be involved in the potentiation of inflammatory pain in the periphery.

5-HT modulation of dopamine release in basal ganglia in psilocybin-induced psychosis in man--a PET study with [11C]raclopride
by Vollenweider FX, Vontobel P, Hell D, Leenders KL Research Department,
Psychiatric University Hospital Zurich, Switzerland.
Neuropsychopharmacology 1999 May; 20(5):424-33

The modulating effects of serotonin on dopamine neurotransmission are not well understood, particularly in acute psychotic states. Positron emission tomography was used to examine the effect of psilocybin on the in vivo binding of [11C]raclopride to D2-dopamine receptors in the striatum in healthy volunteers after placebo and a psychotomimetic dose of psilocybin (n = 7). Psilocybin is a potent indoleamine hallucinogen and a mixed 5-HT2A and 5-HT1A receptor agonist. Psilocybin administration (0.25 mg/kg p.o.) produced changes in mood, disturbances in thinking, illusions, elementary and complex visual hallucinations and impaired ego-functioning. Psilocybin significantly decreased [11C]raclopride receptor binding potential (BP) bilaterally in the caudate nucleus (19%) and putamen (20%) consistent with an increase in endogenous dopamine. Changes in [11C]raclopride BP in the ventral striatum correlated with depersonalization associated with euphoria. Together with previous reports of 5-HT receptor involvement in striatal dopamine release, it is concluded that stimulation of both 5-HT2A and 5-HT1A receptors may be important for the modulation of striatal dopamine release in acute psychoses. The present results indirectly support the hypothesis of a serotonin-dopamine dysbalance in schizophrenia and suggest that psilocybin is a valuable tool in the analysis of serotonin-dopamine interactions in acute psychotic states.

The brain chemistry aspect of the LSD—the language of serotonin, dopamine, and other neurotransmitters—is one of the most heavily investigated, but it's also endlessly confounding. On the level of chemical structure, LSD looks quite a bit like the serotonin molecule, and the LSD-serotonin connection has been explored since the 1950s. The debate over whether LSD is a good model for how schizophrenia works has been raging for nearly half a century. Recently, dopamine, the "feel-good" chemical also implicated in disorders like schizophrenia, is finding a larger role in the LSD story. And as scientists learn more about serotonin receptors, they've localized specific aspects of the LSD experience to different receptors. The flood of kaleidoscopic visual effects that happens upon taking LSD and substances like it seems to be tied to the activation of a particular serotonin receptor called 5-HT2A.

In a study that will soon be published, Nichols and his group trained 25 rats to push levers to distinguish between having received an injection of LSD and an injection of regular old saline solution. Rats don't trip exactly like people do; for one, they don't have the massively overdeveloped frontal lobes of humans that allow for higher cognitive functions and dorm room philosophizing. But they do show some measurable behavioral changes that can be related to the human trip; at first, the rats don't seem to move around too much, and then there's increased locomotor activity.

The first phase of the rats' LSD experience, Nichols found, was indeed mediated by the 5-HT2A receptor, the one responsible for the visuals. But the second phase of the rats' trip was a full-on dopamine response. The "coming down" phase—where bad trips are more likely to form—is where the dopamine D2 receptor kicks in, a receptor that's implicated, among other things, in schizophrenia. It seems that an LSD trip is a two-phase experience—a story that begins with serotonin and ends with dopamine.

cloned 5HT2A and 5HT2C receptors
by Egan CT, Herrick-Davis K, Miller K, Glennon RA, Teitler M
Department of Pharmacology and Neuroscience,Albany Medical College, NY 12208, USA.
Psychopharmacology (Berl) 1998 Apr; 136(4):409-14

ABSTRACT
Evidence from studies with phenylisopropylamine hallucinogens indicates that the 5HT2A receptor is the likely target for the initiation of events leading to hallucinogenic activity associated with LSD and related drugs. Recently, lisuride (a purported non-hallucinogenic congener of LSD) was reported to be a potent antagonist at the 5HT2C receptor and an agonist at the 5HT2A receptor. LSD exhibited agonist activity at both receptors. These data were interpreted as indicating that the 5HT2C receptor might be the initiating site of action for hallucinogens. To test this hypothesis, recombinant cells expressing 5HT2A and 5HT2C receptors were used to determine the actions of LSD and lisuride. LSD and lisuride were potent partial agonists at 5HT2A receptors with EC50 values of 7.2 nM and 17 nM, respectively. Also, LSD and lisuride were partial agonists at 5HT2C receptors with EC50 values of 27 nM and 94 nM, respectively. We conclude that lisuride and LSD have similar actions at 5HT2A and 5HT2C receptors in recombinant cells. As agonist activity at brain 5HT2A receptors has been associated with hallucinogenic activity, these results indicate that lisuride may possess hallucinogenic activity, although the psychopharmacological effects of lisuride appear to be different from the hallucinogenic effects of LSD.

DMT

Lysergic acid diethylamide (LSD) is a partial agonist of D2 dopaminergic receptors and it potentiates dopamine-mediated prolactin secretion in lactotrophs in vitro
by Giacomelli S, Palmery M, Romanelli L, Cheng CY, Silvestrini B
Institute of Pharmacology and Pharmacognosy, University of Rome La Sapienza, Italy.
Life Sci 1998; 63(3):215-22

ABSTRACT
The hallucinogenic effects of lysergic acid diethylamide (LSD) have mainly been attributed to the interaction of this drug with the serotoninergic system, but it seems more likely that they are the result of the complex interactions of the drug with both the serotoninergic and dopaminergic systems. The aim of the present study was to investigate the functional actions of LSD at dopaminergic receptors using prolactin secretion by primary cultures of rat pituitary cells as a model. LSD produced a dose-dependent inhibition of prolactin secretion in vitro with an IC50 at 1.7x10(-9) M. This action was antagonized by spiperone but not by SKF83566 or cyproheptadine, which indicates that LSD has a specific effect on D2 dopaminergic receptors. The maximum inhibition of prolactin secretion achieved by LSD was lower than that by dopamine (60% versus 80%). Moreover, the fact that LSD at 10(-8)-10(-6) M antagonized the inhibitory effect of dopamine (10(-7) M) and bromocriptine (10(-11) M) suggests that LSD acts as a partial agonist at D2 receptors on lactotrophs in vitro. Interestingly, LSD at 10(-13)-10(-10) M, the concentrations which are 10-1000-fold lower than those required to induce direct inhibition on pituitary prolactin secretion, potentiated the dopamine (10(-10)-2.5x10(-9) M)-mediated prolactin secretion by pituitary cells in vitro. These results suggest that LSD not only interacts with dopaminergic receptors but also has a unique capacity for modulating dopaminergic transmission. These findings may offer new insights into the hallucinogenic effect of LSD.

Safety issues of Mushrooms & LSD
Will shrooms harm sperm?

This really breaks down into a number of different questions. Are we talking sperm count or sperm motility, which could affect the chances of impregnation, or genetic damage that could lead to birth defects? Does it make a different to use shrooms every day, for example, versus just once, or is there a window after shroom use where sperm is affected after which they're normal again?

I searched the literature back to 1970 and could find no evidence that psilocybin had any effect on sperm count, sperm motility or chromosomal aberrations, either when taken once or chronically. These problems are not included in even the most exhaustive lists of psilocybin's side effects. On the other hand, absence of evidence is not evidence of absence. So I checked the list of known and suspected human carcinogens at the National Toxicology Program (http://ntp.niehs.nih.gov/ntp/roc/toc11.html). Psilocybin is neither known nor suspected to be a human carcinogen.

Sperm takes about 90 days to mature in the testes then can be stored for about 10 weeks (or not at all if you're having sex every day). In theory if you wanted to be absolutely sure that your sperm was "inexperienced", you could just wait three months.

As an aside, it appears that male sperm counts are about 50% lower today than they were in the time of our grandparents, presumably because of environmental toxins, although this is controversial. Things such as tight underwear and overusing laptop computers (because of the heat) have been known to lower sperm counts 40%. It's a dangerous world out there for the little swimmers!
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Genetic toxicology of lysergic acid diethylamide (LSD-25).
Cohen MM, Shiloh Y.

The acute and the chronic psychotomimetic potentials of the hallucinogen lysergic acid diethylamide (LSD-25) have been recognized for almost 40 years. That additional types of the biological effects should have come under scrutiny was directly attributable to widespread use and abuse of this drug on a world-wide basis. Although "genetic toxicology" encompasses a broad spectrum of disciplines, including many areas of highly specialized research, perhaps the most germane, and those on which this review has concentrated, are Clastogenicity, Mutagenicity, Teratogenicity and Oncogenicity. Based on our current understanding and interpretation of the available data, the genetic toxicology of LSD provides an excellent example of Newton's "third law of motion", e.g., to every force there is an equal and opposite reaction force. >From the published material it is impossible to draw clear cut conclusions regarding any of the above "problem areas" in spite of the considerable scientific effort invested. Most of the in vitro studies performed on the clastogenicity of LSD indicate either suppression of mitosis or enhanced chromosome damage. However, extrapolation of such results to the in vivo situation is very difficult. With regard to in vivo human use of the drug, no concensus is attainable as to chromosome breakage and the inconsistencies within and between studies remain inexplicable. However, several of the "controlled" investigations assessing the in vivo effect of chemically pure LSD suggest a transient increase in lymphocyte chromosome breakage. On the other hand, the results of cytogenetic studies on experimental animals are contradictory. Although human studies are nonexistent, in those experimental organisms tested, using accepted techniques, LSD proved to be, at best, a weak mutagen, if mutagenic at all. Teratogenicity studies in animals are confusing due to the multitude of organisms and plethora of discriminant parameters studied. However, with regard to man there has been ample opportunity and one can conclude that LSD is not teratogenic. As to the drug's oncogenic potential, the 3 reported cases of leukemia in LSD users are most likely the result of coincidence.

The role of mast cells in migraine pathophysiology
Theoharis C. Theoharides, , Jill Donelan, Kristiana Kandere-Grzybowska1 and Aphrodite Konstantinidou2

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and Tufts-New England Medical Center, 136 Harrison Avenue, Boston, MA 02111, USA

Accepted 30 November 2004. Available online 12 February 2005.

ABSTRACT
Mast cells are critical players in allergic reactions, but they have also been shown to be important in immunity and recently also in inflammatory diseases, especially asthma. Migraines are episodic, typically unilateral, throbbing headaches that occur more frequently in patients with allergy and asthma implying involvement of meningeal and/or brain mast cells. These mast cells are located perivascularly, in close association with neurons especially in the dura, where they can be activated following trigeminal nerve, as well as cervical or sphenopalatine ganglion stimulation. Neuropeptides such as calcitonin gene-related peptide (CGRP), hemokinin A, neurotensin (NT), pituitary adenylate cyclase activating peptide (PACAP), and substance P (SP) activate mast cells leading to secretion of vasoactive, pro-inflammatory, and neurosensitizing mediators, thereby contributing to migraine pathogenesis. Brain mast cells can also secrete pro-inflammatory and vasodilatory molecules such as interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF), selectively in response to corticotropin-releasing hormone (CRH), a mediator of stress which is known to precipitate or exacerbate migraines. A better understanding of brain mast cell activation in migraines would be useful and could lead to several points of prophylactic intervention. Keywords: Allergy; CRH; Histamine; Mast cells; Migraines; Stress Abbreviations: BBB, blood–brain barrier; CGRP, calcitonin-gene related peptide; CRH, corticotropin-releasing hormone; IL-6, interleukin-6; NGF, nerve growth factor; NO, nitric oxide; NT, neurotensin; PACAP, pituitary adenylate cyclase activating peptide; SP, substance P; TNF-a, tumor necrosis factor-alpha; VIP, vasoactive intestinal peptide; Ucn, urocortin; VEGF, vascular endothelial growth factor Neuroscience classification codes: Neural-immune interactions, Brain

Corresponding author. Fax: +1 617 636 2456.
1 Present address: Department of Cell and Molecular Biology, Northwestern University Medical School, 303 E. Chicago Avenue, Chicago, IL 60611, USA.
2 Present address: Model Neurology Center, 79 Egnatia Street 54635, Thessaloniki, Greece.

Where Do Triptans Act in the Treatment of Migraine?
Ahn AH, Basbaum AI
Pain. 2005;115(1-2):1-4
Anti-migraine Action of Triptans Is Preceded by Transient Aggravation of Headache Caused by Activation of Meningeal Nociceptors
Burstein R, Jakubowski M, Levy D

Pain. 2005;115 (1-2):21-28

Overview
The basis for the apparent selectivity of triptans in the treatment of migraine pain, but not other kinds of somatic pain, is still not understood. Determining the precise mechanism of triptan action will probably provide important new insights into the unique and essential features of migraine.

Migraine headache is a common and poorly understood primary pain disorder. Sumatriptan and the "triptan" class of serotonin receptor subtype-selective drugs have well-established efficacy in treating the pain of migraine. Although sumatriptan was originally selected to target vasoactive properties believed to be fundamental to the etiology of migraine, other studies point to an action of triptans at several levels of the nervous system. However, to this day it is not clear whether the antimigraine activity of the triptans involves an action only in the peripheral nervous system or in the central nervous system (CNS). Because sumatriptan is hydrophilic, it penetrates the blood-brain barrier poorly, suggesting a peripheral site of action. On the other hand, it has been proposed that the barrier is compromised in migraine, so a CNS site of action has not been ruled out.

Results
Ahn and Basbaum provide commentary on a study by Burstein and colleagues in the same issue. In this discussion, they review the physiologic actions of sumatriptan, shedding light on how we understand headache specifically and pain mechanisms in general. Their most important finding is that migraine, as we know it, involves not only a central source in the vasculature of the inner brain, but relates to nociceptive signaling in the meninges as well. Their 4-part commentary discusses: (1) peripheral mechanisms of triptan action, (2) CNS mechanisms of triptan action, (3) the possibility of migraine-selective triptans, and (4) the blood-brain barrier and migraine.

Commentary
Ahn and Bausbaum propose a biphasic mechanism of action for triptans on meningeal nociceptors during migraine to explain the contradictory findings of past investigations.

Step 1:
Soon after systemic administration, triptan molecules bind to 5HT receptors on the dural branch of the meningeal nociceptor and activate them. This initial action of the drug exacerbates, rather than alleviates, the patient's perception of pain.

Step 2:
Roughly 20 minutes after administration, triptan molecules cross the blood-brain barrier and bind to presynaptic 5HT1B1D receptors on the central branch of the meningeal nociceptor in the dorsal horn. As they activate these receptors, the triptan molecules effectively block synaptic transmission between the nociceptor and the central neuron in the dorsal horn. As long as the central neuron is not sensitized -- that is, as long as its firing remains dependent on incoming impulses from the meninges -- triptan inhibition of synaptic transmission in the dorsal horn renders the central neuron quiescent and eliminates migraine pain.

Abnormal 24-hour urinary excretory pattern of 6-sulphatoxymelatonin in both phases of cluster headache.

Leone M, Lucini V, D'Amico D, Grazzi L, Moschiano F, Fraschini F, Bussone G

Neurological Department and Headache Centre, Istituto Nazionale Neurologico C. Besta, Milan, Italy.

The typical cyclic occurrence of cluster headache suggests the involvement of hypothalamic rhythm regulating centers in the pathogenesis of this primary headache. In previous studies, reduced 24-h plasma melatonin levels during the cluster period, loss of circadian melatonin secretion in remission, as well as permanently reduced excretion of urinary melatonin in both illness phases have been reported, supporting the hypothesis of a hypothalamic derangement. In this study, the 24-h urinary excretion of the main melatonin metabolite, 6-sulphatoxymelatonin, was evaluated in 20 cluster period cluster headache patients. Thirteen were retested 12 months later, in the same period of the year, during remission. Fourteen age- and sex-matched healthy subjects were the controls. As expected, significantly higher levels of 6-sulphatoxymelatonin were present in nocturnal urine than in day-time urine in controls, while in both cluster headache groups urinary levels of this metabolite did not differ between day and night. Nocturnal levels of 6-sulphatoxymelatonin were significantly lower in both cluster headache groups than controls. Day-time levels did not differ significantly between the groups. Altered excretion of urinary 6-sulphatoxymelatonin even during remission indicates that at least some of these anomalies are independent of the pain, and provides further evidence of involvement of the hypothalamic rhythm regulating centers in cluster headache.

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