Cluster Headache, Dreaming & Neurogenesis

Table of Contents

IntroductionOverall HypothesisIntroduction to Cluster HeadachePathophysiology of Cluster HeadacheIntroduction to SleepWhy do we sleep?The importance of sleepHypnotics and stimulantsWhat happens when we sleep?The sleep/wake cycleIntroduction to DreamingLife-stage and other influences on dreamingIntroduction to NeurogenesisIntroduction to the Pineal GlandPineal enzymesDMT – the dream transmitter?Serotonergic neurons and waking dreamsOther dream transmittersDream Transmitters, Mitosis and NeurogenesisEntheogens, Sleep and NeurogenesisThe Sleep/wake cycle and Cluster HeadacheAlternative Medication for Cluster Headache: EntheogensHow Entheogens Work (in Cluster Headache)Medicinal uses of naturally derived substancesA Malfunctioning Pineal Gland?Pathophysiology of CH: RevisitedSummary, Discussion and Conclusions

Cluster Headache, Dreaming & Neurogenesis

1. Introduction

This ‘paper’ has been cobbled together from various sources, mainly from the internet, over the last year or so. Accordingly, most of the information cannot be validated as being strictly accurate, and hence many errors maybe apparent – so apologies in advance should this be the case!

I have also attempted to pull all the relevant information together as quickly as possible and therefore apologise in advance for specific plagiarism and lack of appropriate source data; but naturally I am greatly thankful to those individuals and organisations that have already summarised the information I have used.

Like most of my theories, much of this is based on conjecture and is purely hypothetical. As you will see I am not a scientist so once again apologies in advance for any errors, particularly in terms of neurology and chemistry! I just wished I’d paid a bit more attention to science at school.

This initial document has been designed primarily for discussion purposes, so please feel free to contact me with any comments or suggestions, feedback, revisions, etc.

2. Overall Hypothesis

There appears to be no common consensus in respect of why people sleep; I believe it is so that we are able to dream. There is even less agreement as to the true role of dreaming; although most people do agree that it’s essential. I believe that dreaming is an essential mechanism for ‘neurogenesis’ in the brain.

The basic hypothesis is that neurogenesis – the birth of new neurons in the adult brain – only occurs with the correct ‘type’ and the correct ‘amount’ of sleep; and perhaps more importantly, the correct type and amount of dreaming. If neurogenesis does not occur at sufficiently robust levels then certain neurological disorders may become apparent, including cluster headache.

Sleep and dreaming appear to be regulated by a variety of different chemicals within the brain; including monoamines, neurotransmitters, beta-carbolines, cytokines (IL-1 and TNF), growth hormones etc., and clinical studies have shown that CH sufferers have an imbalance of many of these chemicals.

However, the crucial chemicals that affect dreaming appear to be the endogenously produced psychoactive methylated tryptamines, including DMT, 5-MeO-DMT, pinoline and bufotenine. These are believed to be produced by the epiphysis (pineal body), a fascinating little gland, which is directly linked to the hypothalamus (more particularly the suprachiasmatic nucleus or SCN) via the pineal nerve. Perhaps cluster headache sufferers actually have an ‘abnormal’ pineal gland, which is causing the well-documented irregularity of activity seen within the hypothalamus?

As many CH sufferers know, many traditional prescriptive medications are based on indole ring hallucinogens, but arguably, none of these appear to be as effective as LSD, LSA or psilocybin/psilocin in the overall treatment of CH. Perhaps these unadulterated alternative medications are more effective in mimicking the naturally occurring oneirogenic or somnogenic chemicals that are potentially lacking amongst sufferers; and hence re-set the ‘dream-clock’ and enable normal neurogenesis to occur?

Peter May: 14th February 2006

3. Introduction to Cluster Headache

Cluster headache (CH) normally involves pain that is one sided and occurs together with one or more cranial ‘autonomic’ features including reddening and tearing of the eye, a runny or blocked nostril, droopy eyelid, constriction of the pupil, flushing and facial sweating. In most sufferers the headaches often start at the same time of year and at the same time of day. The pain involved is excruciating and is probably one of the most painful conditions known to humans. Female sufferers have described each attack as being more painful than childbirth. Another name often used for CH is 'suicide headaches'.

The following excerpt is a verbatim quote by a leading practitioner of CH:

“Yeah, sadly I have managed people - cluster patients - who've committed suicide, and I've managed a couple who've died for various reasons during the management. It's a terrible disease. Imagine that you break both of your legs; or imagine that you stick your hand in a fire; or imagine that you're giving birth without any anaesthetic; or imagine that your head was tied down and someone had a drill out, drilling in your teeth; and then imagine that the cluster headache is worse. And pause for a second and imagine that the sufferer is delivering a baby five times a day - just think about that for a second - it would drive people to distraction. It's a horrible condition … now the great thing about cluster headache - to me - is the patients; that they can put up with this problem and they can work through their lives.”

It is estimated that as few as 0.2% (two in a thousand) of the population suffer from CH, approximately the same number as for multiple sclerosis in the UK. Men are more likely to suffer than women, with an estimated male to female ratio of between 2:1 and 5:1. CH can begin at any age, but most sufferers are more likely to start suffering in their 30s or 40s.

Approximately eight out of ten sufferers have episodic cluster headache (ECH), which is diagnosed when they have a series of bouts, each one lasting more than a week and separated by pain-free remission lasting more than four weeks. Most ECH sufferers have one or two cluster bouts per year, each lasting between 1-3 months. The remaining 20% of CH sufferers have chronic cluster headache (CCH), whereby no pain-free remission occurs within one year, or the remission periods last less than four weeks.

A single headache (attack) always focuses on just one side of the head or face although the headache can change sides between attacks and/or bouts. The pain is excruciatingly severe. It is located mainly behind or around the eye, around the top side of the head and within the temple and forehead, although any part of the head or neck can be affected. The headache normally lasts from between 45 minutes and 1½ hours, but can range from between 15 minutes and 3 hours. The pain often reaches its peak very quickly and maintains its intensity over a period of time before ending equally quickly. The cluster attack frequency varies from between one every other day to three times a day, however, some sufferers can have up to eight attacks (or more) each day.

The traditional treatment of CH includes offering advice on general measures to sufferers; actually stopping individual attacks; helping to stop the attacks happening in the first place; and rarely, brain surgery. Conventional drugs used to help stop individual attacks are called abortive agents or acute treatments. The pain of CH builds up so quickly and to such an excruciating peak that most drugs that are designed to be ingested do not work quickly enough. The most effective abortive agents are those that are either administered through the lungs or nose, or by means of injection: beneath the skin, through the muscle, or into a vein. Drugs used to help prevent CH occurring in the first place are called prophylactics or preventative treatments. The aim of preventative treatment is to attempt to reduce the number of attacks with minimal side effects until the cluster bout is over in ECH, or for a longer period in CCH.

Although yet to be medically proven, it has been argued that the long term use of both abortive and preventative prescriptive medication can actually make the condition worse, sometimes turning episodic sufferers chronic.

4. Pathophysiology of Cluster Headache

Cluster headache has two major clinical features: the trigeminal distribution of pain and the associated ipsilateral (same-sided) autonomic symptoms. Firstly, the pain producing innervation (stimulation) of the cranium projects through branches of the trigeminal and upper cervical nerves to the trigeminocervical complex from where nociceptive pathways project to higher centres. Secondly, the accompanying ipsilateral autonomic symptoms suggest cranial parasympathetic activation (that’s the teary eye, runny and blocked nose) and sympathetic hypofunction (the droopy eye and constriction of the pupil). These are called ‘autonomic’ because they are involuntary or automatic responses not caused by any conscious effort or external forces.

However, the third and possibly most important clinical feature is the uncanny timing of both attacks and bouts themselves which originally suggested an involvement in the brain’s master-clock: the hypothalamus or more particularly the suprachiasmatic nucleus (SCN). It is now thought that an abnormality within the hypothalamus is the root cause of the pain, which, when in cycle, releases hormones and chemicals that innervate the trigeminal ganglion, in turn causing the domino effect of pain and cranial autonomic symptoms through the trigeminal nerve down one side of the face and head. This theory is backed up by the regularity of attacks (circannual and circadian), much lower levels of plasma testosterone during attacks and bouts, and alterations in the natural production of a variety of hormones/chemicals that affect the biologic clock.

Furthermore, PET studies (positron emission tomography) conducted in the late 1990s demonstrated that there is also ipsilateral hypothalamic activation: there are direct hypothalamic-trigeminal connections and the hypothalamus is known to have a modulatory role on the nociceptive and autonomic pathways. In summary these studies showed an increase in functional activity of the hypothalamus amongst CH sufferers which is not seen in migraine, and is the prime reason why CH is thought to be caused by an abnormality within the hypothalamus. These abnormalities were seen both when sufferers were undergoing an attack and also whilst pain free and were interpreted as an excessive growth of grey cells within the hypothalamus, or more particularly (or possibly), within the SCN.

The crucial question now appears to be what actually is the cause and effect of these abnormalities?

5. Introduction to Sleep

Sleep: a state of rest during which the eyes are closed, the muscles and nerves relaxed, and the mind is unconscious.

5.1 Why do we sleep?

Sleep researchers can say for certain that sleep overcomes sleepiness, but beyond that, many researchers disagree on why we sleep. Sleeping itself, however, is essential to healthy living. Lack of sleep can cause grumpiness, grogginess, irritability, and forgetfulness. Sleep deprivation not only has a major impact on cognitive functioning but also on emotional and physical health. Interestingly, very long periods of sleeplessness can cause hallucinations!

A variety of explanations as to the role of sleep have been offered over the years, including (in no particular order): -

lowering brain temperature and lower metabolismreinforcing pair-bonds, filial imprintingpredator protectionconservation of energy/calorieserasure of memoryconsolidation of memoryenabling dreaming

OK, that last one is mine! Anyway, there doesn’t appear to be a common consensus, but I’ve found that sleep is a fascinating process, especially because we spend about a third of our lives doing it. One aspect of sleeping that everyone agrees with, however, is its importance to health and well being.

5.2 The Importance of Sleep

Deficits in daytime performance due to sleep loss are experienced universally and associated with a significant social, financial, and human cost. Micro-sleeps, sleep attacks, and lapses in cognition increase with sleep loss as a function of state instability. Sleep deprivation studies repeatedly show a variable (negative) impact on mood, cognitive performance, and motor function due to an increasing sleep propensity and destabilisation of the wake state. Performance deficits associated with sleep disorders are often viewed as a simple function of disease severity; however, recent experiments suggest that individual vulnerability to sleep loss may play a more critical role than previously thought.

Experiments with airline pilots show that short naps - nicknamed "power naps" - can help people boost their brain function. That is especially true for healthy people who aren't getting enough sleep. However, even though naps can be great energisers, they are no substitute for longer periods of healthy sleep.

Sleep is seen even in species that would seem better off without sleep. An example of this is the Indus dolphin. Living in muddy waters over the ages it has become blind, presumably because vision is not useful in their natural habitat. However, despite the dangers caused by sleeping, sleep has not disappeared. It never stops swimming; doing so would result in injury, because of the dangerous currents and the large amounts of debris carried by the river during the monsoon season. Studies showed that they slept a total of seven hours a day, in very brief naps of four to sixty seconds each. If sleep did not perform an important function we might expect that, like its vision, sleep would have been eliminated in this species through the process of natural selection.

For reasons that are still yet unclear, rats deprived of sleep die between 14 and 40 days of deprivation. There have been sad instances of thankfully a very rare disease called familial fatal insomnia amongst humans, who are unable to sleep and who also subsequently die. The pathological processes include degeneration of the thalamus and other brain areas, over activity of the sympathetic nervous system, hypertension, fever, tremors, stupor, weight loss and disruption of the body’s endocrine systems.

5.4 Hypnotics & Stimulants

In the seemingly never-ending quest for people to avoid sleeping too much, or to ensure that they get enough sleep (and hence being able to live life to the full) there appears to be a variety of options available; not least those fuelled by the pharmaceutical industry.

The vast majority of sleeping pills currently available – known in the trade as hypnotics – are quite simply knockout drops, which work by making neurons more sensitive to the soporific effects of GABA (the same mechanism by which alcohol works). Even the newer ‘cleaner’ hypnotics such as Ambien work through the GABA system.

However, over recent years, a new class of sleeping pills are on the horizon that promise to deliver sleep that is deeper and more refreshing than the real thing. Ramelteon (Rozeram), for example, mimics the effect of the sleep-promoting neurohormone melatonin (to be discussed in detail later), and there are at least three other new classes of hypnotic that do not go anywhere near the GABA system.

Another mainly pharmaceutical method of living life to the full is by actually preventing sleep with the aid of stimulants. Traditionally caffeine, cocaine and amphetamines have been used to this end. More recently, a new drug called modafinil has made it possible to have 48 hours of continued wakefulness with few, if any, of the adverse side-effects associated with other stimulants. This drug, plus many others in the pipeline, are known as eugeroics; meaning ‘good arousal’ in Greek. They claim to deliver natural feelings of alertness and wakefulness without the powerful physical and mental jolt of other more traditional stimulants.

Perhaps the most appealing aspect in respect of modafinil is that users don't seem to have to pay back any ‘sleep debt’. Normally, if a person stayed awake for 48 hours straight they would have to sleep for about 16 hours to catch up. This drug somehow allows you to catch up with only eight hours or so.

So it seems we are moving inescapably towards a society where sleep and wakefulness are available, if not on demand, then at least on request. Perhaps it's not surprising, then, that many sleep researchers have deep concerns in respect of the long-term impact of millions of people using drugs to override the natural sleep-wake cycle. Drugs like these may tempt people to overdose on wakefulness at the expense of sleep or indeed, over-promote the wrong type of sleep or wakefulness. In particular it seems that there are likely to be hidden health costs to overriding our natural sleep-wake cycles, with many sleep researchers believing that pharmaceuticals cannot substitute for normal sleep.

5.5 What happens when we sleep?

Sleep researchers have monitored the pattern of individuals’ brain waves or their electroencephalogram (EEG) to determine various levels or stages of sleep. They have found that sleep normally occurs in recurring cycles that last between 90 and 110 minutes in total, although this duration alters the longer we remain asleep. It is normally divided into five stages; stages 1-4 is non rapid eye movement sleep (NREM) and stage 5 is rapid eye movement sleep (REM).

Sleep moves progressively through the four recognised NREM stages into slow-wave sleep (stage 4). However, after approximately 70 minutes the sleep state reverses and stage 4 sleep moves rapidly up to stage 3, then 2, and then 1. Yet at the beginning of the night an individual does not normally wake at this point but passes into stage 5 REM sleep.

The five sleep stages can be summarised as follows:

Non-REM sleepStage one: Light Sleep

During the first stage of sleep, we're half awake and half asleep. Our muscle activity slows down and slight twitching may occur. This is a period of light sleep, meaning we can be awakened easily at this stage.Stage two: True Sleep

Within ten minutes of light sleep, we enter stage two, which lasts around 20 minutes. The breathing pattern and heart rate start to slow down. This period accounts for the largest part of human sleep. Stages three and four: Deep Sleep

During stage three, the brain begins to produce delta waves, a type of wave that is large (high amplitude) and slow (low frequency). Breathing and heart rate are at their lowest levels.

Stage four is characterised by rhythmic breathing and limited muscle activity. If we are awakened during deep sleep we do not adjust immediately and often feel groggy and disoriented for several minutes after waking up. Some children experience bed-wetting, night terrors, or sleepwalking during this stage.

REM sleep

The first rapid eye movement (REM) period usually begins about 70 to 90 minutes after we fall asleep. Although we are not conscious, the brain is very active - often more so than when we are awake. This is the period when most dreams occur. Our eyes dart around (hence the name), our breathing rate and blood pressure rise. However, our bodies are effectively paralysed, said to be nature's way of preventing us from acting out our dreams.

After some minutes of REM sleep there is a switch back to NREM sleep and the whole cycle repeats, up to five times during the night. However these cycles are not identical. The first part of the night is characterised by the occurrence of deep slow wave sleep (stage 3 and 4) and in the second half of the night we undergo more frequent and increasingly longer episodes of REM sleep.

It is thought by many that REM sleep may be much more important than NREM sleep. Sleep researchers have found that if periods of REM sleep are selectively disrupted then this results in a rebound effect whereby the next night, barring any more selective interference from researchers, there will be an extra amount of REM and associated dreaming.

Dreams are most frequently remembered when an individual is woken from REM sleep, but can occur during the different stages of NREM sleep.

5.6 The sleep/wake cycle

There a numerous complex interactions involved within the human brain that influence the sleep/wake cycle. In summary:

Signals from the SCN (suprachiasmatic nucleus within the hypothalamus) communicate timing information to all of the structures involved in the sleep/wake cycle.

The hypothalamus contains structures promoting wake and sleep. Interaction with the brainstem produces a ‘flip/flop’ sleep/wake switch. Hypothalamic signals go primarily to the forebrain.

Brainstem structures promote wakefulness and REM and NREM cycling. Signals from here pass through the thalamus and the hypothalamus, which in turn relays them to the forebrain.

The forebrain generates the electrical activity associated with the different stages of sleep and dreaming.

These interactions are fuelled by different chemicals, neurotransmitters and neurohormones, which vary in type and density depending on their origination within the brain. The most important appear to be:

NoradrenalineHistamineSerotoninGABAOrexinAcetylcholineMelatonin

Perhaps unsurprisingly, many of these may play an important role in cluster headache – to be discussed in detail later.

6. Introduction to Dreaming

Dream: an imagined series of events experienced in the mind when we are asleep.

There also appear to have been a number of theories over the years, both physiological and psychological, which help attempt to explain the role of dreaming. Without wanting to dwell too much on individual theories, I’ve produced my own top twelve of possible reasons why we dream (again in no particular order): -

Dreams …

have no functionhelp us to forgetentertain the mind to keep us asleepare prophetichelp to cope with trauma and stressare a form of wish fulfilmenterase non-essential memory and retain essential informationtest the system to ensure it’s still workingare an important component of memoryhelp solve personal problemsare a prerequisite to neurogenesis

OK, so once again, that last one is mine! Whatever the reason, apart from the very small minority of people who believe that dreaming has no function, most practitioners believe that dreaming is also essential to good health and well being.

Most scientists also believe that dreams occur in all humans with about equal frequency per amount of sleep, so when people say that they don’t dream; they possibly mean they do not recall their dreams. Incidentally, it is thought that all animals dream too (with the possible exception of reptiles), and the likely candidate for the greatest dreamer (those who have the longest periods of REM sleep) is the armadillo!

However, dreaming levels do appear to vary by life-stage and can also be influenced by a number of external factors.

6.1 Life-stage and other influences on dreaming

The amount of dream time varies across an individual’s life time. Firstly, it is believed that foetuses actually dream in the womb. Specialists have measured specific foetal eye movements, which appear to be similar to those that they have after birth whilst dreaming. Whether they have images that accompany the experience is unknown for obvious reasons, but is of course, highly unlikely. The earliest documented dream where there are images accompanying it is an 18-month old child whom a researcher heard talking in their sleep. After the child woke up they told the researcher about the dream.

With newborns there's a tremendous amount of the physical component to dreaming. About 80 percent of the sleep time of the neonatal infant and the newborn infant is in the REM state, where perhaps most dreams occur. Fundamentally, it has been suggested that dreaming helps to actually form the brain; however unfortunately, no conclusive evidence exists to support this.

As people age, their sleep patterns shift. For an adult, approximately 25 percent of sleep time is in the REM state. In older age there is a reduction to around 20 percent or so.

There are also increases in dreaming that occur in special circumstances particularly when people are learning new skills, regardless of the nature of these skills. Whenever people have to really concentrate on something this correlates to a corresponding increase in dreaming.

There also appears to be a link between hormonal levels and the amount of dreaming. Two great spurts of dreaming are at adolescence and during pregnancy, which both show high peaks of dream state sleep.

Dreaming can also be influenced by medication. Nightmares are often associated with prescriptive medications which affect neurotransmitter levels of the central nervous system, such as antidepressants, narcotics or barbiturates. Intense, frightening dreams may occur during the withdrawal of drugs that can cause REM sleep rebound; such as ethanol, barbiturates and benzodiazepines.

And finally symptoms of underlying illness can also occur during REM sleep, including angina, sleep apnoea, peptic ulcer disease, migraine and, of course, cluster headache where it has been hypothesised that the transition from REM sleep to NREM sleep may play a role in triggering night time attacks amongst cluster headache sufferers.

It is now known that both sleep and dreaming involve a complex and highly organised series of physiological states, but to what end?

7. Introduction to Neurogenesis

The more I look at it, the more I realise how truly amazing the human body is. Even with extreme major injury such as heart failure, severe burns, cuts and bruises, the body can repair itself, normally very well. However, up until relatively recently, it was believed that unlike other cells in the body, if brain cells are injured or killed, the damage is irreversible and hence the injury is permanent.

This view was challenged firstly during the 1960s when new technology identified that the birth of new neurons occurred in certain areas of the adult rat brain, under certain circumstances. More recently it has been discovered that this is also true within the adult human brain, but perhaps more interestingly, injury or damage to the brain can actually stimulate neurogenesis.

Neurogenesis is normally defined as the birth of new neurons in the adult brain. The neuron is the basic building block of the human brain and nervous system. Each of the more than ten billion neurons in the brain receives, processes and transmits electrical information from one part of the body to another. A neuron consists of a cell body and two or more extensions, called dendrites and axons, which may be as long as one metre in humans. Dendrites receive inputs and conduct signals toward the cell body, whereas axons conduct signals away from the body where they make connections with other neurons or target cells. These signals convey information that allows a person to interact with his or her environment - from breathing, to thinking, to sneezing.

Evidence of neurogenesis to date seems to focus specifically on certain areas of the brain – including the hippocampus and the olfactory bulb - but there is also evidence that other areas also experience neurogenesis. Although controversial, neurogenesis may also occur within the neocortex (the cerebral cortex) and both the thalamus and the hypothalamus, and I would not wager against the birth of new neurons in other less studied areas of the brain.

One particular study conducted in the 1990s focussed on the brain anatomy of depressed patients versus a control. It was found that one area of the brain (the hippocampus) amongst those suffering from depression was up to 15% smaller - and the longer the period of depression, the smaller the hippocampus.

Further studies showed that the brain damage shown in depression might not just be a result of brain cells dying, but a lack of cells being born (neurogenesis), and hence the condition maybe reversible through specific medication, such as selective serotonin re-uptake inhibitors (SSRIs). It is thought that SSRIs increase the levels of a substance called brain-derived neurotrophine factor (BDNF), which stimulates the birth of new cells.

Another recent study suggests that one of the factors that potentially suppress adult neurogenesis is stress, probably as a result of increased glucocorticoid release. Complementing this, it has recently been found that increasing brain levels of serotonin enhance the basal rate of dentate gyrus neurogenesis. Ongoing neurogenesis is thought to be an important mechanism underlying neuronal plasticity, enabling organisms to adapt to environmental changes and influencing learning and memory throughout life.

A number of different factors that regulate neurogenesis in animals have been identified. Physical activity and environmental conditions have been shown to affect proliferation and survival of neurons in vertebrates as well as invertebrates. For example, it has been found that crayfish in an "enriched" environment had increased neurogenesis and neuronal survival compared to siblings in an "impoverished" environment.

Hormones have also been found to influence the rate of neurogenesis in vertebrates (e.g. testosterone) and invertebrates (e.g. ecdysone). Serotonin is believed to play a key role in neurogenesis in a variety of organisms. In lobsters for example, depletion of serotonin dramatically reduced the proliferation and survival of olfactory projection neurons and local interneurons. Most recently, neurogenesis was found to follow a circadian rhythm in the juvenile lobster.

The key question appears to be that if neurogenesis does occur in the adult human brain, then how so? I believe it may stem from the pineal gland (also known as the ‘third eye’) and may be linked to the endogenously produced entheogens, and ultimately dreaming.

8. Introduction to the Pineal Gland

Located almost in the centre of the brain, the pineal body is a pea sized organ, shaped like a pine cone (hence the name). It is perched on top of the brainstem near to the hypothalamus. Originally thought to be vestigial, it was the last endocrine organ to be discovered in humans. The pineal body contains the epiphysis, a fascinating little gland, about the size of a grain of rice.

While the physiological function of the pineal gland was unknown until recent times, mystical traditions and esoteric schools have long known this area in the middle of the brain to be the connecting link between the physical and spiritual worlds, normally through the act of meditation. It is often referred to as the ‘third eye’. It is said that Herophilus discovered the pineal gland in 300 BC, and Galen labelled the gland ‘konareion’, meaning shaped like a pine cone.

The pineal is regulated by circadian (daily) rhythms. Although the suprachiasmatic nucleus (SCN) is thought to be the ‘master clock’ within the human brain, there are also other important clocks throughout the human body - the pineal itself being one of these. It is now known that the pineal has many functions and one of its primary roles is to make the hormone melatonin, which is then secreted into the blood for transport around the body. In humans the pineal gland begins to produce melatonin at age three months and production falls steadily from puberty on as the gland shrinks.

Despite its small size - it weighs about a tenth of a gram - the pineal gland contains enormous amounts of serotonin, a physiologically active biogenic amine and chemical neurotransmitter. In the brain, serotonin is synthesised from the amino acid precursor l-trytophan. But pineal cells are not neurons and do not use serotonin for neurotransmission. Instead, pineal serotonin functions as a substrate for the enzymatic production of other biologically active molecules.

The mechanisms involved in endogenous pineal synthesis are highly complex. In summary, when light from the retina within the eye stops travelling through the retinohypothalamic tract (i.e. when it becomes dark), the SCN within the hypothalamus stops sending nerve impulses (via the pineal nerve) directly to the pineal gland - the nerve impulses inhibit the production of melatonin. When the nerve impulses are switched off at night, pineal inhibition ceases, and melatonin is produced.

Melatonin was first discovered in 1959, and has since been found to be widely distributed throughout the living world, from algae all the way through to humans. It is available commercially as a dietary supplement in many countries throughout the world, and it is claimed to have a variety of (unproven) benefits, including preventing or curing cancer, diabetes, cataracts, PMS, schizophrenia, epilepsy, Parkinson’s disease, depression, Alzheimer’s disease, cardiovascular disease and, of course, cluster headache.

One pretty much proven property of melatonin, however, is that it has a mild hypnotic effect – it is a sleep inducer; it creates a very natural sleep including dream phases characterised by the REM sleep stage.

Melatonin is available in concentrated form in tablets at far higher levels than would normally be found in the blood. The circulating daytime serum levels of melatonin in healthy adults do not normally exceed 20 nanograms (billionths of a gram) per litre, whereas the night time range normally varies from between 20-170 nanograms per litre. One noteworthy point is that there is a considerable variation in the daily amount of melatonin produced by all individuals, but especially cluster headache sufferers.

So in humans, melatonin is produced mainly by the pineal gland from serotonin, but pineal serotonin is also a precursor to other transmitters that may play an important role in sleep and dreaming. Melatonin is made by the conversion of serotonin through the action of N-Acetyl-transferase (NAT) a naturally occurring enzyme (catalyst). But from serotonin and l-tryptophan, other methoxyindoles are thought to be produced (also through enzymatic change) and these possibly also influence the five phases of sleep and associated types of dreaming ... and hence perhaps neurogenesis.8.1 Pineal enzymes

Another unique biochemical mechanism exists within the human pineal gland. A pair of naturally occurring pineal enzymes - hydroxy-indole-O-methyl transferase (HIOMT) and indole-N-methyl transferase (INMT) - are capable of converting serotonin into a number of potent hallucinogens. Regulated by a variety of neuroendocrine mechanisms, these enzymes normally act on specific substrates and function as catalysts in the formation of biogenic amines. However, if they get out of phase with their normal substrates and act on pineal serotonin, they form potent psychoactive compounds within the human brain.

HIOMT specifically catalyses the transfer of a methyl group to the oxygen, located at the five position on the indole ring. In other words, HIOMT converts a 5-hydroxy-indole into a 5-methoxy-indole. This enzyme converts serotonin (5-hydroxytryptamine), into a psychoactive compound called 5-methoxytryptamine. In turn, this compound becomes a substrate for INMT, the other pineal methyltransferase enzyme.

INMT specifically catalyses the transfer of methyl groups (one at a time) to the amine nitrogen on an indole side chain. The resulting monomethyl intermediate, 5-methoxy-N-methyltryptamine, is also psychoactive, but it is quickly converted to the dimethyl derivative by INMT. This molecule is N,N-dimethyltryptamine (DMT), a relatively unknown but extremely potent hallucinogen.

8.2 DMT – the dream transmitter?

When created in the laboratory, DMT is a white, crystalline solid, which was first synthesised in 1931. It is found in numerous species of plants. South American shamans have been ingesting DMT in the form of Ayahuasca or snuffs for hundreds of years. DMT is an extremely powerful, natural hallucinogen.

As we have seen, DMT is thought to be naturally produced enzymatically through the pineal gland and it is believed to play a role in dreaming and possibly near-death experiences and other mystical states. When used as a recreational or spiritual drug, DMT is a very powerful yet short-lasting (10-15 minutes) hallucinogen (or entheogen), with onset in a matter of seconds. On its own, it is inert orally, and must be smoked or injected. However, DMT can be rendered orally active when taken in combination with a monoamine oxidase inhibitor (MAOI) which greatly increases the length of the effects. This is the combination used in the shamanic potion, Ayahuasca. The effects are similar to other psychedelics, but tend to be much more enveloping and intense, with the user being more of a passive observer than with other psychedelics.

The question as to the true role of endogenous DMT has not yet received a definitive answer. Due to the fact that it is closely similar to the molecular structure of serotonin, it has been suggested that it is also a neurotransmitter, but this has yet to be established.

What I find particularly interesting is that it has been suggested that DMT plays a central role in dreaming. The pineal releases DMT and other psychoactive substances at specific times during the sleep cycle; which as suggested, is thought to lead to the production of visual and emotive imagery during sleep.

8.3 Serotonergic neurons and waking dreams

Neuroscientists have carried out experiments which show that a suppression of serotonergic neuronal activity actually elicits dreaming. If experimental animals are injected with a substance called parachorophenylalanine (PCPA), which is known to block serotonin supplies to all parts of the brain, then they start to exhibit brain-wave patterns consistent with the onset of dreaming despite the fact that they are fully awake. In other words, it is suggested, that they are experiencing ‘waking dreams’.

Therefore, waking dreams are somehow associated with low levels of serotonin. Indeed, during dream sleep serotonergic cells in the raphe system will 'turn off' completely so that they cease having a depressant effect on other parts of the brain, a process which echoes the effects of some psychoactive substances upon the raphe system.

The conclusion reached is that dreaming is associated with a form of neuronal firing normally kept at bay by inhibitory serotonergic neurons until the onset of sleep. More importantly, the visions produced by psychedelic agents might be the result of waking dreams. Or at least they might emerge from neuronal processes which are similar to those processes occurring whilst we dream. Accordingly, it has been suggested that psychoactive substances allows one to experience dream-like consciousness whilst awake and these take the form of intensely moving visions behind closed eyes.

According to the various documented cases, entheogenic visions are indeed dreamlike, the only difference being that one is immeasurably more conscious during such visions than in dreams (even lucid ones) and one is able to remember them vividly, unlike dreams which appear to fade quickly. Whereas most people cannot, offhand, recall most of the thousands of dreams which they all must have had, psychoactive visions remain fairly emblazoned upon the memory, like favourite film clips.

8.4 Other dream transmitters

As mentioned earlier, other psychoactive substances are also believed to be produced by the pineal, including 5-MeO-DMT, (5-methoxy-dimethyltryptamine) bufotenine (5-hydroxy-N, N-dimethyltryptamine) and pinoline (6-methoxy-tetra-dydro-beta carboline).

Pinoline is effectively a beta-carboline (like harmaline) and as such acts as a monoamine oxidase inhibitor (MAOI), but it is also psychoactive. However, unlike other beta-carbolines, it is neuroprotective and shares similar properties to both DMT and 5-MeO-DMT in terms of psychoactiveness.

The biological purpose of all these endogenous tryptamines remains a mystery, but they may be further promoted by the action of other beta-carbolines (like pinoline) for normal psychological purpose; possibly even the production of visual and emotive imagery during sleep i.e. dreaming, so perhaps these can also be classified as ‘dream transmitters’?

It has also been suggested that the periodic altering of consciousness in sleep may even be necessary for the maintenance of normal mental health, since as previously mentioned, only a few days of sleep deprivation will result in a seepage of hallucinatory phenomena into the waking state.

9. Mitosis, Neurogenesis and the Dream Transmitters

Mitosis is a type of cell division in which the nucleus divides into two nuclei each containing the same number of chromosomes as the present nucleus. Through the process of mitosis, new cells are formed from existing brain cells. These new stem cells are born without a function. Stimulation from their physical environment causes these new cells to differentiate, or specialise, into neuronal cells. The differentiated cells migrate to different locations of the brain by means of a chemical signal. Once they move away from their origin, these cells either adapt and develop into mature neuronal cells, or they do not adapt and die. The ability of these cells to adapt to their new environment is known as ‘plasticity’.

At their final migration sites, the neuronal cells mature in the presence of chemical hormones known as neurotrophic growth factors and acquire their lifelong functions. The new neurons become integrated into the existing synaptic circuitry. This ‘regenerative’ development from stem cell to mature neuronal cell is thought to be the basis of neurogenesis.

Apparently, it is a well-known fact that melatonin induces mitosis. In summary, it does this by sending a small electrical signal up the double-helix of DNA, which instigates an 8HZ proton signal that enables the hydrogen bonds of the ‘stair-steps’ to ‘zip open’ and the DNA can replicate. What is lesser known is that pinoline is far superior to melatonin in aiding DNA replication and it is thought that it could be involved in genetic programming and correction of DNA damage. The mind boggles! I wonder if other dream transmitters also aid DNA replication and perhaps neurogenesis.

As previously stated, neurogenesis is an extremely dynamic process that is regulated in both a positive and negative manner by neuronal activity and environmental factors, including learning, memory, and response to memory. In addition, exposure to psychotropic drugs or stress regulates the rate of neurogenesis in the adult brain, suggesting a possible role for neurogenesis in the pathophysiology and treatment of neurobiological illnesses such as depression, post-traumatic stress disorder, drug abuse, and perhaps even primary headache disorders.

Neurogenesis is characterised by DNA synthesis that occurs during the ‘S’ phase of mitosis of the dividing progenitor cells. Incorporation of labelled nucleotide precursors into the DNA of dividing cells is used as a marker for neurogenesis and apparently the best marker is a substance called ‘BrdU’. From this marker, it has been established that neurogenesis is up-regulated by a number of factors including an enriched environment, exercise, learning, oestrogen, certain anti-depressant drugs, electro-convulsive therapy, lithium and rolipram. It has also been found that neurogenesis can be down-regulated by stress, glucocorticoids, age and opiates.

In summary, the possibility that new neurons can form in adult and even aged brains has now been clearly established. The findings of both up- and down-regulation of neurogenesis raise the possibility of developing agents that specifically influence cell proliferation of different areas of the brain. Perhaps one of these agents may well be entheogenic, specifically for the treatment of primary headache disorders.

10. Entheogens, Sleep and Neurogenesis?

Neurogenesis has also been associated with biochemical interaction with certain drugs; particularly LSD, but also naturally occurring compounds such as psilocybin/psilocin, mescaline, and DMT. For example, it has been reported that a group of individuals who regularly partake in DMT usage for spiritual purposes were on average physically and psychologically healthier than a matched control group. Perhaps more importantly, this group of DMT users appeared to have more receptors for the neurotransmitter serotonin, which has been linked to certain neurological disorders, including depression and of course cluster headache.

The study suggested that DMT usage creates a greater than normal density of serotonin uptake sites on blood platelets and possibly an increase in the number of serotonin uptake sites in the brain too – actual plastic changes in the brain! Is this neurogenesis through biochemical interaction; and if so, could psychoactive entheogens play a key role in neurogenesis by the mimicking the naturally occurring oneirogenic or somnogenic chemicals?

I have also found at least one renowned sleep researcher who believes that sleep – particularly the REM phase – actually affects the ‘synaptic plasticity’ of the brain. Sleep is believed to reorder and restore the brain’s ‘synaptic superstructure’ and serves to preserve both acquired and inherited behaviours. Perhaps this function is associated with neurogenesis?

In order to test this theory, the researcher used a rat with half its whiskers shaved – rats rely on their whiskers for spatial location. Shaving one side of those whiskers throws their orientation off somewhat, but immediately afterwards, the somatosensory cortex on the side of the brain opposite to the shaved whiskers begins reorganising itself. This process begins within a few hours of the shave and continues for several days.

What the researchers watch for is a pattern of molecular markers, specific molecules involved in the formation of synapses. But what they're particularly interested in is the effect of sleep on that reorganisation. If the semi-whiskered rat is kept from sleeping, the changes seem to be different from the changes in a well-rested rat. If the lack of sleep blocks the synaptic reorganisation, then the role of sleep has been further defined. This indeed seems to be the case.

Another way of testing the theory was to explore the relationship between memory and the hippocampus in the brain. Among its other roles, the hippocampus is a short-term memory structure as well as being vital to our understanding where we are. Rats are trained on a simple rectangular runway, with six food stations around the perimeter. Even though they are otherwise identical, only three of the stations actually offer food. The rats’ task is to memorise where the food is, which they do after three or four days. However, somewhere along the way, it was observed that when the rat learns to orient itself, immediately before everything clicks for it, its REM sleep increases.

Closer inspection revealed that the rats’ hippocampal neurons were firing in a manner consistent with long-term potentiation - the strengthening of memory. Also, they were firing at its amplitudal peak. Neurons firing at their amplitudal trough, on the other hand, result in de-potentiation - or paring of memory. So what happens during REM sleep? Do cells fire mostly at their peak, strengthening memory? Or do they fire mostly at their trough, breaking apart synapses and perhaps refreshing the hippocampus for learning something new? The answer, it appears, is both.

Neurons associated with memories already well consolidated no longer need the short-term capability of the hippocampus, so they de-potentiate. Somehow those memories are transferred to the cortex. Cells associated with new memories, however, fire during REM at their peak, strengthening, potentiating. In other words, again, the brain during REM sleep both cleans out and puts things in order. It both strengthens and pares; perhaps this is the true definition of neurogenesis, particularly because, as we have seen earlier, learning new skills increases dream time.

As mentioned previously, one of the most common drug treatments for depression (Prozac) acts by stimulating the growth of new neurons in the hippocampus. Recently, researchers wanted to narrow down which steps in neurogenesis the drug was influencing, so they created mice with nuclei in their nerve cells that glow green during neurogenesis, making it easy to count and compare the number of developing neurons.

By tracking other factors associated with different stages of neurogenesis, they found that only one step was actually influenced by the drug: amplifying the neural progenitor cell, just downstream of the stem cell. Now the researchers are testing a range of treatments - from different drugs to deep brain stimulation - to see if they influence the same step in neuron development. It would be interesting to know if any entheogens are planned to be tested in this respect.

11. The Sleep/wake Cycle and Cluster Headache

As we have seen, a prominent feature of primary headache disorders is the diurnal variation in their timing and their relationship to sleep. In particular, the temporal and seasonal distribution of cluster headache indicates that the circadian system and other sleep and wake generating areas in the hypothalamus may play an important role in their pathophysiology. The strongest and most direct evidence for a role of the hypothalamus in cluster headache derives from functional brain imaging studies. Furthermore, alteration in the timing and amplitude of hormonal circadian rhythms point to a possible role of the suprachiasmatic nucleus (SCN) in cluster headache.

We saw earlier that there are a number of neurotransmitters and neurohormones that play an important role in the sleep/wake cycle. Many of these appear to be imbalanced or disrupted amongst cluster headache sufferers, even when out of cycle. As has been noted when discussing the pineal gland, both melatonin and serotonin may be the crucial factors - together with the ‘dream transmitters’ - but others are also possibly implicated.

Let’s start off with serotonin; one of the key transmitters associated with the sleep/wake cycle. Serotonin alterations are more subtle in patients with cluster headache than in migraine. Over 25 years ago researchers found modest elevations of serotonin in whole blood during attacks of cluster headache, whereas platelet serotonin levels fall precipitously during migraine attacks. They also found low whole blood serotonin levels among cluster sufferers both during an active bout and during remissions, comparable to levels found among migraine sufferers. It is now thought that a so called 'serotonin storm' occurs in the brain prior to cluster headache attacks and attacks of vascular headache such as migraine.

As has been seen, melatonin also plays a role in the sleep/wake cycle. Cluster headache sufferers have disrupted melatonin production. The total amount produced is lower than normal, the peak or surge of melatonin at night is not as well defined as it should be, and the timing of the peak is off. In moderate doses, melatonin supplements do not change the structure of sleep; they do not increase the amount of time spent in REM or any other stage of sleep, but they have been proven to be a sleep enhancer (hypnotic). In higher doses, however, melatonin may increase the amount of time spent in REM sleep.

Orexin also appears to be important to the sleep/wake cycle and perhaps, unsurprisingly, it has recently been implicated with cluster headache. There is evidence that genetic factors may play an important role in CH, and although the type and number of genes involved is unclear, one recent study focussed upon orexin (or hypocretin), a neuropeptide used by the hypothalamus for signalling.

There are two types of orexin: A and B (or hypocretin: 1 and 2) which act as signals at receptors called Hcrtr1 and Hcrtr2. Signalling at these receptors influences a wide range of processes including pain transmission and autonomic functions. The study was designed to see if this is relevant to CH i.e. is there a significant differential between sufferers and non-sufferers? The answer appeared to be yes.

The results showed that the 1246 G>A polymorphism of the HCRT2 gene is significantly associated with CH. This was true for both sexes and probably both CCH and ECH. Results suggest that the hypocretin/orexin system may therefore be one of the reasons why some people get CH.

As mentioned, hypocretin neurons play an important role in regulating the sleep-wake cycle but they also affect stress reactions, pain threshold and sympathetic functions, which are known to be impaired in cluster headache. Therefore, measuring the concentrations of hypocretin amongst cluster headache sufferers may help to determine the true mechanism of the disease, but much more research is required in this respect. Another possible angle is that the HCRT2 gene is just ‘out-of-whack’ with other associated genes (again, more research required).

I know very little about genealogy, but I would also hazard a guess that this polymorphism of the hypocretin receptor 2 gene is probably inherited, something that a lot of cluster sufferers have been debating for quite some time. My hunch is that this polymorphism may also add to impaired neurogenesis.

Histamine also plays a role in the sleep/wake cycle. Histamine is also responsible for some of the pain and inflammation that occurs during a cluster headache, although several other compounds, including Substance P, nitric oxide and NMDA/Glutamate also play a role. Complex abnormalities in histamine production in cluster headache have also been noted and histamine release is linked to several types of antibodies, particularly those in the IgE class. IgE levels are generally elevated in cluster headache, both during a cycle and in remission.

Finally, it has been known for many years that the red blood cells of CH sufferers in a cycle have choline levels that were about a half of the normal expected value. Choline is a simple organic compound that is essential to a number of processes in the body but is also a building block of the neurotransmitter acetylcholine, yet another sleep transmitter. It is possible that a shortage of choline leads to low levels of acetylcholine.

All this information leads ultimately to a ‘chicken and egg’ type question. Is the imbalance and disruption of these sleep transmitters and processes a function of CH, or is it a function of an abnormality within the hypothalamus and/or the pineal gland? Whatever the answer, an improved understanding of the relationship between circadian rhythms, sleep and primary headache disorders is for me an exciting area of investigation which could lead to innovative circadian and sleep based treatment strategies; and provide us with a greater understanding as to how and why entheogens work so effectively in the treatment of cluster headache.

12. Alternative Medication for CH: Entheogens

It has recently been argued that perhaps the most effective unconventional treatment of CH is by using LSD, LSA or psilocybin/psilocin as medication. The most interesting aspect that differentiates this therapy from other CH medications is that it can not only abort a single attack, nor just prevent an attack from occurring in the first place, but it can actually terminate an entire bout for an extended period of time, long after all traces of it have vanished from the body. In the case of some chronic sufferers this period may be as short as two weeks, in the case of episodic CH, this period may be as long as a year (or much more). There is strong anecdotal evidence to suggest that there are hundreds of CH sufferers throughout the world who rely on psychedelics (or ‘entheogens’) to treat their lifelong disorder, and although it is not known how many there are currently in the UK, this figure is growing monthly. In an ideal world, sufferers should be able to pick up a prescription from their GP for laboratory manufactured LSD, LSA or psilocybin; or perhaps more appropriately, go into hospital and receive a specific dose of pharmacologically pure entheogens under safe guidance. However, due to the almost ubiquitous world-wide ban on research into the efficacy of hallucinogens in the treatment of headache and other disorders, this is unlikely to occur in the near future. Proposed clinical trials of LSD and psilocybin as treatment for CH are currently underway in the USA, but realistically, at least a five year time frame is envisaged before this drug will be made available through primary or secondary care. In the meantime, I believe personally that it is unethical to potentially deprive sufferers of medication that could prove to be so efficacious in the long term, particularly when it is readily available, albeit only in natural and/or illegal form. It appears that the chief concern of the established medical profession in respect of the alternative treatment focuses on the potential long term adverse effects that these medications may have, particularly in terms of increased psychosis; however, it appears that no empirical evidence is available to confirm these concerns. Indeed, all available evidence suggests this not to be the case.

The second largest epidemiological study of LSD’s contribution to mental illness was conducted in the early 1960s and reviewed a compilation of therapy studies including 44 psychiatric doctors representing almost 5,000 patients and 25,000 uses of LSD or mescaline ingested in controlled psychotherapy sessions. The researchers found the risk of psychosis lasting longer than 48 hours to be less than one half of one percent.

A larger study performed a decade later involving 49,500 psychedelic-assisted therapy sessions revealed like results of less than one percent. Similar results arose again more recently in 1998 when a medical team conducted a comprehensive review of 34 years of psychedelic research and concluded, “At present the literature tentatively suggests that there are few, if any, long term neuropsychological deficits attributable to long-term use.”

In addition, the U.S. Army, which began extensive investigation into the effects of LSD on its soldiers in 1955, concluded “There has not been a single case of residual ill effect. Study of the prolific scientific literature on LSD-25 and personal communication between U.S. Army Chemical Corps personnel and other researchers in this field have failed to disclose an authentic instance of irreversible change being produced in normal humans by the drug.”

I am pretty sure that medical researchers and their pharmaceutical benefactors completely understand the economic threat posed to their ‘customer base’ by a substance in which a lifetime supply of medicine can be grown in one's own home. Accordingly, medical researchers and practitioners will likely continue to espouse their claims of possible psychosis with long-term use because of the emotional reaction it will elicit in those who might considerer the entheogenic alternative.

13. How Entheogens work and their efficacy in CH

After many years of research, the site of action for entheogenic drugs has now been identified and they are believed to act in the brain at a specific receptor subtype as the previously discussed chemical neurotransmitter – serotonin. However, the understanding of their mechanism for action in cluster headache and other disorders is somewhat limited.

Although a large number of drugs may be considered psychoactive, only a small group are generally identified as hallucinogenic or entheogenic, namely: LSD, LSA, DOM, mescaline DMT, psilocybin, psilocin, and their congeners. They can all be considered members of the same drug class for two important reasons: firstly they elicit a common set of psychological effects and secondly, these drugs display both tolerance and cross-tolerance (to be discussed later). However, certain molecular differentials do exist: LSD and LSA are classified as ergot derivatives; mescaline and DOM are phenylethylamines; and psilocybin/psilocin and DMT are indoleamines.

Before proceeding further, it may be helpful to once again discuss briefly the events which allow brain cells (neurons) to influence one another. Most neurons in the adult brain communicate chemically. These chemicals (neurotransmitters) are released from the axon terminals of one neuron and cross a small gap (the synaptic cleft) between neurons to form a chemical bond with a protein receptor, producing either excitation or inhibition of the target neuron. If all the inputs to the target neuron combine to produce a sufficient level of excitation at the cell body, the neuron fires or discharges an action potential which propagates down through the axon, repeating the cycle of release of neurotransmitter into the synaptic gap.

I found the following superb analogy which hopefully simplifies the complexity of the workings at the synapse. Consider two train tunnels that do not meet but have an intervening space of, say, 100 feet between the ends of each of them. Furthermore, imagine that a train speeds along one of the tunnels at huge speed. This is akin to the high velocity impulse travelling along a neuron. Not dogged by track problems, this 'Intercity Electrochemical Impulse Express' reaches the end of the tunnel and duly crashes onto specially constructed buffers. The dramatic impact upon the said buffers causes a group of strategically placed gas canisters to explode, thus dispersing their gaseous contents into the gap between the two tunnels. The gases instantaneously diffuse across the gap and cause a reaction to occur to another stationary train situated at the start of the next tunnel. As soon as molecules of the gas reach this next train, a clever reaction occurs in which the engine roars up and the train is off, at the same speed as the first train. Meanwhile the gas molecules in the gap are immediately 'mopped up' (and then conveniently re-cycled) so that they do not cause the replacement train (which magically appears almost instantly to replace the one that just sped off) to start up also. And in the first tunnel the original train has also been removed in order to allow another to follow if needs be.

One complication of this simple picture of chemical neurotransmission that is of special relevance to entheogens is the fact that each neurotransmitter can act at more than one type of receptor. It is assumed that these receptor subtypes exist for the purpose of diversifying the cellular effects of any given neurotransmitter. For example, serotonin acts at the 5-HT1A, 5HT1B, possibly 5-HT1C, and the 5-HT2 receptor subtypes in the brain. Because the protein molecules, which constitute receptor sites have slightly different conformations for each subtype, drugs can be developed to stimulate (or block) a particular receptor subtype.

So focussing on the historical analysis of entheogens, firstly it was discovered early on that many of them had a molecular structure similar to that of serotonin. Secondly, a series of animal studies examining brain neurochemistry following the administration of hallucinogens invariably reported changes in the levels of serotonin. Finally, data from a variety of different sources led to the conclusion that hallucinogenic drugs exert their critical action at a specific serotonin receptor subtype: 5-HT2. Depending on the particular brain area, the action may be either excitatory or inhibitory. This does not preclude the possible involvement of other neurotransmitters in the action of hallucinogenic drugs; in fact, structural differences in the drug molecules are probably responsible for variations in the phenomenological effects produced by them.

The medicinal efficacy of entheogens in cluster headache, however, still remains largely a mystery. As we have seen, the current understanding of the mechanism of indole ring based entheogens is that when consumed they initially excite seroternergic neurons, specifically the 5-HT2 receptors. Soon afterwards, the number of active 5-HT2 receptors is reduced in the brain. This process can be simplified in the following way: The body maintains stability or homeostasis. Upon the over-activation of 5-HT2 receptors, the body 'decides' to greatly reduce the 5-HT2 activity in order to maintain homeostasis. Soon after dosing, there are fewer 5-HT2 receptors that are able to bind to serotonin which may be one of the reasons CH improves. This process of reducing the number of active 5-HT2 receptors takes about three days (in rats), a similar time frame for which it usually takes to see the benefit of a therapeutic dose in sufferers. This theory, however, may be flawed in its simplicity. Unlike other medications, this effect lasts well after the drug has cleared the system and can provide relief for weeks, even months.

One interesting theory posed by a fellow CH sufferer is based upon one of the most widely reported yet least understood subsidiary effect of entheogens – tolerance and cross-tolerance – that is, a decrease of efficacy of one entheogen taken shortly after another. Thus, if a person has a full-blown experience following ingestion of say LSD, the normal entheogenic response to say psilocybin or LSA taken the next day will be dramatically blunted or abolished.

As mentioned, it takes several days for the receptivity of the binding sites to return to their ‘pre-dose’ state and this effect manifests itself even though all detectable traces of the entheogen have left the bloodstream. This suggests that it's not just a case of the psychedelic molecule hanging around the receptor site for days and days, but that the receptor site has been in some way temporarily altered by the psychedelic experience.

The precise nature of this alteration was not further hypothesised in great detail but I would suggest that this altered state actually reflects ‘plastic’ changes within the brain caused through neurogenesis. The hypothesis does further suggest that for the period of time it takes for the tolerance effect to wear off, the synapses are also operating in a slightly different manner than normal in regards to how they react to (or even perhaps generate?) cluster headaches. The evidence for this is the widely-reported phenomenon of CH sufferers whom prior to dosing with entheogens could normally set their watch by the timing and severity of their attacks, but then experience more frequent and/or more severe attacks than usual in the few days after dosing. It was surmised that perhaps the synapses are in a state of confusion. I would suggest that rather than a state of confusion, the brain itself is going through a state of re-programming and re-building, once again through the action of neurogenesis.

14. Medicinal uses of entheogenically derived substances

Many efficacious medications sold in western pharmacies come from plants. Aspirin started out that way as did two widely used analgesics; morphine and codeine, together with the heart medication digoxin; colchicine for gout; theophylline for asthma; and quinine for malaria and leg cramps. The active ingredient in marijuana (THC) eases nausea, vomiting and wasting syndrome; Marinol, a synthetic version, is available in some countries, normally through prescription only.

There are also a number of entheogenic based medications that have been hugely successful in western pharmacy. Arguably the most successful product developed following entheogenic research has been hydergine, a valuable geriatric medicine used as a cerebral vasodilator. It improves oxygenation of the brain so much that it is widely used as an adjunct to surgery in case of cardiac arrest, to resuscitate the patient before brain damage occurs. Hydergine has also shown valuable stimulant effects even in healthy young adults, and has been shown to improve mental processing and performance in 9-12mg daily doses.

Another product, methergine, is an important life saving medicine for obstetric control of postpartum haemorrhage. Parlodel is used to treat Parkinson’s disease and also cocaine addition; and pindolol (like psilocin) a 4-hydroxy-indole derivative, is used as a hypotensive agent. And finally, LSD (originally marketed as Delysid) was used primarily to assist psychotherapy but also for pain management in terminal cancer.

As many practitioners (and no doubt pharmaceutical companies) know, many traditional prescriptive medications for both the acute and prophylactic treatment of primary headaches are based on indole-ring and related hallucinogens.

Methysergide, a serotonin antagonist, can be a very effective preventative treatment amongst CH but is not without its side-effects. It can be an ideal choice for sufferers whose bouts last less than 4-5 months and doses of up to 12mg per day can be used if the side effects are tolerated. Sufferers can be started on 1mg once a day and then the dose is increased by a further 1mg after every three days until the dose is 5mg per day. After this, the dose is increased by 1mg every five days. Although rare, prolonged use of this drug can cause side effects including damage to the heart, lungs and kidneys. Although this drug can be used in the chronic form of cluster headache, it is necessary to keep a close eye on possible side effects and a break from taking the drug (a drug holiday) is recommended every six months.

Methysergide is closely related to LSD; the chemical formula for methysergide is C21 H27 N3 O2 whereas LSD is C20 H25 N3 O2. Like LSD, methysergide can also produce psychedelic effects. The threshold dosage for these is 4.3mg. Full blown effects can be felt with dosages of 8-20mg.

Ergotomine, an active ingredient of the ergot fungus that grows primarily on rye, has been a mainstay in the management of severe primary headaches for around 100 years. It has a complex pharmacology, involving interaction with a wide variety of serotonin receptors, as well as alpha adrenergic receptors and others. Ergotomine is believed to have a vasoconstrictor effect on inflamed dilated blood vessels, but it also penetrates the blood-brain barrier and effects trigeminal relay pathways in the brainstem. Dihydroergotomine (DHE), also a potent vasoconstrictor used in the treatment of CH, is barely absorbed orally, so it is generally administered parenterally or nasally. Perhaps interestingly, LSD is also a derivative of ergot and hence has a similar molecular structure to ergotomine.

Some of the most favoured and widely used drugs used for the acute treatment of severe primary headaches are a number of different selective 5HT1 agonists, known collectively as the triptans. These drugs are believed to constrict extracerebral intracranial vessels (via 5HT1B receptors), inhibit activity in peripheral trigeminal neurons (5HT1D/1F), and block transmission in the trigeminal nucleus (also 5HT1D/1F). Sumatriptan was the first to be developed, followed by zolmitriptan, naratriptan, rizatriptan, almotriptan frovatriptan and finally, eletriptan. Sumatriptan, perhaps interestingly, is sulphonated DMT, one of the proposed dream transmitters discussed earlier. Psilocybin, the active ingredient in entheogenic mushrooms, is phosphorylated DMT.

Finally lithium, another of the stalwart prescriptive medications for the prevention of cluster headache – although not an indole-ring based medication – is one of the few drugs that is thought to up-regulate neurogenesis.

15. A Malfunctioning Pineal Gland?

The pineal gland has been implicated in a number of disorders including amongst others, cancer, sexual dysfunction, hypertension, epilepsy and Paget’s disease. If we consider the underlying hypothesis that the pineal gland is malfunctioning amongst CH sufferers; either through an inherent abnormality or through other internal and/or external influences, then how so? The answer may possibly lie in pineal calcification.

The pineal gland contains several calcified concretions called "brain sand" or acervuli, known as corpora arenacea. Predominantly composed of calcium and magnesium salts, corpora arenacea are numerous in older people but they can be present in smaller numbers in children as well. The presence of calcified concretions is not thought to indicate a pathological condition except when they are found in young patients when they then may suggest the presence of pineal germinomas. Pineal calcification used to be an important landmark of an intracranial mass in the pre-CT era, when only plain films were available but it has now lost almost all of its diagnostic value. I wonder if it should be re-visited to assist in the future pathophysiology of cluster headache.

Interestingly, more recent studies suggest that abnormal melatonin functions may be implicated in the pathophysiology of schizophrenia. Since there is evidence that the presence of pineal calcification may relate, amongst other factors, to disturbances in melatonin secretion, one study looked at the relationship of pineal calcification size by CT scanning a number of schizophrenic sufferers. The findings suggested that the nature of onset of schizophrenia may be influenced by the activity of the pineal gland. I wonder how many cluster sufferers, if any, have had their pineal glands scanned, particularly both before and after the onset of their condition?

Unfortunately though, it appears that the actual size of pineal calcification is not actually directly associated with melatonin secretion. This is in line with the lack of association between the size of calcification and pathogenesis of disease (including, I would guess if applicable, cluster headache). Also, there is no association with pineal size and age, which suggests that the size of the gland is genetically pre-determined, that is, the adult shape and size are determined early in life and reach their final stage at around the first year of life. Similarly, the weight and dimensions of the pineal gland are highly variable – up to a 20 fold difference between individuals; therefore the notion of an ‘averaged size’ is probably inadequate.

However, one recent study that actually focussed of the “degree of calcification” within the pineal gland showed for the first time that an approximation of the size of uncalcified pineal tissue (representing active pinealocytes – the stuff that makes the gland tick) is significantly and positively associated with the total amount of melatonin secretion in urine. More interestingly, the well-known negative correlation between age and melatonin secretion did not persist when data were adjusted to uncalcified tissue. Accordingly, it was safe for the researchers to conclude that the decrease of melatonin secretion with age is predominantly due to increasing pineal calcification and not determined by the aging process per se.

Another possibility is that CH sufferers may have a natural imbalance of the catalyst enzymes that help convert serotonin into the other dream transmitters; particularly NAT, HIOMT and INMT which have been discussed previously. If the pineal is malfunctioning in any way, it may not be producing enough of these naturally occurring pineal enzymes, or they may not be catalysing effectively, leading ultimately to lower levels of dream transmitters. It is interesting to note that 5-HTP, the precursor to serotonin, is sometimes used effectively in the treatment of CH, but can actually appear to make the condition worse amongst some sufferers. Perhaps an imbalance of these enzymes amongst sufferers is the reason for this?

So, apart from genetics and hereditary issues, what might cause these enzymatic imbalances? Perhaps controversially, one recent study suggests that increased fluoride consumption (by adding to drinking water) may adversely affect the pineal gland although the final results are largely hypothetical and yet to be completed. Perhaps even more controversially, an even more recent study suggests that watching too much television (in adolescence) may also have an adverse affect on melatonin secretion, and therefore possibly the other dream transmitters.

Other areas of investigation may also warrant further investigation in respect of pineal dysfunction; for example the pineal nerve, the retinohypothalamic tract or even the function of the eye itself. If any of these are malfunctioning in association with the hypothalamus it may even help explain the strictly unilateral (one-sided) nature of CH attacks amongst the majority of sufferers.

Given that there is a tremendous, genetically determined, inter-individual variability as to the amount of melatonin excretion, the question arises whether there is an individual threshold for the amount of melatonin required to maintain a healthy system. Moreover, it remains unexplored as to what degree the circadian timing system may actually adapt to decreased melatonin production as the result of increasing pineal calcification; and perhaps this adaptation is markedly skewed in cluster headache, leading us back nicely to the hypothalamus. If the degree of calcification is an accurate indicator to pineal functionality then presumably it may also relate to the production of the other dream transmitters, which in turn, may or may not influence neurogenesis as previously discussed.

16. Pathophysiology of Cluster Headache: Re-visited

As with many things in life, I believe cluster headache is a factor of both nature and nurture. Firstly, I think that sufferers are born with a natural propensity to develop the symptoms and pain of these so-called headaches. This is a hereditary factor based on genes of one of the parents; and the reason why it can and does skip generations is that the abnormal genes that cause CH can lie dormant unless triggered by external factors.

All the clinical evidence suggests that we have to start with the hypothalamus. Most practitioners who specialise in CH agree that the abnormality within the hypothalamus is the root cause of the pain, which when in cycle releases hormones and chemicals that innervate (stimulate) the trigeminal ganglion, which in turn causes the domino effect of pain and cranial autonomic symptoms through the trigeminal nerve down one side of the face and head. This theory is backed up by the uncanny regularity of attacks (circannual and circadian), much lower levels of plasma testosterone (amongst men) during attacks and bouts, and alterations in the natural production of hormones/chemicals that affect the biologic clock. The most recent research involving PET studies amongst CH sufferers put the icing on the cake for me, which in summary showed an increase in functional activity of the hypothalamus amongst CH sufferers, which is not seen in migraine. However, could it be that an abnormality within the pineal body is causing this apparent abnormality within the hypothalamus?

So, sufferers may possibly inherit a brain abnormality from their parent’s genes. The extent of this abnormality determines the pattern(s) of CH amongst sufferers; so in fact, there may well be a variety of different types of CH based on the extent of this abnormality and how sufferers live their lives. This may be why specific triggers of attacks are not ubiquitous and not all medications work for everyone.

I’ve no idea as to how many different types of CH there are, but it’s likely to be on a sliding scale based on the current yardstick of episodic to chronic, something like this: -

Extreme abnormality: chronic from onsetHigh abnormality: episodic with limited remissionMedium abnormality: half on half offLow abnormality: episodic yearlySlight abnormality: single/infrequent episodes

The crucial thing is that the abnormality that sufferers are born with is not fixed. Everyone who is unlucky enough to have the abnormality has the propensity for it to develop over time - classically from episodic to chronic and sometimes vice versa. This is where the controversy may start creeping in. Although the abnormality is pre-determined at birth, I also believe that there are other external factors (nurture) that can influence the pattern and type of CH. Sufferers who are born with a particularly low abnormality may not develop CH until they are exposed to specific external forces. So in a nutshell, someone who has a slight abnormality may move up the ‘intensity’ scale because of external forces, and conversely, sufferers who have extreme abnormalities can and do move down the scale due to external forces.

Here’s the tricky bit: what are these external forces? I would suggest that they are anything that can alter the natural balance of hormones and chemicals in the body; so it would make sense that it’s all to do with consumption and lifestyle, possibly (not exclusive and in no particular order) as follows: -

Diet: especially alcohol, nicotine and caffeineTrauma: bangs to the head, disease etc.Stress: particularly stark changes in the level of stressEnvironment: temperature, humidity, seasons, altitude, latitudeMedication: preventatives, abortives, suppressives, regulators of neurogenesisHealth: general well being, sleep behaviour and illnessLifestage: hormonal imbalance

I personally have major doubts as to the current classification system of CH, especially in terms of just episodic and chronic. This system appears to be based on an arbitrary remission timescale as determined (and recently changed) by the International Headache Society, presumably purely for medical classification purposes to assist in structured research programmes into differing treatments, and to make appropriate recommendations for abortive and preventative medication over time.

So in summary, I believe that there is just one type of CH, but within this there are many different strains. To understand the potential mechanisms involved we have to go right back to the root cause, which is currently thought to be due to an abnormality within the hypothalamus or possibly as discussed previously, the pineal gland. The extent of an individual’s abnormality (possibly genetically linked) will dictate the initial onset and subsequent pattern of CH, but these are not fixed and in turn are influenced by specific external factors. As external factors change over time, so does the pattern of an individual’s CH, modifying these different strains. So CH isn’t black or white (episodic or chronic) but should be classified more in terms of a continuum: still largely dictated by periods of remission, but also frequency of occurrence and the extent of influence of differing external factors.

Accordingly, I think that the way forward for future pathogenesis should focus upon: -

a) The possible genetic link of CHb) The precise nature of hypothalamic and/or pineal abnormalityc) How these abnormalities differ by sufferer typed) The identification and extent of influence of specific external factors, including medicinal entheogens

So what does this all mean? For the medical profession, firstly I think they should concentrate on determining how precisely abnormal the hypothalamus and/or pineal body is based on physiology, and to what extent this varies from sufferer to sufferer. For sufferers, I think they need to focus on their individual history and carefully monitor their episodes and attacks, with and without different types of medication, and any potential external influences.

17. Summary and Conclusions

This ‘paper’ was cobbled together from various sources, mainly from the internet, over the last couple of years or so. Accordingly, much of the information cannot be validated as being strictly accurate and hence many errors may be apparent. In previous chapters I attempted to pull all the relevant information together as quickly as possible and therefore many apologies for any specific plagiarism and for the lack of appropriate source data; but naturally I am greatly thankful to those individuals and organisations that had already summarised much of the information I have used.

Like most of my theories, much of the previous information is based on conjecture and is purely hypothetical. As you will have seen I am not a scientist, particularly in terms of neurology and chemistry, but here is the overall summary:

Cluster headache (CH) is a devastating and disabling disease for many sufferers with as yet no known cause. A specific abnormality within the hypothalamus is likely to be important in its pathophysiology, but a dysfunctional pineal gland and associated systems may also warrant further investigation.

All the previous evidence suggests that no one truly understands why we sleep, and more particularly why we dream; but most specialists do not deny the importance of both sleep and dreaming.

There are a number of endogenous neurotransmitters and neurohormomes that play an important role in sleep, and possibly dreaming. Many of these also play a role in the pathophysiology of CH.

Sleep and wakefulness is determined largely by the hypothalamus which is linked directly to the pineal gland.

It has recently been ascertained that neurogenesis can and does occur in various parts of the adult brain. How this mechanism works is not precisely understood.

REM sleep, or more particularly any form of dream sleep, may promote neurogenesis in the adult brain. This may be associated with various ‘dream transmitters’ produced endogenously through the pineal gland.

Dream transmitters have been hypothesised to be associated with mitosis, a key element to neurogenesis. If levels of dream transmitters are low then perhaps the brain may need to re-adjust accordingly.

Neurogenesis has been associated with biochemical interaction with entheogenic drugs. Some of these drugs are possibly the most effective treatment of CH, and although their mechanism of action is poorly understood, they may well be working by mimicking the previously discussed dream transmitters.

So in summary, the current theory is based on the hypothesis that the pineal glands’ of CH sufferers are malfunctioning in some way, which in turn leads to an imbalance of certain neurotransmitters, neurohormones and possibly catalyst enzymes. The various types of psychedelic drugs or entheogens used for the treatment of CH may actually work by mimicking some of these chemicals, particularly those that may be produced by the pineal gland.

The reason why this medication works better than most conventional treatments is that they do not just abort individual attacks, and prevent further bouts from occurring, but also continue to work long after the effects have left the body. I think they do this by actually helping repair specific areas of the brain whilst sufferers sleep, but perhaps more importantly through the action of ‘waking dreams’ whilst the medication is taking effect.

There may not be much that CH sufferers can do currently about an abnormal hypothalamus, or indeed a malfunctioning pineal gland; but perhaps one day, bearing in mind recent developments in stem cell research and possible nanotechnology in neurosurgery, this may well change. In the meantime, entheogenic treatment therapy appears to be the best way forward for many cluster headache sufferers. Sweet dreams.

Many thanks to:Bob Bowling, Jonathan Byron, Helen Williams, Ben Khan, Bob Wold, James Joseph, Pinky,