This essay has been submitted by a student. This is not an example of the work written by our professional essay writers.
Disease Definition: 'Mental and neurological illness is a psychiatric disorder that results in disturbance of an individual's thinking, feelings, mood and ability to relate to others.' It is dissimilar from the idea of insanity. Some psychiatrists feature mental illness to organic/neuro chemical causes that are cured by medication, psychotherapy, change in the lifestyle and supportive therapy. As such the cause for mental illness is still idiopathic. The examples of this illness can be enlisted as:
Migrainous neuralgia: Cluster headache- it can be broadly classified as Episodic (common pattern) and Chronic.
Obsessive Compulsive disorder: which is an anxiety disorder characterised by frequent obsessions/ compulsions having symptoms marked fear and distress.
Anxiety: it is a chronic condition characterised by unnecessary and continuous sense of apprehension displaying symptoms of sweating and palpitations.
Disease Prevalence: According to the U.S. Mental Health (2003), the major cause of disability in the U.S is due to the mental illness which includes clinical depression. Approximately 9%-13% of the children below 18years suffer from mental disturbance and functional impairment as per NAMI (National Alliance for the Mentally Ill).
Cluster headache which is a type of neurological disorder has a comparatively low prevalence. Many studies have been conducted and results were drawn showing the prevalence of 124 per 10000 and 1 year prevalence of 53 per 100000. The resultant sex ratio was 4.3(male to female), which was higher with chronic type and 3.8 with episodic type. The prevalence rate for Obsessive- compulsive disorder is around 3.3 million adult Americans, 1 in 82 or 1.21 people in the USA.
Target Definition: Serotonin receptors are classified into 7 types, 5-HT1 to 5HT7. Each type has many other subtypes. These receptors are confined to a small area in brain and in other peripheral organs but their allocation are not identical. The main receptors are postsynaptic but 5-HT1A and B are mainly presynaptic and adjust serotonin release. Serotonin receptors are G proteins coupled apart from 5-HT3 receptors which are receptor- channels, also called ionotropic receptors and in the deactivated state, are open and permeable to sodium and potassium cations.
Target History: History of serotonin receptors binding started nearly three decades ago with the pioneering work of Marchbanks who studied interactions of [H] serotonin with synaptosomes from rat brain. Farrow and Vanukis were the first who showed that [H]-d-LSD labels serotonin receptors, using an equilibrium technique.
Sir Henry Gaddum explored many areas of neurotransmission including the function of 5HT in the peripheral organs and also in the brain. In the mid 1950s, Gaddum and his associate carried out a chain classical organ bath experiments on the pharmacological properties of 5HT in the ileum of guinea pigs. Gaddum postulated that there were two kinds of 5-HT receptors, one that was sensitive to LSD and other ergot derivatives, and another that was not.
Definition of Drug: 'A drug that causes hallucinations which means profound distortions in a person's perceptions of reality'. Under the hallucinogenic effect, people see images, hear sounds, and feel sensations that seem real but are non existence. Their effect is caused by disturbing the interface of neurons and serotonin. This is circulated throughout the brain and spinal cord and the serotonin is involved in the control of behavioural, perceptual, and regulatory systems, including mood, hunger, body temperature, sexual behaviour, muscle control, and sensory perception.
LSD (lysergic acid diethylamide) is the drug most frequently known as hallucinogen and is extensively used in this category of drugs.
Mechanism of action: Psilocybin and its metabolite psilocin acts directly on many serotonergic receptors without having any effect on the neurotransmitter system. Few research based studies have been conducted which shows the LSD (lysergic acid diethylamide) like effects of psilocybin and its metabolite proving that these tryptamines are 5HT2a,5HT2c,5HT1a agonists. It has low affinity for dopamine receptors and exhibits effects on norepinephrine receptors in very high doses only.
This drug has a strong affinity for 5HT2a receptors in human than in rats. After conducting a series of drug discrimination studies it was proved in rats that 5HT2 receptors and not 5HT1A antagonists prevented them to recognize the drug psilocybin. Reduced number of 5HT2A receptors was found in rat brain with daily administration of psilocybin. Research based on compound specific effects on secondary messenger systems shows that both the psilocybin and LSD stimulate the arachidonic acid while activating rat 5HT2a receptor, but psilocybin was not able to stimulate the phosphoinositide pathway as LSD could do it. Direct application of this drug to the dorsal raphe nucleus cells exhibits low firing. It has also shown affinity for 5HT1D receptors proving a possibility to cure cluster headache.
Drug history: Psilocybin is a tryptamine and a major psychoactive agent found in mushrooms belonging to Psilocybe genus (Psilocybe cubensis and Psilocybe mexcanus). The Mexico natives used to include mushrooms in religious ceremonies and for healing. Various archives suggest its use in the 16th century prior to its exclusion by the Spanish. Hoffman in 1957 first extracted the drug from the psilocybe mushrooms and later in 1958 synthesised them. Early and mid 1960 until scheduling in 1970 in US and 1980 in Germany, it was used in psychotherapy. Its research was resumed in mid 1990, and now it used as study compound for serotonergic hallucinogen effect. Now it's in not frequently used in humans but few preclinical studies have occurred.
Patent Status: In The Drug Abuse Control Amendments (1965) psilocybin and its metabolite psilocin were subjected to federal regulation for the first time in the United States. The law product was funded by Senator Thomas J. Dodd who passed it in July 1965 and took effect from February 1, 1966.
On October 24, 1968 the federal law was enacted which particularly banned psilocybin and psilocin claiming that the substances have a high abuse potential and not accepted for current medical use. Lastly, on October 27, 1970 psilocybin and psilocin were classified as Schedule I and were at the same time under a section of the Comprehensive Drug Abuse Prevention and Control Act known as the Controlled Substances Act were labeled as hallucinogen.
Market share: Under the United Nations Convention (1971) on Psychotropic substances Psilocybin and psilocin are listed as Schedule I drugs. Most national drug laws have been amended to reflect this convention for example, the US Psychotropic Substances Act, the UK Misuse of Drugs Act 1971, and the Canadian Controlled Drugs and Substances Act with possession and use of psilocybin and psilocin being prohibited under almost all circumstances, and often carrying severe legal penalties.
Possession and use of psilocybin mushrooms, including Psilocybe are prohibited by extension. However, in many national, state, and provincial drug laws, there is a great deal of uncertainty about the legal and market status of these mushrooms and its spores .Because of the ease of growing psilocybin mushrooms or gathering wild species, purified psilocybin is practically nonexistent on the illegal drug market.
Drug discovery Process this Drug went through
Target identification: The main target identified with psilocybin is receptor agonists. This target produces hallucinogenic effects in humans and rodents. Like any other serotonergic hallucinogen, it also acts as an agonist for 5HT2a receptor. Base on many drug discrimination studies conducted in rats it has been suggested that 5HT2a antagonist and not 5HT1a antagonists prevent rats in recognising psilocybin. Even daily doses of psilocybin cause reduction of 5HT2a receptors in rat brain. Compound specific effects research on secondary messenger system has shown that psilocybin stimulate arachidonic acid while activating rat 5HT2a receptor but was not able to stimulate phosphoionsitide pathway. Direct action of these receptors on the dorsal raphe nucleus cells cause declined firing.
Target Validation: Research studies in humans have found out that administration of psilocybin along with 5Ht2a antagonist (ketanserin, resperidone) completely eliminates the subjective and perpetual effects of this drug. Human imaging study involving use of a radiolabelled agent (raclopride) which is a D2 receptor antagonist detected decrease binding in caudate and putamer after the administration of psilocybin, suggesting the indirect relation of this drug with the increased levels of dopamine in brain acting through the 5HT2a receptors. Based on these studies it is proved that psilocybin chiefly but not wholly exerts effect in humans due to 5HT2a receptor. It may produce effects through other serotoinin receptors (5HT1a, 5HT2c) and also may have an indirect effect on the dopamine system.
Compound Screening, Lead identification and optimisation: The methods used to evaluate and extract the quantity of psilocybin from mushrooms are:
1. Thin layered chromatography
2. Gas chromatography coupled to mass spectrometry
3. Ion mobility spectrometry.
4. Capillary zone electrophoresis.
5. Ultraviolet/ Infrared spectroscopy.
6. High performance chromatography.
7. Aqueous organic extraction method.
An aqueous method of extraction for isolation of psilocybin from the genus Psilocybe Cubensis mushrooms, which involves the process of dephosphorylation of the phosphate ester of psilocybin aiding in better yielding of product. The drug extracted by this method is adequately concentrated making it co-contamination free and allowing identification by infrared/mass spectroscopy and gas chromatography. Significant amount of research has been conducted on psilocybin and psilocin from the time of their isolation by Hoffman.
Quite a lot extraction techniques of have been employed for the isolation of psilocin and psilocybin from species of mushrooms in four genera (Conocybe. Panaeolus, Psilocybe, Stropharia). The dephosphorylation of the drug to its metabolite has been very well accepted and is also thought to describe about all the activities in the central nervous system. The conversion of psilocybin to psilocin is required for the aqueous extraction involving organic solvents as psilocybin has very low lipid solubility.
Because of the growing fame of these types of mushrooms and the accessible drug publications for raising mushrooms including psilocin and psilocybin in cow manure a simple aqueous extraction method has been developed which extracts original psilocin from mature mushrooms. This method simplifies the detection of psilocin from those mushrooms by infrared spectroscopy and gas chromatography/mass spectrometry.
2 to 10g of dried mushroom sample is finely ground into powder and mixed with 100 ml of dilute acetic acid. The pH is readjusted to pH 4 with glacial acetic acid. After standing for an hour the beaker is positioned in hot water bath for 8 to 10 minutes or until the internal temperature of the acid mixture becomes 70°C. After removal and cooling of the beaker the mixture is separated from the powdered mushroom by suction filtration using glass wool. The filtrate is brought to pH 8 with concentrated ammonium hydroxide and quickly extracted with two 50-mL portions of diethyl ether. Gentle mixing is done to prevent an emulsion. The ether is dried over sodium sulphate, filtered, and evaporated under nitrogen with no applied heat .Crude psilocin appears as a greenish residue.
Preclinical Evaluation: The studies conducted in humans and non human animals are suggestive of psilocybin been an extremely low toxic drug. LD50 is ranged from 285mg/kg in rats and mice to 12.5mg/kg in rabbits. The human is much likely to exceed the lethal dose to produce an intense change in the consciousness. Preclinical studies using trained rats to differentiate between LSD and saline injections actually treated psilocybin as if it was LSD suggesting that these drugs may have similar characteristics. Rats trained in identifying psilocybin, identified it as psilocin, showing that the drug and its metabolite has similar effects. Due to this fact it was later documented that psilocybin is converted to psilocin as a metabolite which in turns exerts the physiological effects.
The metabolism of the drug was estimated based on the previous research on non- human animals. It was found that the phosphoric ester group of the drug was cleaved by alkaline phosphatise, psilocin and not psilocybin was taken up by rats intestines. It suggests that the metabolite is more readily absorbed and distributed in the body than any unmetabolised active drug. No recent studies on metabolism have been conducted.
Other physiological effects of psilocybin were demonstrated by research done on animals like rats, cats, dogs and rabbits. These animals showed the effects like piloerection, minor increase in breathing rate and other symptoms of sympathetic stimulation, as such no enhance in loco motor activity. It leads to an increase in the prolactin levels in rats. Based on the behavioural reports it suggested that psilocybin produced similar effects as that of LSD and other tryptamines. Similar effects were seen between LSD and psilocybin when psilocybin decreased and changed the exploratory patterns in rats. Self administered psilocybin in monkey's revealed behaviour suggesting visual disturbance and change in consciousness including grasping of unseen things and fixed staring. But there is no such effect seen in rodents and non human primates.
Presently this drug is placed in schedule 1, as having no medical use and having high abuse potential. Although having this label the nonhuman primates' studies are suggestive of this drug having little or no abuse potential. Study conducting on monkeys for the rewarding properties of four serotonergic compounds found out that the animals did not self administer the drug. It was therefore observed in rhesus monkeys that the pharmacological and subjective effects of a similar drug (LSD) were taken to be aversive. The drug did not produce any reproductive toxicities and mutagenicity when conducted in micronucleus models for mutagenicity. These findings that psilocybin is less likely to cause any damage to DNA. As far as the reproductive toxicity concerned no evidence of any birth defects were observed. Therefore the reproductive toxicity with this drug though minimal still remains unknown.
Clinical Evaluation: The subjective and physiological effects of the drug were estimated in humans by giving them an orally administered dose which produced its effects in 20-30 minutes after administration and the peak effects appeared in 60-90 minutes. Alteration in perception and cognition were not noticed after 7 days. Whereas the intravenous drug administration effects appeared in 2 minutes with the subjective effects appearing after 20 minutes. It causes minor sympathetic activation which was observed in a 26 year old man with obsessive compulsive disorder in whom absence of anxiety was seen after receiving 0.2mg/kg of the drug.
Human studies of this drug report the effects like perception change, weird thoughts, anxiety and unreal appearance of the body, dizziness, altered concentration. Many PET (positron emission tomography) studied in humans have observed elevated glucose metabolism n the frontal and anterior cingulated areas with much of activity in the right hemisphere. A number of studies have shown the LSD aided psychotherapy decreased anxiety and enhanced the quality of life for patients suffering from advanced stage illness.
A human study in which self administered psilocybin was used as a measure to cure cluster headache proved that it could abort the cycles of headache.
Summary and Conclusion:
References: 1) undefined (2010) Mental illness - Definition, Available at: http://www.cs.qub.ac.uk/emm/10170987/cite2write/harvard3l.html (Accessed: 10th Janauary 2010)