List of psychedelic drugs

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Serotonin (Template:PronEng) (5-hydroxytryptamine, or 5-HT) is a monoamine neurotransmitter synthesized in serotonergic neurons in the central nervous system (CNS) and enterochromaffin cells in the gastrointestinal tract of animals including humans. Serotonin is also found in many mushrooms and plants, including fruits and vegetables.

In the central nervous system, serotonin is believed to play an important role as a neurotransmitter, in the inhibition of anger, aggression, body temperature, mood, sleep, vomiting, sexuality, and appetite.

In addition, serotonin is also a peripheral signal mediator. For instance, serotonin is found extensively in the human gastrointestinal tract (about 90%),^[1] and the major storage place is platelets in the blood stream.

As with all neurotransmitters, the effects of 5-HT on the human mood and state of mind, and its role in consciousness, are very difficult to ascertain.

The neurons of the raphe nuclei are the principal source of 5-HT release in the brain.^[2] The raphe nuclei are neurons grouped into about nine pairs and distributed along the entire length of the brainstem, centered around the reticular formation. ^[3]

Axons from the neurons of the raphe nuclei form a neurotransmitter system, reaching large areas of the brain. Axons of neurons in the caudal dorsal raphe nucleus terminate in e.g.:

• Deep cerebellar nuclei
• Cerebellar cortex
• Spinal cord

On the other hand, axons of neurons in the rostral dorsal raphe nucleus terminate in e.g.:

Thus, activation of this serotonin system has effects on large areas of the brain, which explains the effects of therapeutic modulation of it.

5-HT is thought to be released from serotonergic varicosities into the extra neuronal space, in other words from swellings (varicosities) along the axon, rather than from synaptic terminal buttons (in the manner of classical neurotransmission). From here it is free to diffuse over a relatively large region of space (>20µm) and activate 5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons.

5-HT receptors are the receptors for serotonin. They are located on the cell membrane of nerve cells and other cell types in animals and mediate the effects of serotonin as the endogenous ligand and of a broad range of pharmaceutical and hallucinogenic drugs. With the exception of the 5-HT₃ receptor, a ligand gated ion channel, all other 5-HT receptors are G protein coupled seven transmembrane (or heptahelical) receptors that activate an intracellular second messenger cascade.

Genetic variations in alleles which code for serotonin receptors are now known to have a significant impact on the likelihood of the appearance of certain psychological disorders and problems. For instance, a mutation in the allele which codes for the 5-HT_2A receptor appears to double the risk of suicide for those with that genotype. [2]. However, evidence for this has yet to be replicated satisfactorily, and doubts over the validity of this finding have been raised. It is very unlikely that one individual gene could be responsible for increased suicides. It is more probable that a number of genes combine with environmental factors to affect behaviour in this way.

Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is through the specific monoamine transporter for 5-HT, 5-HT reuptake transporter, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake including MDMA (ecstasy), amphetamine, cocaine, dextromethorphan (an antitussive), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs).

Recent research suggests that serotonin plays an important role in liver regeneration and acts as a mitogen (induces cell division) throughout the body.^[4]

If neurons of the brainstem that make serotonin — serotonergic neurons — are abnormal in infants, there is a risk of sudden infant death syndrome (SIDS).^[5][6] Low levels of serotonin may also be associated with intense religious experiences.^[7]

It has also been discovered that serial killers consistently have low levels of serotonin. This is possibly a result of the aggressive and angry behaviors also associated with low levels of serotonin).

Recent research conducted at Rockefeller University shows that in both patients who suffer from depression and in mice that model that disease, levels of the p11 protein are decreased. This protein is related to serotonin transmission within the brain.^[8]

In the body, serotonin is synthesized from the amino acid tryptophan by a short metabolic pathway consisting of two enzymes: tryptophan hydroxylase (TPH) and amino acid decarboxylase (DDC). The TPH-mediated reaction is the rate-limiting step in the pathway. TPH has been shown to exist in two forms: TPH1, found in several tissues, and TPH2, which is a brain-specific isoform. There is evidence that genetic polymorphisms in both these subtypes influence susceptibility to anxiety and depression. There is also evidence that ovarian hormones can affect the expression of TPH in various species, suggesting a possible mechanism for postpartum depression and premenstrual stress syndrome.

Serotonin taken orally does not pass into the serotonergic pathways of the central nervous system because it does not cross the blood-brain barrier. However, tryptophan and its metabolite 5-hydroxytryptophan (5-HTP), from which serotonin is synthesized, can and do cross the blood-brain barrier. These agents are available as dietary supplements and may be effective serotonergic agents.

One product of serotonin breakdown is 5-Hydroxyindoleacetic acid (5 HIAA), which is excreted in the urine. Serotonin and 5 HIAA are sometimes produced in excess amounts by certain tumors or cancers, and levels of these substances may be measured in the urine to test for these tumors.

Several classes of drugs target the 5-HT system including some antidepressants, antipsychotics, anxiolytics, antiemetics, and antimigraine drugs as well as the psychedelic drugs and empathogens.

The psychedelic drugs psilocin/psilocybin, DMT, mescaline, and LSD mimick the action of serotonin at 5-HT_2A receptors. The empathogen MDMA (ecstasy) releases serotonin from synaptic vesicles of neurons.

The MAOIs prevent the breakdown of monoamine neurotransmitters (including serotonin), and therefore increase concentrations of the neurotransmitter in the brain. MAOI therapy is associated with many adverse drug reactions, and patients are at risk of hypertensive emergency triggered by foods with high tyramine content and certain drugs.

Some drugs inhibit this re-uptake of serotonin, again making it stay in the synapse longer. The tricyclic antidepressants (TCAs) inhibit the re-uptake of both serotonin and norepinephrine. The newer selective serotonin re-uptake inhibitors (SSRIs) have fewer (though still numerous) side-effects and fewer interactions with other drugs.

Like many centrally active drugs, prolonged use of SSRIs may not be effective for increasing levels of serotonin as homeostasis may reverse the effects of SSRIs via negative feedback, tolerance or downregulation.

5-HT₃ antagonists such as ondansetron, granisetron, and tropisetron are important antiemetic agents. They are particularly important in treating the nausea and vomiting that occur during anticancer chemotherapy using cytotoxic drugs. Another application is in treatment of post-operative nausea and vomiting. Applications to the treatment of depression and other mental and psychological conditions have also been investigated with some positive results.

Extremely high levels of serotonin can have toxic and potentially fatal effects, causing a condition known as serotonin syndrome. In practice, such toxic levels are essentially impossible to reach through an overdose of a single anti-depressant drug, but require a combination of serotonergic agents, such as an SSRI with an MAOI.^[9] The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at non-toxic levels.^[10] For example, recreational doses of MDMA (ecstasy) will generally cause such symptoms but only rarely lead to true toxicity.

In blood, serotonin stored in platelets is active wherever platelets bind, as a vasoconstictor to stop bleeding, and also as a fibrocyte mitotic, to aid healing. Because of these effects, overdoses of serotonin, or serotonin agonist drugs, may cause acute or chronic pulmonary hypertension from pulmonary vasoconstriction, or else syndromes of retroperitoneal fibrosis or cardiac valve fibrosis (endocardial fibrosis) from overstimulation of serotonic growth receptors on fibrocytes.

Serotonin itself may cause a syndrome of cardiac fibrosis when it is eaten in large quantities in the diet (the Matoki banana of East Africa) or when it is over-secreted by certain mid-gut carcinoid tumors. The valvular fibrosis in such cases is typically on the right side of the heart, since excess serotonin in the serum outside platelets is metabolized in the lungs, and does not reach the left circulation.

Serotonergic agonist drugs in overdose in experimental animals not only cause acute (and sometimes fatal) pulmonary hypertension, but there is epidemiologic evidence that chronic use of certain of these drugs produce a chronic pulmonary hypertensive syndrome in humans, also. Some serotinergic agonist drugs also cause fibrosis anywhere in the body, particularly the syndrome of retroperitoneal fibrosis, as well as right-sided cardiac valve fibrosis.

In the past, three groups of serotonergic drugs have been epidemiolgically linked with these syndromes. They are the serotonergic vasoconstrictive anti-migraine drugs (ergotamine and methysergide), the serotonergic appetite suppressant drugs (fenfluramine, chlorphentermine, and aminorex), and certain anti-parkinsonian dopaminergic agonists, which also stimulate serotonergic 5-HT_2B receptors. These include (pergolide and cabergoline, but not the more specific lisuride). A number of these drugs have recently been withdrawn from the market after groups taking them showed a statistical increase of one or more off the side effects described.

Because neither the amino acid L-tryptophan nor the SSRI-class antidepressants raise blood serotonin levels, they are not under suspicion to cause the syndromes described. However, since 5-hydroxytryptophan (5-HTP) does raise blood serotonin levels, it is under some of the same scrutiny as actively serotonergic drugs.

Serotonin is used by a variety of single-cell organisms for various purposes. Selective serotonin re-uptake inhibitors (SSRIs) have been found to be toxic to algae.^[11] The gastrointestinal parasite Entamoeba histolytica secretes serotonin, causing a sustained secretory diarrhea in some patients.^[12][13] Patients infected with Entamoeba histolytica have been found to have highly elevated serum serotonin levels which returned to normal following resolution of the infection.^[14]Entamoeba histolytica also responds to the presence of serotonin by becoming more virulent.^[15]

Serotonin is found in mushrooms and plants, including fruits and vegetables. The highest values of 25–400 mg/kg have been found in nuts of the walnut (Juglans) and hickory (Carya) genuses. Serotonin concentrations of 3–30 mg/kg have been found in plantain, pineapple, banana, kiwifruit, plums, and tomatoes. Moderate levels from 0.1–3 mg/kg have been found in a wide range of tested vegetables.^[16] Serotonin is one compound of the poison contained in the stinging hairs of the stinging nettle (Urtica dioica). It should be noted that serotonin, unlike its precursors 5-HTP and tryptophan, does not cross the blood–brain barrier. Several plants contain serotonin together with a family of related tryptamines that are methylated at the amino (NH₂) and hydroxy (OH) groups, are N-oxides, or miss the OH group. Examples are plants from the Anadenanthera genus that are used in the hallucinogenic yopo snuff.

Serotonin as a neurotransmitter is found in all animals, including insects. Several toad venoms, as well as that of the Brazilian Wandering Spider and stingray, contain serotonin and related tryptamines.

Isolated and named in 1948 by Maurice M. Rapport, Arda Green, and Irvine Page of the Cleveland Clinic,^[17] the name serotonin is something of a misnomer and reflects the circumstances of the compound’s discovery. It was initially identified as a vasoconstrictor substance in blood serum – hence serotonin, a serum agent affecting vascular tone. This agent was later chemically identified as 5-hydroxytryptamine (5-HT) by Rapport, and, as the broad range of physiological roles were elucidated, 5-HT became the preferred name in the pharmacological field.

• PsychoTropicalResearch Extensive reviews on serotonergic drugs and Serotonin Syndrome.
• Molecule of the Month: Serotonin at University of Bristol

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The terms empathogen and entactogen are different terms used to describe a class of psychoactive drugs that produce distinctive emotional and social effects similar to MDMA (“ecstasy”). Other members of this class are MDA, MDEA, MBDB, BDB and AET. When referring to MDMA and related analogs the term ‘MDxx’ is often used, the exception being MDPV which is purely a stimulant. Entactogens are often incorrectly referred to as hallucinogens or stimulants. The chemical structure of most entactogens contains a substituted amphetamine core.

The term “empathogen” was coined in 1983 by Ralph Metzner to denote chemical agents inducing feelings of empathy.

“Entactogen” was coined by David E. Nichols as an alternative to “empathogen”, attempting to avoid the potential for improper association of the latter with negative concepts related to the Greek root “pathos” (sympathy); Nichols also thought the word was limiting, and did not cover other therapeutic uses for the drugs which go beyond instilling feelings of empathy. The word “entactogen” is derived from the roots “en” (Greek: within), “tactus” (Latin: touch) and “gen” (Greek: produce). Neither term is dominant in usage, and despite their difference in connotation are essentially interchangeable as they refer to precisely the same chemicals.

These drugs appear to produce a different spectrum of psychological effects from stimulants such as methamphetamine and amphetamine or from psychedelic drugs such as LSD or Psilocybin. As implied by the category names, users of entactogens say the drugs often produce feelings of empathy, love, and emotional closeness to others. However, there have been only very preliminary comparisons of these different drugs in humans in properly controlled laboratory studies.

If MDMA is taken as a representative entactogen, the pharmacological mechanisms of this class appear to resemble those of methamphetamine. Extracellular dopamine, serotonin, and norepinephrine are all increased by both MDMA and methamphetamine. However, MDMA tends to release greater amounts of serotonin proportionately compared to methamphetamine, which might account for its different effects. It has also been noted anecdotally that the combination of IAP, a primarily serotonin releasing amphetamine, and amphetamine, a primarily norepinephrine and dopamine releasing amphetamine, is remarkably similar in psychopharmaceutical effect to MDA. Entactogens other than MDMA have received relatively little scientific attention, making it difficult to draw conclusions about the mechanisms of entactogens in general.

• Nichols, D.E., Hoffman, A.J., Oberlender, R.A., Jacob P 3rd & Shulgin A.T. Derivatives of 1-(1,3-benzodioxol-5-yl)-2-butanamine: representatives of a novel therapeutic class 1986 J Med Chem 29 2009-15
• Nichols, D.E. Differences between the mechanism of action of MDMA, MBDB, and the classic hallucinogens. Identification of a new therapeutic class: entactogens 1986 J Psychoactive Drugs 18 305-13

• Phenethylamine
• Entheogen

• Nichols 1986: Abstract and full text online
• The Great Entactogen – Empathogen Debate from MAPS newsletter

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Cannabinoids are a group of terpenophenolic compounds present in Cannabis (Cannabis sativa L). The broader definition of cannabinoids refer to a group of substances that are structurally related to tetrahydrocannabinol (THC) or that bind to cannabinoid receptors. The chemical definition encompasses a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the nonclassical cannabinoids, the aminoalkylindoles, the eicosanoids related to the endocannabinoids, 1,5-diarylpyrazoles, quinolines and arylsulphonamides and additional compounds that do not fall into these standard classes but bind to cannabinoid receptors.^[1] The term cannabinoids also refers to a unique group of secondary metabolites found in the cannabis plant, which are responsible for the plant’s peculiar pharmacological effects. Currently, there are three general types of cannabinoids: herbal cannabinoids occur uniquely in the cannabis plant; endogenous cannabinoids are produced in the bodies of humans and other animals; and synthetic cannabinoids are similar compounds produced in a laboratory.

Before the 1980’s, it was often speculated that cannabinoids produced their physiological and behavioral effects via nonspecific interaction with cell membranes, instead of interacting with specific membrane-bound receptors. The discovery of the first cannabinoid receptors in the 1980s helped to resolve this debate. These receptors are common in animals, and have been found in mammals, birds, fish, and reptiles. There are currently two known types of cannabinoid receptors, termed CB1 and CB2.

• CB1 receptors are found primarily in the brain, specifically in the basal ganglia and in the limbic system, including the hippocampus. They are also found in the cerebellum and in both male and female reproductive systems. CB1 receptors are essentially absent in the medulla oblongata, the part of the brain stem that is responsible for respiratory and cardiovascular functions. Thus, there is not a risk of respiratory or cardiovascular failure as there is with many other drugs. CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis.

• CB2 receptors are almost exclusively found in the immune system, with the greatest density in the spleen. CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis.

Type	Skeleton	Cyclization
Cannabigerol-type CBG
Cannabichromene-type CBC
Cannabidiol-type CBD
Tetrahydrocannabinol- and Cannabinol-type THC, CBN
Cannabielsoin-type CBE
iso– Tetrahydrocannabinol- type iso-THC		Chemical structure of the iso-CBN-type cyclization of cannabinoids.
Cannabicyclol-type CBL
Cannabicitran-type CBT

Natural cannabinoids, also called herbal cannabinoids and classical cannabinoids, are nearly insoluble in water but soluble in lipids, alcohols, and other non-polar organic solvents. However, as phenols they form more water-soluble phenolate salts under strongly alkaline conditions. All natural cannabinoids are derived from their respective 2-carboxylic acids (2-COOH) by decarboxylation; that is, catalyzed by heat, light, or alkaline conditions. Natural cannabinoids are only known to occur naturally in the cannabis plant, and are concentrated in a viscous resin that is produced in glandular structures known as trichomes. In addition to cannabinoids, the resin is rich in terpenes, which are largely responsible for the odour of the cannabis plant.

There are today seventy known herbal cannabinoids. To the right the main classes of natural cannabinoids are shown. All classes derive from cannabigerol-type compounds and differ mainly in the way this precursor is cyclized.

Tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) are the most prevalent natural cannabinoids and have received the most study. Other common ones are listed below:

• CBG Cannabigerol
• CBC Cannabichromene
• CBL Cannabicyclol
• CBV Cannabivarin
• THCV Tetrahydrocannabivarin
• CBDV Cannabidivarin
• CBCV Cannabichromevarin
• CBGV Cannabigerovarin
• CBGM Cannabigerol Monoethyl Ether

THC is the primary psychoactive component of the plant. Medically, it appears to ease moderate pain and to be neuroprotective. THC has approximately equal affinity for the CB1 and CB2 receptors.^[2] Its effects are perceived to be more cerebral.

CBD is not psychoactive, and appears to moderate the euphoric effects of THC. It may decrease the rate of THC clearance from the body, perhaps by interfering with the metabolism of THC in the liver. Medically, it appears to relieve convulsion, inflammation, anxiety, and nausea. CBD has a greater affinity for the CB2 receptor than for the CB1 receptor. It is perceived to have more effect on the body.

CBN is the primary product of THC degradation, and there is usually little of it in a fresh plant. CBN content increases as THC degrades in storage, and with exposure to light and air. It is only mildly psychoactive, and is perceived to be sedative or stupefying.

These compounds may be in different forms depending on the position of the double bond in the alicyclic carbon ring. There is potential for confusion because there are different numbering systems used to describe the position of this double bond. Under the dibenzopyran numbering system widely used today, the major form of THC is called delta-9-THC, while the minor form is called delta-8-THC. Under the alternate terpene numbering system, these same compounds are called delta-1-THC and delta-6-THC, respectively.

Most herbal cannabinoid compounds are 21 carbon compounds. However, some do not follow this rule, primarily because of variation in the length of the side chain attached to the aromatic ring. In THC, CBD, and CBN, this side chain is a pentyl (5 carbon) chain. In the most common homologue, the pentyl chain is replaced with a propyl (3 carbon) chain. Cannabinoids with the propyl side chain are named using the suffix “varin”, and are designated, for example, THCV, CBDV, or CBNV. It appears that shorter chains increase the intensity and decrease the duration of the activity of the chemicals.

Cannabinoids were first discovered in the 1940s, when CBD and CBN were identified. The structure of THC was first determined in 1964. Due to molecular similarity and ease of synthetic conversion, it was originally believed that CBD was a natural precursor to THC. However, it is now known that CBD and THC are produced independently in the cannabis plant. Cannabinoid production starts when an enzyme causes geranyl pyrophosphate and olivetolic acid to combine and form CBG. Next, CBG is independently converted to either CBD or CBC by two separate synthase enzymes. CBC is then enzymatically cyclized to THC. For the propyl homologues (THCV, CBDV and CBNV), there is a similar pathway that is based on CBGV.

Cannabis plants can exhibit wide variation in the quantity and type of cannabinoids they produce. The mixture of cannabinoids produced by a plant is known as the plant’s cannabinoid profile. Selective breeding has been used to control the genetics of plants and modify the cannabinoid profile. For example, strains which are used as fiber (commonly called hemp), are bred such that they are low in psychoactive chemicals like THC. Strains used in medicine are often bred for high CBD content, and strains used for recreational purposes are usually bred for high THC content, or for a specific chemical balance. Some strains of more than 20% THC have been created.

Quantitative analysis of a plant’s cannabinoid profile is usually determined by gas chromatography (GC), or more reliably by gas chromatography combined with mass spectrometry (GC/MS). Liquid chromatography (LC) techniques are also possible, although these are often only semi-quantitative or qualitative. There have been systematic attempts to monitor the cannabinoid profile of cannabis over time, but their accuracy is impeded by the illegal status of the plant in many countries.

Cannabinoids can be administered by smoking, vaporizing, oral ingestion, transdermal patch, intravenous injection, sublingual absorption, or rectal suppository. Once in the body, most cannabinoids are metabolized in the liver, although some is stored in fat. Delta-9-THC is metabolized to 11-hydroxy-delta-9-THC, which is then metabolized to 9-carboxy-THC. Some cannabis metabolites can be detected in the body after several weeks.

Cannabinoids can be separated from the plant by extraction with organic solvents. Hydrocarbons and alcohols are often used as solvents. However, these solvents are flammable and many are toxic. Supercritical solvent extraction with carbon dioxide is an alternative technique. Although this process requires high pressures, there is minimal risk of fire or toxicity, solvent removal is simple and efficient, and extract quality can be well-controlled. Once extracted, cannabinoid blends can be separated into individual components using wiped film vacuum distillation or other distillation techniques. However, to produce high purity cannabinoids, chemical synthesis or semisynthesis is generally required.

Endocannabinoids are naturally produced in the bodies of animals. After the first cannabinoid receptor was discovered in 1988, scientists began searching for natural compounds that activate these receptors.

In 1992, the first such compound was identified as arachidonoyl ethanolamide and named anandamide, a name derived from the Sanskrit word for bliss and amide. Anandamide is derived from the essential fatty acid arachidonic acid. It has a pharmacology similar to THC, although its chemical structure is different. Anandamide binds to both the central (CB1) and peripheral (CB2) cannabinoid receptors, and is found in nearly all tissues in a wide range of animals. It is about as potent as THC. Two analogs of anandamide, 7,10,13,16-docosatetraenoylethanolamide and homo-γ-linolenoylethanolamide, have similar pharmacology. All of these are members of a family of signalling lipids called N-acylethanolamides which also include the noncannabimimetic palmitoylethanolamide and oleoylethanolamide which have anti-inflammatory and orexigenic effects, respectively. Another endocannabinoid, 2-arachidonoyl glycerol, binds to both the CB1 and CB2 receptors, and is more abundant and a full efficacy agonist, clearly more potent than anandamide, in mediating CB, receptor-dependent G-protein activity in native membranes.^[3] Many N-acylethanolamides have also been identified in plant seeds^[4] and in molluscs.^[5] In 2001 was reported a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), isolated from porcine brain.^[6] It binds to the CB1 cannabinoid receptor (Ki = 21.2 nM) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds weakly to the CB2 receptor.

Endocannabinoids serve as intercellular ‘lipid messengers‘, signaling molecules that are released from one cell and activate the cannabinoid receptors present on other nearby cells. Although in this intercellular signaling role they are similar to the well-known monoamine neurotransmitters, such as acetylcholine, GABA or dopamine, endocannabinoids differ in numerous ways from them. Neurotransmitters are commonly small, water-soluble molecules that are contained within, and released from, tiny membrane-bound vesicles inside cells. Vesicles are often found in the tips, ‘terminals’, of long cellular branches called axons, and complex morphological and biochemical specializations mark the location from which vesicular release occurs. Endocannabinoids are lipophilic molecules that are not very soluble in water. They are not stored in vesicles, and exist as integral constituents of the membrane bilayers that make up cells. They are believed to be synthesized ‘on-demand’ rather than made and stored for later use. The mechanisms and enzymes underlying the biosynthesis of endocannabinoids remain elusive and continue to be an area of active research.

Conventional neurotransmitters are released from a ‘presynaptic’ cell and activate appropriate receptors on a ‘postsynaptic’ cell, where presynaptic and postsynaptic designate the sending and receiving sides of a synapse, respectively. Endocannabinoids are described as ‘retrograde’ transmitters because they most commonly travel ‘backwards’ against the usual synaptic transmitter flow. They are in effect released from the postsynaptic cell and act on the presynaptic cell, where the target receptors are densely concentrated on axonal terminals in the zones from which conventional neurotransmitters are released. Activation of cannabinoid receptors temporarily reduces the amount of conventional neurotransmitter released. This endocannabinoid mediated system permits the postsynaptic cell to control its own incoming synaptic traffic. The ultimate effect on the endocannabinoid releasing cell depends on the nature of the conventional transmitter that is being controlled. When the release of the inhibitory transmitter, GABA, is reduced, the net effect is an increase in the excitability of the endocannabinoid-releasing cell. Conversely, when release of the excitatory neurotransmitter, glutamate, is reduced, the net effect is a decrease in the excitability of the endocannabinoid-releasing cell.

Endocannabinoids are hydrophobic molecules. They cannot travel unaided for long distances in the aqueous medium surrounding the cells from which they are released, and therefore act locally on nearby target cells. Hence, although emanating diffusely from their source cells, they have much more restricted spheres of influence than do hormones, which can affect cells throughout the body.

Endocannabinoids constitute a versatile system for affecting neuronal network properties in the nervous system.

Scientific American published an article in December of 2004, entitled “The Brain’s Own Marijuana” discussing the endogenous cannabinoid system. ^[7]

The current understanding recognizes the role that endocannabinoids play in almost every major life function in the human body. Cannabinoids act as a bioregulatory mechanism for most life processes, which reveals why medical cannabis has been cited as treatments for many diseases and ailments in anecdotal reports and scientific literature. Some of these ailments include: pain, arthritic conditions, migraine headaches, anxiety, epileptic seizures, insomnia, loss of appetite, GERD (chronic heartburn), nausea, glaucoma, AIDS wasting syndrome, depression, bipolar disorder (particularly depression-manic-normal), multiple sclerosis, menstrual cramps, Parkinson’s, trigeminal neuralgia (tic douloureux), high blood pressure, irritable bowel syndrome, and bladder incontinence.

Historically, laboratory synthesis of cannabinoids were often based on the structure of herbal cannabinoids and a large number of analogs have been produced and tested, especially in a group led by Roger Adams as early as 1941 and later in a group led by Raphael Mechoulam. Newer compounds are no longer related to natural cannabinoids or are based on the structure of the endogenous cannabinoids.

Synthetic cannabinoids are particularly useful in experiments to determine the relationship between the structure and activity of cannabinoid compounds, by making systematic, incremental modifications of cannabinoid molecules.

Medications containing natural, synthetic, or cannabinoids analogs:

• Dronabinol (Marinol), an analog of Δ9-tetrahydrocannabinol (THC), used as an appetite stimulant, anti-emetic and analgesic.
• Nabilone (Cesamet), a synthetic cannabinoid and an analog of Marinol. It is Schedule II unlike Marinol which is Schedule III.
• Sativex, a cannabinoid extract oral spray containing both THC and CBD used for neuropathic pain and spasticity in Canada and Spain.
• Rimonabant (SR141716), a selective cannabinoid (CB1) receptor antagonist used as an anti-obesity drug under the proprietary name, Acomplia. It is also used for smoking cessation.

Other notable synthetic cannabinoids include:

• CP-55940, produced in 1974, this synthetic cannabinoid receptor agonist is many times more potent than THC
• HU-210, about 100 times as potent as THC^[8].
• SR144528, a CB2 receptor antagonists
• WIN 55,212-2, a potent cannabinoid receptor agonist
• JWH-133, a potent selective CB2 receptor agonist.
• Levonantradol (Nantrodolum), an anti-emetic and analgesic but not currently in use in medicine.

• delta-9-Tetrahydrocannabinol (Δ⁹-THC, THC) and delta-8-tetrahydrocannabinol (Δ⁸-THC), mimic the action of anandamide, a neurotransmitter produced naturally in the body. The THCs produce the high associated with cannabis by binding to the CB₁ cannabinoid receptors in the brain.
• Tetrahydrocannabivarin (THCV), prevalent in certain South African and Southeast Asian strains of Cannabis. It is an antagonist of THC at CB₁ receptors and attenuates the psychoactive effects of THC.^[9]
• Cannabidiol (CBD), non-psychoactive and not affecting psychoactivity of THC.^[10] CBD has anti-inflammatory effects. CBD shares a precursor with THC and is the main cannabinoid in low-THC Cannabis strains.
• Cannabinol (CBN), a degradation product of THC, produces a depressant effect
• Cannabichromene (CBC), non-psychoactive and not affecting psychoactivity of THC,^[10] a precursor of CBD and THC
• Cannabigerol (CBG), non-psychoactive
• Cannabinoids are good substrates for cytochrome P450 mixed-function oxidases, mainly CYP 2C9. Thus suplementing with CYP 2C9 inhibitors leads to extended intoxication.

Cannabigerol-type (CBG)
Cannabigerol (E)-CBG-C5	Cannabigerol monomethyl ether (E)-CBGM-C5 A	Cannabinerolic acid A (Z)-CBGA-C5 A	Cannabigerovarin (E)-CBGV-C3
Cannabigerolic acid A (E)-CBGA-C5 A	Cannabigerolic acid A monomethyl ether (E)-CBGAM-C5 A		Cannabigerovarinic acid A (E)-CBGVA-C3 A
Cannabichromene-type (CBC)
(±)-Cannabichromene CBC-C5	(±)-Cannabichromenic acid A CBCA-C5 A	(±)-Cannabivarichromene, (±)-Cannabichromevarin CBCV-C3	(±)-Cannabichromevarinic acid A CBCVA-C3 A
Cannabidiol-type (CBD)
(−)-Cannabidiol CBD-C5	Cannabidiol momomethyl ether CBDM-C5	Cannabidiol-C4 CBD-C4	(−)-Cannabidivarin CBDV-C3	Cannabidiorcol CBD-C1
Cannabidiolic acid CBDA-C5			Cannabidivarinic acid CBDVA-C3
Cannabinodiol-type (CBND)
Cannabinodiol CBND-C5	Cannabinodivarin CBND-C3
Tetrahydrocannabinol-type (THC)
Δ9-Tetrahydrocannabinol Δ9-THC-C5		Δ9-Tetrahydrocannabinol-C4 Δ9-THC-C4	Δ9-Tetrahydrocannabivarin Δ9-THCV-C3	Δ9-Tetrahydrocannabiorcol Δ9-THCO-C1
Δ9-Tetrahydro- cannabinolic acid A Δ9-THCA-C5 A	Δ9-Tetrahydro- cannabinolic acid B Δ9-THCA-C5 B	Δ9-Tetrahydro- cannabinolic acid-C4 A and/or B Δ9-THCA-C4 A and/or B	Δ9-Tetrahydro- cannabivarinic acid A Δ9-THCVA-C3 A	Δ9-Tetrahydro- cannabiorcolic acid A and/or B Δ9-THCOA-C1 An and/or B
(−)-Δ8–trans-(6aR,10aR)- Δ8-Tetrahydrocannabinol Δ8-THC-C5	(−)-Δ8–trans-(6aR,10aR)- Tetrahydrocannabinolic acid A Δ8-THCA-C5 A	(−)-(6aS,10aR)-Δ9– Tetrahydrocannabinol (−)-cis-Δ9-THC-C5
Cannabinol-type (CBN)
Cannabinol CBN-C5	Cannabinol-C4 CBN-C4	Cannabivarin CBN-C3	Cannabinol-C2 CBN-C2	Cannabiorcol CBN-C1
Cannabinolic acid A CBNA-C5 A	Cannabinol methyl ether CBNM-C5
Cannabitriol-type (CBT)
(−)-(9R,10R)-trans– Cannabitriol (−)-trans-CBT-C5	(+)-(9S,10S)-Cannabitriol (+)-trans-CBT-C5	(±)-(9R,10S/9S,10R)- Cannabitriol (±)-cis-CBT-C5	(−)-(9R,10R)-trans– 10-O-Ethyl-cannabitriol (−)-trans-CBT-OEt-C5	(±)-(9R,10R/9S,10S)- Cannabitriol-C3 (±)-trans-CBT-C3
8,9-Dihydroxy-Δ6a(10a)– tetrahydrocannabinol 8,9-Di-OH-CBT-C5	Cannabidiolic acid A cannabitriol ester CBDA-C5 9-OH-CBT-C5 ester	(−)-(6aR,9S,10S,10aR)- 9,10-Dihydroxy- hexahydrocannabinol, Cannabiripsol Cannabiripsol-C5	(−)-6a,7,10a-Trihydroxy- Δ9-tetrahydrocannabinol (−)-Cannabitetrol	10-Oxo-Δ6a(10a)– tetrahydrocannabinol OTHC
Cannabielsoin-type (CBE)
(5aS,6S,9R,9aR)- Cannabielsoin CBE-C5		(5aS,6S,9R,9aR)- C3-Cannabielsoin CBE-C3
(5aS,6S,9R,9aR)- Cannabielsoic acid A CBEA-C5 A	(5aS,6S,9R,9aR)- Cannabielsoic acid B CBEA-C5 B	(5aS,6S,9R,9aR)- C3-Cannabielsoic acid B CBEA-C3 B
Cannabiglendol-C3 OH-iso-HHCV-C3	Dehydrocannabifuran DCBF-C5	Cannabifuran CBF-C5
Isocannabinoids
(−)-Δ7–trans-(1R,3R,6R)- Isotetrahydrocannabinol	(±)-Δ7-1,2-cis– (1R,3R,6S/1S,3S,6R)- Isotetrahydro- cannabivarin	(−)-Δ7–trans-(1R,3R,6R)- Isotetrahydrocannabivarin
Cannabicyclol-type (CBL)
(±)-(1aS,3aR,8bR,8cR)- Cannabicyclol CBL-C5	(±)-(1aS,3aR,8bR,8cR)- Cannabicyclolic acid A CBLA-C5 A	(±)-(1aS,3aR,8bR,8cR)- Cannabicyclovarin CBLV-C3
Cannabicitran-type (CBT)
Cannabicitran CBT-C5
Cannabichromanone-type (CBCN)
Cannabichromanone CBCN-C5	Cannabichromanone-C3 CBCN-C3	Cannabicoumaronone CBCON-C5

• [2] Homepage of the ICRS – the International Cannabinoid Research Society

• Cannabis Report (Ministry of Public Health of Belgium) – 2002 at trimbos.nl

• Senate Report on Cannabis (Canada) – 2002 at Parliament of Canada

• The Health and Psychological Effects of Cannabis Use (Australia – Monograph 44) – 2001 at Department of Health and Ageing (Australia)

• Marijuana and Medicine – Assessing the Science Base (Institute of Medicine) – 1999 at National Academies Press

• House of Lords Report – Cannabis (United Kingdom) – 1998 at Parliament of the United Kingdom

• Cannabis: A Health Perspective and Research Agenda – 1997 at World Health Organization

• Overview of the Endocannabinoid signalling System at endocannabinoid.net

• Chemical Ecology of Cannabis (J. Intl. Hemp Assn. – 1994) at hempfood.com

• What Every Doctor Should Know About Cannabinoids at California Cannabis Research Medical Group

• Therapeutic Potential in Spotlight at Cannabinoid Researchers’ Meeting at California Cannabis Research Medical Group

• THC (tetrahydrocannabinol) accumulation in glands of Cannabis (Cannabaceae) at hempreport.com

• Inheritance of Chemical Phenotype in Cannabis Sativa (Genetics) at Genetics Society of America

• Medicinal marijuana laws, policies and news at cannabishq.com

• Compounds found in Cannabis sativa at Erowid

• Elsohly MA, Slade D (2005). “Chemical constituents of marijuana: the complex mixture of natural cannabinoids”. Life Sci. 78 (5): 539–48. doi:10.1016/j.lfs.2005.09.011. PMID 16199061.

• Hanus L (1987). “Biogenesis of cannabinoid substances in the plant”. Acta Universitatis Palackianae Olomucensis Facultatis Medicae. 116: 47–53. PMID 2962461.

• Hanuš L., Krejčí Z. Isolation of two new cannabinoid acids from Cannabis sativa L. of Czechoslovak origin. Acta Univ. Olomuc., Fac. Med. 74, 161-166 (1975)

• Hanuš L., Krejčí Z., Hruban L. Isolation of cannabidiolic acid from Turkish variety of cannabis cultivated for fibre. Acta Univ. Olomuc., Fac. Med. 74, 167-172 (1975)

• Turner C. E., Mole M. L., Hanuš L., ElSohly H. N. Constituents of Cannabis sativa L. XIX. Isolation and structure elucidation of cannabiglendol. A novel cannabinoid from an Indian variant. J. Nat. Prod. – Lloydia 44 (1), 27-33 (1981)

• Devane WA, Hanus L, Breuer A; et al. (1992). “Isolation and structure of a brain constituent that binds to the cannabinoid receptor”. Science. 258 (5090): 1946–9. PMID 1470919.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)

• Hanus L, Gopher A, Almog S, Mechoulam R (1993). “Two new unsaturated fatty acid ethanolamides in brain that bind to the cannabinoid receptor” (PDF). J. Med. Chem. 36 (20): 3032–4. PMID 8411021.CS1 maint: Multiple names: authors list (link)

• Mechoulam R, Ben-Shabat S, Hanus L; et al. (1995). “Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors”. Biochem. Pharmacol. 50 (1): 83–90. PMID 7605349.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)

cs:Endocannabinoidy de:Cannabinoide it:Cannabinoidi nl:Cannabinoïde fi:Kannabinoidi sv:Cannabinoid Template:Jb1

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