including direct effects on mitochondrial membranes and receptor-mediated effects. however, an integrated hypothesis of cannabinoids' actions on these processes has yet to be formulated due to conflicting data and the complexity of the pathways involved. cannabinoid-based pharmaceuticals nabiximols (brand name sativex) is an aerosolized mist for oral administration containing a near 1:1 ratio of cbd and thc. also included are minor cannabinoids and terpenoids, ethanol and propylene glycol excipients, and peppermint flavoring. the drug, made by gw pharmaceuticals, was first approved by canadian authorities in 2005 to alleviate pain associated with multiple sclerosis, making it the first cannabis-based medicine. it is marketed by bayer in canada. sativex has been approved in 25 countries; clinical trials are underway in the united states to gain fda approval. in 2007, it was approved for treatment of cancer pain. in phase iii trials, the most common adverse effects were dizziness, drowsiness and disorientation; 12% of subjects stopped taking the drug because of the side effects. dronabinol (brand name marinol) is a thc drug used to treat poor appetite, nausea, and sleep apnea. it is approved by the fda for treating hiv/aids induced anorexia and chemotherapy induced nausea and vomiting. the cbd drug epidiolex has been approved by the food and drug administration for treatment of two rare and severe forms of epilepsy, dravet and lennox-gastaut syndromes. separation 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. butane may be used, which evaporates extremely quickly. supercritical solvent extraction with carbon dioxide is an alternative technique. once extracted, isolated components can be separated using wiped film vacuum distillation or other distillation techniques. also, techniques such as spe or spme are found useful in the extraction of these compounds. history the first discovery of an individual cannabinoid was made, when british chemist robert s. cahn reported the partial structure of cannabinol (cbn), which he later identified as fully formed in 1940. two years later, in 1942, american chemist, roger adams, made history when he discovered cannabidiol (cbd). progressing from adams research, in 1963 israeli professor raphael mechoulam later identified the stereochemistry of cbd. the following year, in 1964, mechoulam and his team identified the stereochemistry of tetrahydrocannabinol (thc). due to molecular similarity and ease of synthetic conversion, cbd was originally believed to be a natural precursor to thc. however, it is now known that cbd and thc are produced independently in the cannabis plant from the precursor cbg. endocannabinoids further information on the functions and regulation of the endocannabinoids: endocannabinoid system anandamide, an endogenous ligand of cb1 and cb2 endocannabinoids are substances produced from within the body that activate cannabinoid receptors. after the discovery of the first cannabinoid receptor in 1988, scientists began searching for endogenous ligand for the receptors. arachidonoylethanolamine (anandamide or aea) main article: arachidonoylethanolamine anandamide was the first such compound identified as arachidonoyl ethanolamine. the name is derived from the sanskrit word for bliss and -amide. it has a pharmacology similar to thc, although its structure is quite different. anandamide binds to the central (cb1) and, to a lesser extent, peripheral (cb2) cannabinoid receptors, where it acts as a partial agonist. anandamide is about as potent as thc at the cb1 receptor. anandamide is found in nearly all tissues in a wide range of animals. anandamide has also been found in plants, including small amounts in chocolate. two analogs of anandamide, 7,10,13,16-docosatetraenoylethanolamide and homo-γ-linolenoylethanolamine, have similar pharmacology. all of these compounds are members of a family of signalling lipids called n-acylethanolamines, which also includes the noncannabimimetic palmitoylethanolamide and oleoylethanolamide, which possess anti-inflammatory and anorexigenic effects, respectively. many n-acylethanolamines have also been identified in plant seeds and in molluscs. 2-arachidonoylglycerol (2-ag) another endocannabinoid, 2-arachidonoylglycerol, binds to both the cb1 and cb2 receptors with similar affinity, acting as a full agonist at both. 2-ag is present at significantly higher concentrations in the brain than anandamide, and there is some controversy over whether 2-ag rather than anandamide is chiefly responsible for endocannabinoid signalling in vivo. in particular, one in vitro study suggests that 2-ag is capable of stimulating higher g-protein activation than anandamide, although the physiological implications of this finding are not yet known. 2-arachidonyl glyceryl ether (noladin ether) in 2001, a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), was isolated from porcine brain. prior to this discovery, it had been synthesized as a stable analog of 2-ag; indeed, some controversy remains over its classification as an endocannabinoid, as another group failed to detect the substance at "any appreciable amount" in the brains of several different mammalian species. it binds to the cb1 cannabinoid receptor (ki = 21.2 nmol/l) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. it binds primarily to the cb1 receptor, and only weakly to the cb2 receptor. n-arachidonoyl dopamine (nada) discovered in 2000, nada preferentially binds to the cb1 receptor. like anandamide, nada is also an agonist for the vanilloid receptor subtype 1 (trpv1), a member of the vanilloid receptor family. virodhamine (oae) a fifth endocannabinoid, virodhamine, or o-arachidonoyl-ethanolamine (oae), was discovered in june 2002. although it is a full agonist at cb2 and a partial agonist at cb1, it behaves as a cb1 antagonist in vivo. in rats, virodhamine was found to be present at comparable or slightly lower concentrations than anandamide in the brain, but 2- to 9-fold higher concentrations peripherally. lysophosphatidylinositol (lpi) lysophosphatidylinositol is the endogenous ligand to novel endocannabinoid receptor gpr55, making it a strong contender as the sixth endocannabinoid. function endocannabinoids serve as intercellular 'lipid messengers', signaling molecules that are released from one cell and activating 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 dopamine, endocannabinoids differ in numerous ways from them. for instance, they are used in retrograde signaling between neurons. furthermore, 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. as hydrophobic molecules, endocannabinoids 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. the mechanisms and enzymes underlying the biosynthesis of endocannabinoids remain elusive and continue to be an area of active research. the endocannabinoid 2-ag has been found in bovine and human maternal milk. a review by matties et al. (1994) summed up the phenomenon of gustatory enhancement by certain cannabinoids. the sweet receptor (tlc1) is stimulated by indirectly increasing its expression and suppressing the activity of leptin, the tlc1 antagonist. it is proposed that the competition of leptin and cannabinoids for tlc1 is implicated in energy homeostasis. retrograde signal 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, on the other hand, are described as retrograde transmitters because they most commonly travel ‘backward’ 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 being controlled. for instance, when the release of the inhibitory transmitter gaba is reduced, the net effect is an increase in the excitability of the endocannabinoid-releasing cell. on the converse, when release of the excitatory neurotransmitter glutamate is reduced, the net effect is a decrease in the excitability of the endocannabinoid-releasing cell. "runner's high" the runner's high, the feeling of euphoria that sometimes accompanies aerobic exercise, has often been attributed to the release of endorphins, but newer research suggests that it might be due to endocannabinoids instead. synthetic cannabinoids main article: synthetic cannabinoid historically, laboratory synthesis of cannabinoids was 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. when synthetic cannabinoids are used recreationally, they present significant health dangers to users. in the period of 2012 through 2014, over 10,000 contacts to poison control centers in the united states were related to use of synthetic cannabinoids. medications containing natural or synthetic cannabinoids or cannabinoid analogs: dronabinol (marinol), is δ9-tetrahydrocannabinol (thc), used as an appetite stimulant, anti-emetic, and analgesic nabilone (cesamet, canemes), a synthetic cannabinoid and an analog of marinol. it is schedule ii unlike marinol, which is schedule iii rimonabant (sr141716), a selective cannabinoid (cb1) receptor inverse agonist once used as an anti-obesity drug under the proprietary name acomplia. it was also used for smoking cessation other notable synthetic cannabinoids include: jwh-018, a potent synthetic cannabinoid agonist discovered by john w. huffman at clemson university. it was often sold in legal smoke blends collectively known as "spice". several countries and states have moved to ban it legally. jwh-073 cp-55940, produced in 1974, this synthetic cannabinoid receptor agonist is many times more potent than thc. dimethylheptylpyran hu-210, about 100 times as potent as thc hu-211, a synthetic cannabinoid derived drug that acts on nmda instead of endocannabinoid system hu-331 a potential anti-cancer drug derived from cannabidiol that specifically inhibits topoisomerase ii. sr144528, a cb2 receptor antagonist/ inverse agonist 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 am-2201, a potent cannabinoid receptor agonist recently, the term "neocannabinoid" has been introduced to distinguish these designer drugs from synthetic phytocannabinoids (thc or cbd obtained by chemical synthesis) or synthetic endocannabinoids.