least nine monohydroxylated metabolites, three of which have been shown to be full agonists of the cb1 receptors, compared to the metabolism of thc, which only results in one psychoactive monohydroxylated metabolite. the metabolite n-(3-hydroxypentyl) jwh-018 was found to have toxic effects that its parent compound does not. some metabolites even appear to be cannabinoid antagonists. lastly, they may contain unwanted substances, be mislabeled, or contain different doses than advertised (in one analysis, a difference of one log unit was found). no official studies have been conducted on the effects of synthetic cannabinoids on humans (as is often the case with illegal and potentially toxic compounds); however, user reports and the effects experienced by patients seeking medical care after taking synthetic cannabinoids have been published. each of the many different synthetic cannabinoids can have different effects at different dosages. the cdc described synthetic cannabinoid overdoses between 2010 and 2015 and of 277 drug overdose patients who reported synthetic cannabinoid as the sole agent, 66.1% reported problems in the central nervous system (e.g., agitation, coma, toxic psychosis), 17% reported cardiovascular problems (e.g., tachycardia, bradycardia), 7.6% reported pulmonary problems (5.4% of which had respiratory depression), and 4% reported acute kidney injury. four postmortem cases linked to the synthetic cannabinoids 5f-pb-22 have been reviewed. the postmortem blood specimens contained a range of 1.1-1.5 ng/ml of 5f-pb-22. three of the four cases were sudden episodes and the symptoms leading to death included acute shortness of breath; vasocongestion in the liver, spleen, and kidneys; bilateral pulmonary edema; dead inflamed tissue (necrotizing granulomatous inflammation); and congestion of most internal organs. the fourth case presented to the hospital with severe problems that deteriorated over the course of a day, ending with circulatory, respiratory, central nervous system, and renal failure. addiction there have been reports of a strong compulsion to re-dose, withdrawal symptoms, and persistent cravings lasting up to a week after taking synthetic cannabinoids, indicating that synthetic cannabinoids may be more addictive than marijuana. psychosis studies are currently available that suggest an association between synthetic cannabinoids and psychosis. the use of synthetic cannabinoids can be associated with psychosis and physicians are beginning to investigate if some patients with inexplicable psychotic symptoms may have at one point used synthetic cannabinoids. in contrast to most other recreational drugs, the dramatic psychotic state induced by use of synthetic cannabinoids has been reported, in multiple cases, to persist for several weeks, and in one case for seven months, after complete cessation of drug use. some studies suggest that not only can synthetic cannabinoids induce psychosis, but they can worsen previously stable psychotic disorders and might trigger a chronic (long-term) psychotic disorder among vulnerable individuals such as those with a family history of mental illness. individuals with risk factors for psychotic disorders are often counseled against using synthetic cannabinoids. psychiatrists have suggested that the lack of an antipsychotic chemical, like cbd in natural cannabis, may make synthetic cannabinoids more likely to induce psychosis than natural cannabis. structural classifications table 1. structural classifications of synthetic cannabinoids classification examples adamantoylindoles or indazole carboxamide 5f-akb-48, apica, sts-135 benzimidazoles az-11713908, azd-1940 phenylacetylindoles jwh-250, rcs-8 cyclohexylphenols cp-47,947, cp-55,940 dibenzopyrans jwh-051, jwh-056 eicosanoids am-883, am-1346, o-585, o-689 naphtylindenes jwh-171, jwh-176 indazole carboxamides ab-pinaca, ab-fubinaca indazole-3-carboxamides ab-chminaca, ab-fubinaca, px-2, px-3 indole-3-carboxamides cumyl-bica, cumyl-cbmica, org 28312, org 28611 indole-3-carboxylates or aryloxycarbonylindole fdu-pb-22, fub-pb-22 naphthoylindazoles thj-018, thj-2201 naphthoylindoles am-1221, am-2201, jwh-007, jwh-018, jwh-073, jwh-200, jwh-398, win-55,212-2 phenylacetylindoles jwh-167, jwh-203 pyrazolecarboxamides 5f-ab-fuppyca, ab-chfupyca pyrrolobenzoxazines or naphtoylindole win 55,212-2 quinolinyl esters or aryloxycarbonylindole pb-22, 5f-pb-22 tetramethylcyclo-propylcarbonylindazoles fab-144 tetramethylcyclo-propylcarbonylindoles a-796,260, a-834,735, ur-144, xlr-11, xlr-12 there are five major categories for synthetic cannabinoids: classical cannabinoids, non-classical cannabinoids, hybrid cannabinoids, aminoalkylindoles, and eicosanoids. classical cannabinoids are analogs of thc that are based on a dibenzopyran ring. they were developed starting in the 1960s, following the isolation of thc, and were originally the only cannabinoids synthesized. classical cannabinoids include nabilone and dronabinol, and one of the best known synthetic classical cannabinoids is hu-210. hu-210 is a chiral compound first synthesized by raphael mechoulam at hebrew university in the 1980s. it was discovered in herbal incense products by the u.s. customs and border protection in january 2009; however, classical cannabinoids are not often seen in synthetic cannabinoid blends for recreational use, likely because they are difficult to synthesize. non-classical cannabinoids include cyclohexylphenols (cp), which were first synthesized in the late 1970s to 1980s by pfizer as potential analgesics. the c8 homologue of cp-47,497 (cp-47,497-c8) was one of the first synthetic cannabinoids being used recreationally. cp-47,497-c8 is made by extending the dimethylheptyl side chain of cp-47,497 to a dimethyloctyl side chain. it was discovered by forensic scientists in an herbal blend known as "spice" in 2008, along with jwh-018, an aminoalkylindole. hybrid cannabinoids have a combination of classical and non-classical cannabinoid structural features. for example, am-4030, a derivative of hu-210, is a hybrid cannabinoid because it has the dibenzopyran ring common of classical cannabinoids and an aliphatic hydroxyl group common in the cp family of nonclassical cannabinoids. aminoalkylindoles are structurally dissimilar to thc and include naphthoylindoles (jwh-018), phenylacetylindoles (jwh-250), and benzoylindoles (am-2233). aminoalkylindoles are considered to be the most common synthetic cannabinoids found in synthetic cannabinoid blends, likely due to the fact that these molecules are easier to synthesize than classical and non-classical cannabinoids. the jwh molecules were first synthesized by john william huffman at clemson university in the late 1990s. the fbi concluded in a 2012 memo that as a result of the publication of j.w. huffman's research, people searching for a "marijuana-like-high" would follow his recipes and methods. eicosanoid synthetic cannabinoids are analogs of endocannabinoids, such as anandamide. endocannabinoids are cannabinoids naturally occurring in the body. one of the best known synthetic analogs of anandamide is methanandamide. the synthetic cannabinoids that have emerged recently have even greater structural diversity, possibly to subvert legal regulations on earlier generations of synthetic cannabinoids. there are a few different structural classifications of synthetic cannabinoids that include many of the new structures, some of which are shown in table one. the indazole carboxamide group, including apinaca (akb-48), an adamantyl indazole carboxamide, and ab-pinaca, an aminocarbonyl indazole carboxamide, is an example of a new group of synthetic cannabinoids. most clandestine manufacturers and producers only make small changes to the structure of a synthetic cannabinoid, such as changing an indole to indazole structure (am-2201 to thj-2201) or terminal fluorine replacement; however, one group that was unprecedented when discovered by forensic scientists in 2013, was the quinolinyl ester synthetic cannabinoids. pb-22 and 5f-pb-22 were the first synthetic cannabinoids to include a quinoline substructure and an ester linkage. these compounds are thought to have been synthesized with the intention of making a synthetic cannabinoid prodrug, which might improve absorption and confound detection. ester bonds are easily biodegradable through spontaneous or endogenous, nonspecific esterase hydrolysis, which has been commonly used in medicinal chemistry to make ester prodrugs. the reason for the change to the quinolone substructure is unknown, but it may have been found to be a suitable replacement for the naphthoyl moiety that is currently regulated by us scheduling laws. although most synthetic cannabinoids are not direct analogs of thc, they share many common features with thc. most are lipid-soluble, non-polar, small molecules (usually 20-26 carbon atoms) that are fairly volatile, making them "smokable," like thc. another common feature of most synthetic cannabinoids and thc is a side-chain of five to nine saturated carbon atoms. it has been found that this chain of carbons is required for optimal psychotropic activity from binding cb1 receptors. also, most synthetic cannabinoids are agonists of both cannabinoid receptors, cb1 and cb2, like thc; however, they often have greater binding affinity and therefore greater potency than thc, as seen in table two. due to the greater potency, the standard doses of many synthetic cannabinoids may be less than 1 mg. table 2. structure, binding affinity, and potency of popular synthetic cannabinoids and thc name year identified by forensics structural classification structure cb1 binding affinity (nm) cb2 binding affinity (nm) cb1 ec50 (nm) cb2 ec50 (nm) δ9-thc (control phytocannabinoid) classical cannabinoid 41 ± 2 36 ± 10 250 1157 hu-210 2009 classical cannabinoid 0.061 ± 0.007 0.52 ± 0.04 (c8) cp 47,497 2008 non-classical cannabinoid (cyclohexylphenol) 2.20 ± 0.47 jwh-018 2008 aminoalkylindole (naphthoylindoles) 9.0 ± 5.0 2.94 ± 2.65 102 133 am-2201 (fluorinated jwh-018) 2011 aminoalkylindole (naphthoylindoles) 1.0 2.6 38 58 ur-144 2010 tetramethylcyclopropylindoles 29 ± 0.9 4.5 ± 1.7 421 72 xlr-11 (fluorinated ur-144) 2012 tetramethylcyclopropylindoles 24 ± 4.6 2.1 ± 0.6 98 83 apica 2012 adamantoylindole 128 29 sts-135 (fluorinated apica) adamantoylindole 51 13 ab-pinaca 2012 indazole carboxamide 1.2 2.5 pb-22 2013 quinolinyl ester 5.1 37 5f-pb-22 (fluorinated pb-22) quinolinyl ester 0.468 0.633 2.8 11 stereospecificity most classical, non-classical, and hybrid synthetic cannabinoids have stereospecificity (one stereoisomer is usually much more potent than the other(s)). for example, hu-210 is the (–) enantiomer of 11-oh-δ8-thc-dmh and a full agonist of the cb1 receptor; the (+) enantiomer of 11-oh-d8-thc-dmh, known as hu-211, is a nmda receptor antagonist and is largely inactive as a cannabinoid. on the other hand, aminoalkylindoles, eicosanoids, and the other new synthetic cannabinoid groups typically do not have an asymmetric center, so they are usually not stereospecific. fluorination of terminal carbon recently there has been an increase in the emergence of terminally fluorinated synthetic cannabinoids, such as 5f-pb-22 (fluorinated version of pb-22) and xlr-11 (fluorinated version of ur-144). south korea's national forensic service reported that 90% of all seized synthetic cannabinoids in 2013 were fluorinated, compared to no fluorinated synthetic cannabinoids reported in 2010. 5f-derivations (terminal fluorination) of the synthetic cannabinoids have been found to be about 2-5 times more potent at cb1 receptors than their un-fluorinated counterparts, as shown in table two. detection in bodily fluids synthetic cannabinoids are typically not identified by the standard marijuana drug tests including the immunoassay test (emit), gc-ms screening, and multi-target screening by lc-gc/ms because those tests only detect the presence of thc and its metabolites. although most synthetic cannabinoids are analogs of thc, they are structurally different enough that, for example, the specific antibodies in the emit for marijuana do not bind to them. also, due to their high potency, a very small dose of synthetic cannabinoids is used; moreover, synthetic cannabinoids are highly metabolized by the body, so the window to detect the parent drug (the synthetic cannabinoid itself) in blood and oral fluid is very small. serum concentrations of synthetic cannabinoids are generally in the 1–10 μg/l range during the first few hours after recreational usage and the metabolites are usually present in urine at similar concentrations. little to no parent drug is present in urine, so there is a lot of research to try and identify the major urinary metabolites that could be used as markers of synthetic cannabinoid intake. the major urinary metabolites in most cases are formed by oxidation of the alkyl side-chain to an alcohol and carboxylic acid followed by glucuronide conjugation and also by n-dealkylation and aromatic hydroxylation. for example, the main metabolites of jwh-018, of which there are over 20, include carboxylated, monohydroxylated, dihydroxylated, and trihydroxylated metabolites, but they are mostly excreted in urine as glucuronide conjugates. the presence of synthetic cannabinoids or their metabolites in bodily fluids may be determined using specifically targeted commercially available immunoassay screening methods (emit), while liquid chromatography-mass spectrometry is most often used for confirmation and quantitation. there are commercially available emit kits for the screening of the synthetic cannabinoids jwh-018, jwh-073, jwh-398, jwh-200, jwh-019, jwh-122, jwh-081, jwh-250, jwh-203, cp-47,497, cp-47,497-c8, hu-210, hu-211, am-2201, am-694, rcs-4, and rcs-8 through companies like nms labs, cayman chemical, and immunoanalysis corporation. notable incidents on october 20, 2011, the louisiana state university football program announced that it had suspended three players, including star cornerback tyrann mathieu, who tested positive for synthetic cannabinoids. in the autumn of 2014, more than two thousand spice consumers in russia sought medical attention, one-thousand were admitted to hospitals, and 40 people died. on july 12, 2016, 33 people were intoxicated by an herbal "incense" product called "ak-47 24 karat gold," and dozens overdosed, in brooklyn. 18 people were transported to local hospitals. the herbal "incense" product was determined to be a synthetic cannabinoid called amb-fubinaca. since march 2018, illinois, wisconsin, maryland, and 8 other states in the united states have had an outbreak of severe