Synthetic cannabinoids

It is often difficult to determine what is in these products without reagent testing because masking agents, such as tocopherol (or vitamin E acetate that causes vaping-associated pulmonary injury), eugenol, and fatty acids, are added to confound identification. Just as the synthetic used differ between each synthetic cannabinoid product sold, so do the other contents of the counterfeit product. Counterfeit black market cannabis products • Counterfeit cannabis-liquid (c-liquid) for e-cigarettes: Synthetic cannabinoids are increasingly offered in e-cigarette form as "c-liquid". Several schoolchildren in Greater Manchester collapsed after vaping synthetic cannabinoids mis-sold as THC e-liquid. • Counterfeit cannabis buds: Hemp buds (or low-potency cannabis buds) laced with synthetic cannabinoids. • Counterfeit cannabis edible: The Florida Poison Information Center in Jacksonville warned parents in September 2020 that the number of people poisoned by fake marijuana edibles and candies has tripled. • Counterfeit hashish: From December 2018, different samples of hashish have been found to contain synthetic cannabinoids. Counterfeit CBD products Synthetic cannabinoids appear in many CBD brands in products such as gummy bears and vape cartridges. "Herb/incense" blends Synthetic cannabinoids found in herb blends Synthetic cannabinoid components of 'Spice' (a non-exhaustive list): Non-cannabinoid chemicals found in herb blends Most blends consist of synthetic cannabinoids sprayed onto inert vegetable matter, but some contain other psychoactive substances, including psychoactive herbs, e.g., wild dagga and Indian warrior, and psychoactive alkaloids, e.g., betonicine, aporphine, leonurine, nuciferine, and nicotine. In 2013, AH-7921 was detected in smoking blends in Japan. In 2018, there was an outbreak of synthetic cannabinoids contaminated with anticoagulants, mainly brodifacoum, in at least 11 states in the US that caused coagulopathy (prolonged or excessive bleeding) and resulted in the treatment of over 300 people and at least eight deaths. One of the most common non-cannabinoid ingredients in these products is oleamide, a fatty acid derivative that acts similarly to a cannabinoid and has hypnotic properties. Analysis of 44 products synthetic cannabinoid revealed oleamide in 7 of the products tested. Other non-cannabinoid ingredients that have been found in synthetic cannabinoid blends include harmine and harmaline, reversible monoamine oxidase inhibitors, which have been found with myristicin and asarone; substituted cathinone derived stimulant drugs such as 4-methylbuphedrone and 4'-methyl-alpha-PPP; and psychedelic tryptamine derivatives such as 4-HO-DET. Herbs labeled on packages marketed as legal high Packages of synthetic cannabinoid products can claim to contain a wide array of plants. However, oftentimes, none of the listed ingredients have been detectable. Herbal components of 'Spice' (a non-exhaustive list): ==Naming synthetic cannabinoids==

Many of the early synthetic cannabinoids that were synthesized for use in research were named after either the scientist who first synthesized them or the institution or company where they originated. Some of the names of synthetic cannabinoids synthesized for recreational use were given names to help market the products. For example, AKB-48 (also known as APINACA) is also the name of a popular Japanese girl band; 2NE1 (also known as APICA) is also a South Korean girl band; and XLR-11 was named after the first US-developed liquid fuel rocket for aircraft. Now many synthetic cannabinoids are assigned names derived from their four main structural components, core, tail, linker, and linked group, where the name is formatted as LinkedGroup-TailCoreLinker. For example, in 5F-MDMB-PINACA (also known as 5F-ADB), 5F stands for the terminal fluorine or "fluorine on carbon 5" of the pentyl chain; MDMB stands for "methyl-3,3-dimethyl butanoate", the linked group; and PINACA stands for "pentyl chain (tail) indazole (core) carboxamide (linker)". Common names Use of the term "synthetic marijuana" to describe products containing synthetic cannabinoids is controversial and, according to Lewis Nelson, a medical toxicologist at the NYU School of Medicine, a mistake. Nelson claims that relative to marijuana, products containing synthetic cannabinoids "are really quite different, and the effects are much more unpredictable. It's dangerous". Since the term synthetic does not apply to the plant, but rather to the cannabinoid that the plant contains (THC), the term synthetic cannabinoid is more appropriate. Nearly 700 "herbal incense" blends exist. They are often called "synthetic marijuana", "natural herbs", "herbal incense", or "herbal smoking blends" and often labeled "not for human consumption". Neocannabinoids Because of these controversies, and in particular the difficulty of distinguishing natural cannabinoids obtained in laboratory (for example, CBD or synthetic THC) from artificial novel synthetic cannabinoid analog compounds not present in nature (like nabilone, Spice, the HU, JWH series, etc.), the term "neocannabinoid" has been proposed to name the latter. ==Uses==

Synthetic cannabinoids were made for cannabinoid research focusing on tetrahydrocannabinol (THC), cannabinoid receptors, and the endocannabinoids that activate them in the body. Synthetic cannabinoids were needed partly due to legal restrictions on natural cannabinoids, which make them difficult to obtain for research. Many have been useful because they bind selectively to either the CB1 or CB2 receptors, whereas THC has a similar affinity for both. Tritium-labelled cannabinoids such as CP-55,940 were instrumental in discovering the cannabinoid receptors in the early 1990s. Some early synthetic cannabinoids were also used clinically. Nabilone, a first generation synthetic THC analog, has been used as an antiemetic to combat vomiting and nausea since 1981. Synthetic THC (marinol, dronabinol) has been used as an antiemetic since 1985, and an appetite stimulant since 1991, although synthetic THC is often not listed among the "synthetic cannabinoids" but as a "synthetic phytocannabinoid". The drug is most commonly used in populations that cannot easily acquire or consume marijuana, such as teenagers, inmates, people on probation or parole, and members of the armed forces subjected to regular drug testing. ==Toxicity==

Because they activate the cannabinoid CB1 and CB2 receptors, many of the effects of synthetic cannabinoids are similar to those of THC. These are achieved at lower doses, because many synthetic cannabinoids are more potent than marijuana, and users are often unaware of exactly what they are getting and how potent it is. For example, Δ9-THC has an EC50 of 250 nM at CB1 and 1157 nM at CB2, whereas PB-22 has an EC50 of 5.1 nM at CB1 and 37 nM at CB2. Some negative effects of 5F-PB-22 reported by users included nausea, vomiting, confusion, poor coordination, anxiety, and seizures. Some of the negative effects of 5F-AKB-48 reported by users included palpitations, paranoia, intense anxiety, and a taste like burned plastic. there are deaths linked to synthetic cannabinoids each year. The most common mechanisms leading to death following synthetic cannabinoid use include behavioral risks, such as self-harm and suicide, falling from a height, and wandering into traffic; cardiovascular effects; and central nervous system depression. Researchers have pointed out a few ways that synthetic cannabinoids differ from marijuana, and therefore may be more dangerous. First, they often have greater intrinsic activity. Many of the synthetic cannabinoids are full agonists of the cannabinoids receptors, CB1 and CB2, compared to THC, which is only a partial agonist. Secondly, they may have other actions in the body, in addition to activating cannabinoid receptors. Some may work on NMDA glutamate receptors. and increasing 5-HT1A expression, or by directly binding to serotonin receptors, including the 5-HT1A and 5-HT3 Third, synthetic cannabinoids may break down into metabolites, or create other by-products when heated, that may differ from marijuana. Phase 1 metabolism of JWH-018 results in at 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). 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. 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==

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, 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. 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 (+) 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. Due to their high potency, a very small dose of synthetic cannabinoids is used. 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. 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. 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==

New Zealand In September 2018, at least 10 people overdosed on a synthetic cannabinoid, either AMB-FUBINACA or AB, in Christchurch over two days. Some of the people were in critical condition in the Intensive Care Unit. United States In October 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. On July 12, 2016, 33 people were intoxicated by an herbal "incense" product called "AK-47 24 Karat Gold", and dozens overdosed, in Brooklyn. Eighteen people were transported to local hospitals. The herbal "incense" product was determined to be a synthetic cannabinoid called AMB-FUBINACA. and on April 5, 2018, the CDC issued a Clinical Action alert to health care providers across the United States advising of 89 confirmed cases of "serious unexplained bleeding" in Illinois. The cases are still being studied; however, 63 of the patients reported synthetic cannabinoid use, and laboratory analysis confirmed brodifacoum was present in at least 18 patients. As of April 24, 2018, 153 cases, including four deaths, linked to this outbreak have been reported to the Illinois Department of Public Health (IDPH) since March 7, 2018. On September 18, 2018, the Wisconsin Department of Health Services confirmed 16 more cases, bringing the total number of people affected by the outbreak in Wisconsin to 80 people since March 2018, including one death in July 2018. In August 2018, there were almost one hundred overdose cases reported over two days in New Haven, Connecticut, from a bad batch of K2. The synthetic cannabinoid was believed to have been mixed with fentanyl, although no fentanyl was identified in samples of the drug tested by the DEA. From September 21–22, 2018, almost 50 people overdosed and two people died in the Kensington area of Philadelphia. Officials believed the cause to be a combination of heroin or fentanyl and a synthetic cannabinoid. This same area in Philadelphia had 155 people overdose and 10 people die from a combination of heroin, fentanyl, and a synthetic cannabinoid called 5F-ADB over one weekend in July 2018. The Department of Public Health released that they believe "5F-ADB was the primary cause of the cluster of patients with these adverse drug reactions." On December 10, 2021, the Hillsborough County, Florida department of health reported cases of "rat poison" contaminated synthetic blends linked to symptoms associated with coagulopathy, a condition where the blood's ability to clot is impaired. Two deaths and over 41 hospitalizations have been directly linked to this specific outbreak as of December 16, 2021. ==Research==

Vaping-associated pulmonary injury Synthetic cannabinoids have been speculated to be involved in vaping-associated pulmonary injury (VAPI). ==Legal restrictions and regional availability==

Europe Austria The Austrian Ministry of Health announced in December 2008 that Spice would be controlled under their drug-law on the grounds that it contains an active substance that affects the functions of the body, and the legality of JWH-018 is under review. Germany JWH-018, CP 47,497 and the C6, C8, and C9 homologues of CP 47,497 have been illegal in Germany since January 2009. Since November 2016, about 80–90% of the substances belonging to the group of synthetic cannabinoids are illegal in Germany as the law does not cover all chemical structures. France JWH-018, CP 47,497 (and its homologues), and HU-210 were all made illegal in France in February 2009. Ireland From June 2010, JWH-018, along with a variety of other designer drugs, has been illegal. Latvia JWH-018, JWH-073, CP 47,497 (and its homologues), and HU-210, as well as leonotis leonurus, have been all banned in Latvia since 2005. After the first confirmed lethal case from the use of legal drugs in late 2013, parliament significantly increased the number of temporarily banned substances used in Spice and similar preparations. In April 2014, parliament made selling of the temporarily banned substances a criminal offense. Poland JWH-018 and many of the herbs mentioned on the ingredient lists of Spice and similar preparations were made illegal in May 2009. The bill was passed by Polish Sejm and Polish Senat and was signed by the President. Romania Spice was made illegal in Romania in February 2010. In September 2018, Spice was made legal for personal use. A new law is being discussed to make spice illegal for personal use again. Russia In April 2009, the Chief Medical Officer of the Russian Federation issued a resolution on reinforcing control over the sales of smoking-blends. These blends, marketed under the trade names AM-HI-CO, Dream, Spice (Gold, Diamond), Zoom, Ex-ses, Yucatán Fire and others, have been declared to contain Salvia divinorum, Hawaiian wood rose, and blue lotus, and are prohibited to be sold. These substances have been found to have "psychotropic, narcotic effects, contain poisonous components and represent potential threat for humans". The resolution does not mention JWH-018 or other synthetic cannabinoids. In January 2010, the Russian government issued a statement including 23 synthetic cannabinoids found in smoking blends Hawaiian Rose and Blue Lotus on the list of prohibited narcotic and psychotropic substances. About 780 new psychoactive substances were added to the list from 2011 to 2014. The drug-makers avoided all the bans by making slight changes to the drugs. In the autumn of 2014, more than 2000 Spice consumers in Russia sought medical attention, 1000 were admitted to hospitals, and 40 people died. In October 2014, President Vladimir Putin brought in a bill that increased the penalty for selling or consuming smoking blends from a fine to up to eight years in prison. Slovakia Spice is legal in Slovakia. The National Anti-Drug Unit is considering adding it to the list of controlled substances. The latest anti-drug law version (468/2009) valid since January 2010 does not mention active compounds of Spice. Spain Spice is unregulated in Spain. For this reason, Spice is available in grow shop stores or cannabis related stores, and it can be bought and shipped online without any legal impediment from those kind of stores. Sweden CP 47,497-C6, CP 47,497-C7, CP 47,497-C8, CP 47,497-C9, JWH-018, JWH-073, and HU-210 were all made illegal in Sweden in September 2009. Switzerland Spice has been banned in Switzerland. Turkey Spice, which is colloquially called bonzai in Turkey, was added to the list of drugs and psychotropic substances in July 2011. United Kingdom The UK controls synthetic cannabinoids by analog under the Misuse of Drugs Act 1971 as Class B drugs. Until 2016, synthetic cannabinoids were legally sold in head shops, although the exact compounds available changed over time based on the legislation. The UK saw three generations of synthetic cannabinoids within five years where the second and third generations emerged in response to amendments to the Misuse of Drugs Act 1971 (Amendment) Orders 2009 and 2013, which classified many first and second generation synthetic cannabinoids as Class B drugs. There were two additional amendments in 2016 and 2019, which included in the analog controls many of the most popular synthetic cannabinoids circulating at the time. In May 2016, the Psychoactive Substances Act 2016 was enacted, which made illegal the production, distribution, sale, supply, and possession in correctional institutions of any substance for human consumption with psychoactive effects. This stopped the open sale of synthetic cannabinoids in head shops, although they are still found in use. North America Canada Spice is not specifically prohibited in Canada, but synthetic cannabis mimics are listed as a schedule II drug. Schedule II to the Controlled Drugs and Substances Act makes reference to specific synthetic compounds JWH-XXX and AM-XXXX, although is not limiting to those identified. Health Canada is debating the subject. Schedule II has consisted entirely of synthetic cannabinoids since October 2018. These remain illegal following the removal from the schedule of cannabis and its constituents derived from nature. United States The case of David Mitchell Rozga, an American teenager from Indianola, Iowa, brought international attention to K2. Rozga shot himself in the head with a family-owned hunting rifle in an apparent suicide on June 6, 2010. After news of Rozga's death, it was reported by friends that they had smoked K2 with Rozga approximately one hour before his death. The nature of his death and reports from numerous family members, led investigators to suspect that Rozga was under the influence of a mind-altering substance when he died. The death of Rozga influenced political lobbying against K2, and other legal synthetic drugs such as bath salts. Following the incident, the "David Mitchell Rozga Act" to ban the use and distribution of K2 was introduced by Iowa Senator Chuck Grassley. It was passed by the United States Congress in June 2011. On July 10, 2012, President Barack Obama signed the Synthetic Drug Abuse Prevention Act of 2012 into law. It banned synthetic compounds commonly found in synthetic marijuana, placing them under Schedule I of the Controlled Substances Act. Prior to that, some synthetic cannabis compounds (HU-210) were scheduled in the US under federal law, while others (JWH-073) were temporarily scheduled until final determination of their status could be made. The Drug Enforcement Administration (DEA) considered K2 to be a "drug of concern", citing "a surge in emergency-room visits and calls to poison-control centers. Adverse health effects associated with its use include seizures, hallucinations, paranoid behavior, agitation, anxiety, nausea, vomiting, racing heartbeat, and elevated blood pressure." Several states independently passed acts making it illegal under state law, including Kansas in March 2010, Georgia and Alabama in May 2010, Tennessee and Missouri in July 2010, Louisiana in August 2010, Mississippi in September 2010, and Iowa. An emergency order was passed in Arkansas in July 2010 banning the sale of synthetic cannabis mimics. In October 2010, the Oregon Board of Pharmacy listed synthetic cannabinoid chemicals on its Schedule 1 of controlled substance, which means that the sale and possession of these substances is illegal under the Oregon Uniform Controlled Substances Act. According to the National Conference of State Legislatures, several other states also considered legislation, including New Jersey, New York, Florida, and Ohio. Michigan banned synthetic cannabinoids in October 2010. South Dakota banned these products in February 2012. Indiana banned synthetic cannabinoids in March 2012. North Carolina banned synthetic cannabis mimics by a unanimous vote of the state senate, due to concerns that its contents and effects are reasonably similar to cannabis, and may cause equal effects in terms of psychological dependency. Following cases in Japan involving the use of synthetic cannabinoids by navy, army and marine corps personnel, they were officially banned. A punitive general order issued in January 2010, by the Commander Marine Corps Forces, Pacific prohibits the actual or attempted possession, use, sale, distribution and manufacture of synthetic cannabis mimics as well as any derivative, analogue or variant of it. In June 2010, the US Air Force issued a memorandum that banned the possession and use of Spice, or any other mood-altering substance except alcohol or tobacco, among its service members. Usage among 8th, 10th, and 12th graders has been decreasing since 2011, while use of botanical marijuana has remained stable. There are important regional differences, with large declines in the Western and Southern US, and increases in the Northeast and Midwest. Dronabinol Exceptional are synthetic ∆9-THC (dronabinol) -containing FDA-approved drug products with a currently accepted medical use in treatment in the United States, such as Syndros and Marinol, which are, respectively, under Schedule II and Schedule III of the CSA.