Synthetic cannabinoids

Synthetic cannabinoids are a class of

Typically, synthetic cannabinoids are sprayed onto plant matter[5] and are usually smoked,^[6] although they have also been ingested as a concentrated liquid form in the US (United States) and UK (United Kingdom) since 2016.^[7] They have been marketed as herbal incense, or "herbal smoking blends",^[6] and sold under common names like K2, spice,^[8] and synthetic marijuana.^[5] They are often labeled "not for human consumption" for liability defense.^[8] A large and complex variety of synthetic cannabinoids are designed in an attempt to avoid legal restrictions on cannabis, making synthetic cannabinoids designer drugs.^[6]

Most synthetic cannabinoids are

Synthetic marijuana compounds began to be manufactured and sold in the early 2000s.[6] From 2008 to 2014, 142 synthetic cannabinoid receptor agonists were reported to the European Monitoring-Center for Drugs and Drug Addiction (EMCDDA).^[12]

Reported user negative effects include

• Counterfeit cannabis-liquid (c-liquid) for e-cigarettes: Synthetic cannabinoids are increasingly offered in e-cigarette form as "c-liquid".^[16] Several schoolchildren in Greater Manchester collapsed after vaping synthetic cannabinoids mis-sold as THC e-liquid.^{[17][18][19][20][21][22][23][24][25]}
• Counterfeit cannabis buds: Hemp buds (or low-potency cannabis buds) laced with synthetic cannabinoids.^{[26][27][28][29][30]}
• 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.^[31]
• Counterfeit hashish: From December 2018, different samples of hashish have been found to contain synthetic cannabinoids.^{[32][33][34][35]}

Counterfeit CBD products

Synthetic cannabinoids appear in many CBD brands in products such as

Synthetic cannabinoid components of 'Spice' (a non-exhaustive list):[37]

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. Some synthetic cannabinoids products have also been found to contain synthetic opioids. For example, in 2010, nine people died due to the combination of O-desmethyltramadol, a μ-opioid agonist and analgesic drug, and kratom, an Asiatic medicinal plant containing mitragynine, another μ-opioid agonist, in a synthetic cannabinoid product called "Krypton".^[38] And in 2013, AH-7921 was detected in smoking blends in Japan.^[39] 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.^[40]

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.^[41] Analysis of 44 products synthetic cannabinoid revealed oleamide in 7 of the products tested.^[42] 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;^[38] substituted cathinone derived stimulant drugs such as 4-methylbuphedrone and 4'-methyl-alpha-PPP; and psychedelic tryptamine derivatives such as 4-OH-DET.^[43][44]

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):^[45]

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 USA-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)".^[46]

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".^[47] 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.^[48]

Nearly 700 "herbal incense" blends exist.^[49] They are often called "synthetic marijuana", "natural herbs", "herbal incense", or "herbal smoking blends" and often labeled "not for human consumption".^[8] In some Spanish-speaking countries, such as Chile and Argentina, such preparations are often referred to as cripy.

According to the Psychonaut Web Mapping Research Project, synthetic cannabinoids, sold under the brand name Spice, were first released in 2005 by the now-dormant company the Psyche Deli in London. In 2006, the brand gained popularity. According to the Financial Times, the assets of the Psyche Deli rose from £65,000 in 2006 to £899,000 in 2007. The EMCDDA reported in 2009 that Spice products were identified in 21 of the 30 participating countries.^[50]

Neocannabinoids

Because of these controversies,^[51] and in particular the difficulty to distinguish 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.^[52]

Uses

Synthetic cannabinoids were made for

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,^[54] although synthetic THC is often not listed among the "synthetic cannabinoids" but as a "synthetic phytocannabinoid".^[52]

In the early 2000s, synthetic cannabinoids began to be used for recreational drug use in an attempt to get similar effects to cannabis. Because synthetic cannabinoid molecular structures differ from THC and other illegal cannabinoids, synthetic cannabinoids were not technically illegal. Since the discovery of the use of synthetic cannabinoids for recreational use in 2008, some synthetic cannabinoids have been made illegal, but new analogs are continually synthesized to avoid the restrictions. Synthetic cannabinoids have also been used recreationally because they are inexpensive and are typically not revealed by the standard marijuana drug tests. Unlike nabilone, the synthetic cannabinoids found being used for recreational use did not have any documented therapeutic effects.^[38]

Toxicity

Because they activate the

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);^[72] 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.^[73]

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.^[74]

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.^[12]

Psychosis

Studies are currently available that suggest an association between synthetic cannabinoids and psychosis.^[75][76] 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.^[77] 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.^[78] Individuals with risk factors for psychotic disorders are often counseled against using synthetic cannabinoids.^[79] 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.^[80]

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,^[50] and were originally the only cannabinoids synthesized.^[82] Classical cannabinoids include nabilone and dronabinol, and one of the best known synthetic classical cannabinoids is HU-210.^[83] 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.^[84]

Non-classical cannabinoids include cyclohexylphenols (CP), which were first synthesized in the late 1970s to 1980s by Pfizer as potential analgesics.^[83] 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 a herbal blend known as "Spice" in 2008, along with JWH-018, an aminoalkylindole.^[8]

Hybrid cannabinoids have a combination of classical and non-classical cannabinoid structural features.^[82] 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.^[85]

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.^[83] 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;^[7] however, one group that was unprecedented when discovered by forensic scientists in 2013, was the quinolinyl ester synthetic cannabinoids.^[8]

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.^[81]

Although most synthetic cannabinoids are not direct analogs of THC, they share many common features with THC. Most are

Structure, binding affinity, and potency of popular synthetic cannabinoids and THC

Name	Year identified by forensics	Structural classification	Structure	CB1 binding affinity (nM)[86]	CB2 binding affinity (nM)[86]	CB1 EC50 (nM)[8]	CB2 EC50 (nM)[8]
Δ9-THC (control phytocannabinoid)		Classical cannabinoid		41 ± 2	36 ± 10	250	1157
HU-210	2009[38]	Classical cannabinoid		0.061 ± 0.007	0.52 ± 0.04
(C8) CP 47,497	2008[8]	Non-classical cannabinoid (cyclohexylphenol)		2.20 ± 0.47
JWH-018	2008[8]	Aminoalkylindole (naphthoylindoles)		9.0 ± 5.0[8]	2.94 ± 2.65[8]	102	133
AM-2201 (Fluorinated JWH-018)	2011[8]	Aminoalkylindole (naphthoylindoles)		1.0	2.6	38	58
UR-144	2010[8]	Tetramethylcyclopropylindoles		29 ± 0.9	4.5 ± 1.7	421	72
XLR-11 (Fluorinated UR-144)	2012[8]	Tetramethylcyclopropylindoles		24 ± 4.6	2.1 ± 0.6	98	83
APICA	2012[citation needed]	Adamantoylindole				128[87]	29[87]
STS-135 (Fluorinated APICA)		Adamantoylindole				51	13
AB-PINACA	2012[88]	Indazole carboxamide				1.2	2.5
PB-22	2013[8]	Quinolinyl ester				5.1	37
5F-PB-22 (Fluorinated PB-22)		Quinolinyl ester		0.468[89]	0.633[89]	2.8	11

Stereospecificity

Most classical, non-classical, and hybrid synthetic cannabinoids have

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.^[92][93] 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.^[94] 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.^[95]

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.^[101]

United States

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.^[102]

On July 12, 2016, 33 people were intoxicated by an herbal "incense" product called "AK-47 24 Karat Gold",^[103] and dozens overdosed, in Brooklyn. 18 people were transported to local hospitals.^[104] The herbal "incense" product was determined to be a synthetic cannabinoid called AMB-FUBINACA.^[103]

Since March 2018, Illinois, Wisconsin, Maryland, and 8 other states in the United States have had an outbreak of severe bleeding caused by a synthetic cannabinoid contaminated with brodifacoum, a rat poison that causes bleeding. Illinois was hit the hardest^[105] 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.^[106] 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.^[107] 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.^[108]

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.^[109]

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.^[110] 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."^[111]

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.^{[112][113][114]} 2 deaths and over 41 hospitalizations have been directly linked to this specific outbreak as of December 16, 2021.^[115][116]

Research

Vaping-associated pulmonary injury

Synthetic cannabinoids have been speculated to be involved in vaping-associated pulmonary injury (VAPI).^{[117][unreliable source?]}

Legal restrictions and regional availability

Europe

Austria

The Austrian Ministry of Health announced on December 18, 2008, that Spice would be controlled under Paragraph 78 of 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.^{[118][119][120]}

Germany

JWH-018, CP 47,497 and the C6, C8, and C9 homologues of CP 47,497 have been illegal in Germany since January 22, 2009.^[121][122] Since November 26, 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.^[123]

France

JWH-018, CP 47,497 (and its homologues), and HU-210 were all made illegal in France on February 24, 2009.^[124]

Ireland

From June 2010, JWH-018, along with a variety of other designer drugs, has been illegal.^[125]

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.^[126] 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. On April 3, 2014, parliament made selling of the temporarily banned substances a criminal offense.^[127]

Poland

Spice was made illegal in Romania on February 15, 2010. As on 12 September 2018 Spice was made legal for personal use.[132] A new law is being discussed to make spice illegal for personal use again.^[133][134]

Russia

On April 9, 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.^[135] On January 14, 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.^[136]

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 two-thousand Spice consumers in Russia sought medical attention, one-thousand were admitted to hospitals, and 40 people died^[137] On October 30, 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.^[138]

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.^[137]

Slovakia

Spice is legal in Slovakia. The National Anti-Drug Unit is considering adding it to the list of controlled substances.^[139] The latest anti-drug law version (468/2009) valid since January 2010 does not mention active compounds of Spice.^[140]

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.^[141]

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 on September 15, 2009. The bill was accepted on July 30, 2009, and was put in effect on September 15, 2009.^[142]

Switzerland

Spice has been banned in Switzerland.^[143]

Turkey

Spice, which is colloquially called bonzai in Turkey, was added to the list of drugs and psychotropic substances on July 1, 2011, by the law numbered as 2011–1310 B.K.K. (February 13, 2011 and the Official Gazette No. 27845).^[144]

United Kingdom

The UK controls synthetic cannabinoids by analog under the Misuse of Drugs Act, 1971 as Class B drugs.^[145] 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, Order 2009^[146] and Order 2013,^[147] 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.^[148][149] In May 2016, the Psychoactive Substances Act was enacted, which made illegal the production, distribution, sale, supply, and possession in correctional institutions of any substance for human consumption with psychoactive effects.^[150] This stopped the open sale of synthetic cannabinoids in head shops, although they are still found in use.^[151]

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.^[152][153] Health Canada is debating the subject.^[154][155] 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