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Wikipedia

Synthetic cannabinoids

November 27, 2023

"Spice (drug)" redirects here. For the fictional drug in Frank Herbert's Dune novels, see Melange (fictional drug).

Synthetic cannabinoids are a class of designer drug molecules that bind to the same receptors to which cannabinoids (THC, CBD and many others) in cannabis plants attach.[1] These novel psychoactive substances should not be confused with synthetic phytocannabinoids (obtained by chemical synthesis) or synthetic endocannabinoids from which they are in many aspects distinct.[2][3][4]

Bag and contents of a well-known early brand of synthetic cannabinoids named Spice that contains herbs covered with synthetic cannabinoids, now illegal throughout much of the world

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 agonists of the cannabinoid receptors. They have been designed to be similar to THC,[9] the natural cannabinoid with the strongest binding affinity to the CB1 receptor, which is linked to the psychoactive effects or "high" of marijuana.[10] These synthetic analogs often have greater binding affinity and greater potency to the CB1 receptors. There are several synthetic cannabinoid families (e.g. AM-xxx, CP-xx,xxx, HU-xx, JWH-xxx) which are classified by the creator of the substance (e.g. JWH stands for John W. Huffman), which can include several substances with different base structures such as classical cannabinoids and unrelated naphthoylindoles.[11]

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 palpitations, paranoia, intense anxiety, nausea, vomiting, confusion, poor coordination, and seizures. There have also been reports of a strong compulsion to re-dose, withdrawal symptoms, and persistent cravings.[12] There have been several deaths linked to synthetic cannabinoids. The Centers for Disease Control and Prevention (CDC) found that the number of deaths from synthetic cannabinoid use tripled between 2014 and 2015.[13][14] In 2018, the United States Food and Drug Administration warned of significant health risks from synthetic cannabinoid products that contain the rat poison brodifacoum, which is added because it is thought to extend the duration of the drugs' effects.[15] Severe illnesses and death have resulted from this contamination.[15]

Synthetic cannabinoid products edit

Synthetic cannabinoids reagent testing kits have recently become economical. 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 cannabinoid(s) used differ between each synthetic cannabinoid product sold, so do the other contents of the counterfeit product.

Counterfeit black market cannabis products edit

See also: Lacing (drugs) § Cannabis
 
Cannabis buds sold on the street may be adulterated.
  • 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 edit

See also: Lacing (drugs) § CBD

Synthetic cannabinoids appear in many CBD brands in products such as gummy bears and vape cartridges.[36]

"Herb/incense" blends edit

Synthetic cannabinoids found in herb blends edit

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

Compound Type
HU-210 Classic cannabinoid
AM-694 Benzoylindole
RCS-4 Benzoylindole
WIN 48,098 Benzoylindole
CP-47,497 Cyclohexylphenol
JWH-018 Naphthoylindole
JWH-019 Naphthoylindole
JWH-073 Naphthoylindole
JWH-081 Naphthoylindole
JWH-122 Naphthoylindole
JWH-210 Naphthoylindole
AM-2201 Naphthoylindole
JWH-203 Phenylacetylindole
JWH-250 Phenylacetylindole
RCS-8 Phenylacetylindole

Non-cannabinoid chemicals found in herb blends edit

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 edit

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]

Common name Psychoactive alkaloids Species Family
Beach bean Unknown Canavalia maritima; syn. C. rosea Fabaceae
Blue/Sacred lotus Nuciferine and aporphine Nelumbo nucifera Nelumbonaceae
Dog rose/Rosehip Unknown Rosa canina Roseceae
Dwarf skullcap Unknown Scutellaria nana Lamiacae
Honeyweed/Siberian motherwort Leonurine Leonurus sibiricus Lamiaceae
Indian warrior Unknown Pedicularis densiflora Orobanchaceae
Lion's ear/tail, Wild dagga Leonurine Leonotis leonurus Lamiacae
‘Maconha brava’ Genistein, apigenin Zornia latifolia or Z. diphylla Fabaceae
Marshmallow Unknown Althaea officinalis Malvaceae
White and blue water lily Nupharine, nymphaeine, respectively aporphine Nymphaea alba and N. caerulea Nymphaeaceae

Naming synthetic cannabinoids edit

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 edit

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 edit

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 edit

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.[53]

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 edit

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.[55] 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.[8] Adverse effects observed due to synthetic cannabinoid use include acute kidney injury, cardiac toxicity, seizure, stroke, tremor, hypokalemia, and rhabdomyolysis.[56][57][58][59][60][61] 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.[12] In addition, while there are no fatal overdose cases linked to marijuana,[62] there are deaths linked to synthetic cannabinoids each year.[14][63][64] 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.[65]

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.[66] Secondly, they may have other actions in the body, in addition to activating cannabinoid receptors. Some may work on NMDA glutamate receptors.[60] Some may also work on serotonin, either indirectly by inhibiting MAO[67] and increasing 5-HT1A receptor expression,[68] or by directly binding to serotonin receptors, including the 5-HT1A and 5-HT3[60] subtypes; some researchers speculate that this activity may be because the indole moiety that some synthetic cannabinoids possess is similar to the structure of serotonin.[69] 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.[70] Some metabolites even appear to be cannabinoid antagonists.[71] 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).[70]

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 edit

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 edit

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 edit

See also: Comparison of phytocannabinoids
Table 1. Structural classifications of synthetic cannabinoids[81]
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,[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]

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.[83] 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.[5]

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.[82]

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 lipid-soluble, non-polar, small molecules (usually 20-26 carbon atoms) that are fairly volatile, making them "smokable", like THC.[50] 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.[38] 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.[50]

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)[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 edit

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;[90] the (+) enantiomer of 11-OH-D8-THC-DMH, known as HU-211, is a NMDA receptor antagonist and is largely inactive as a cannabinoid.[91] 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.[82]

Fluorination of terminal carbon edit

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,[8] as shown in table two.

Detection in bodily fluids edit

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]

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.[96] 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.[7] 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.[97] 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.[84] 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.[98][99][100] 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.[95]

Notable incidents edit

New Zealand edit

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 are in critical condition in the Intensive Care Unit.[101]

United States edit

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]

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.[103]

On July 12, 2016, 33 people were intoxicated by an herbal "incense" product called "AK-47 24 Karat Gold",[104] and dozens overdosed, in Brooklyn. 18 people were transported to local hospitals.[105] The herbal "incense" product was determined to be a synthetic cannabinoid called AMB-FUBINACA.[104]

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[106] 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.[107] 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.[108] 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.[109]

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.[110]

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.[111] 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."[112]

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.[113][114][115] 2 deaths and over 41 hospitalizations have been directly linked to this specific outbreak as of December 16, 2021.[116][117]

Research edit

Vaping-associated pulmonary injury edit

Synthetic cannabinoids have been speculated to be involved in vaping-associated pulmonary injury (VAPI).[118]

Legal restrictions and regional availability edit

Europe edit

Austria edit

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.[119][120][121]

Germany edit

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.[122][123] 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.[124]

France edit

JWH-018, CP 47,497 (and its homologues), and HU-210 were all made illegal in France on February 24, 2009.[125]

Ireland edit

From June 2010, JWH-018, along with a variety of other designer drugs, has been illegal.[126]

Latvia edit

 
A store selling synthetic cannabinoids in Riga in 2012

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.[127] 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.[128]

Poland edit

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[129][130] and Polish Senat[131] and was signed by the President.[132]

Romania edit

Spice was made illegal in Romania on February 15, 2010. As on 12 September 2018 Spice was made legal for personal use.[133] A new law is being discussed to make spice illegal for personal use again.[134][135]

Russia edit

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.[136] 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.[137]

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[103] 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]

Slovakia edit

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 edit

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 edit

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 edit

Spice has been banned in Switzerland.[143]

Turkey edit

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 edit

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 edit

Canada edit

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 edit

See also: JWH-018 § 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.[156] 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.[157]

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.[158][159][160][161] The Drug Enforcement Administration (DEA) considered K2 to be a "drug of concern",[162] 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."[163][164]

Several states independently passed acts making it illegal under state law, including Kansas in March 2010,[165] Georgia and Alabama in May 2010,[166][167] Tennessee and Missouri in July 2010,[168][169] Louisiana in August 2010,[citation needed] Mississippi in September 2010,[citation needed] and Iowa.[170] An emergency order was passed in Arkansas in July 2010 banning the sale of synthetic cannabis mimics.[171] 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.[172] According to the National Conference of State Legislatures, several other states also considered legislation, including New Jersey, New York, Florida, and Ohio.[169] Illinois passed a law on July 27, 2010, banning all synthetic cannabinoids as of January 1, 2011.[173] Michigan banned synthetic cannabinoids in October 2010,[174] and the South Dakota Legislature passed a ban on these products which was signed into law by Gov. Dennis Daugaard on February 23, 2012 (and which took immediate effect under an emergency clause of the state constitution).[175] Indiana banned synthetic cannabinoids in a law which became effective in March 2012.[176] 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.[177][178]

Following cases in Japan involving the use of synthetic cannabinoids by navy, army and marine corps personnel, they were officially banned.[179] A punitive general order issued on January 4, 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.[180] On June 8, 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.[181]

Usage among 8th, 10th, and 12th graders has been decreasing since 2011, while use of botanical marijuana has remained stable.[182] There are important regional differences, with large declines in the Western and Southern US, and increases in the Northeast and Midwest.[183]

South America edit

Chile edit

The Chilean Ministry of Health on April 24, 2009, declared the sale of synthetic cannabis mimics to be illegal.[184]

Asia edit

South Korea edit

South Korea officially added JWH-018, CP 47,497 and HU-210 to the controlled substance list on July 1, 2009, effectively making these chemicals illegal.[185]

Indonesia edit

Tembakau Gorilla (Gorilla Tobacco), a catch-all term for synthetic cannabinoids blended in tobacco products, were listed as Class I Narcotics with no therapeutic use in 2017.[186][187]

Japan edit

Japan has banned JWH-018, CP 47, 497, and homologues, and HU-210 since October 2009.[citation needed]

United Arab-Emirates edit

The United Arab Emirates had stated that Spice is an illegal substance and possession or intent to sell is a jailable offense.[188]

Australasia edit

Australia edit

On June 17, 2011, the Western Australian government banned all of the synthetic cannabinoids found in already existing products, including brands such as Kronic, Kalma, Voodoo, Kaos, and Mango Kush. Western Australia was the first state in Australia to prohibit the sale of certain synthetic cannabinoids.[189][190] On June 18, 2013, an interim ban made a large list of product brands and synthetic substances illegal to sell anywhere in Australia.[191] This ban lapsed on October 13, 2013, and a permanent ban has not been imposed.[192] Synthetic cannabinoids and related products remain illegal in NSW, where a bill was passed on September 18, 2013, that bans entire families of synthetic drugs instead of only banning existing compounds that have been identified.[193][194] The introduction of this law makes NSW the first state in Australia to completely ban substances with psychoactive properties.[194]

New Zealand edit

Synthetic Cannabinoids are illegal in New Zealand, it is classified as a Class A controlled drug.[195] The New Zealand Parliament passed a law in July 2013 banning the sale of legal highs in dairies and supermarkets, but allowing some "low risk" drugs to continue to be sold through speciality licensed shops.[196] Synthetic cannabinoids, as well as all other legal highs were outlawed at midnight on 7 May 2014, after a law was passed a week prior by the New Zealand government.[197]

An analysis of 41 different synthetic cannabis mimic blends sold commercially in New Zealand, conducted by the Institute of Environmental Science and Research and released in July 2011, found 11 different synthetic cannabinoid ingredients used, including JWH-018, JWH-073, AM-694, AM-2201, RCS-4, RCS-4 butyl homologue, JWH-210, JWH-081, JWH-250 (or possibly JWH-302, isomer not determined), JWH-203, and JWH-122—with between one and five different active ingredients, though JWH-018 was present in 37 of the 41 blends tested. In two brands, the benzodiazepine anxiolytic drug phenazepam was also found, which is classified as a prescription medicine in New Zealand, and these brands were ordered to be removed from the market by emergency recall.[198][199] Since this time, a further 15 cannabinoid compounds have been detected as ingredients of synthetic cannabis mimicking blends in New Zealand and banned as temporary class drugs.[200] In 2013, another hypnotic medication, zaleplon, was found to have been used as an active ingredient in a blend that had been sold in New Zealand during 2011 and 2012.[201]

See also edit

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Further reading edit

  • Roque-Bravo, Rita; Silva, Rafaela Sofia; Malheiro, Rui F.; Carmo, Helena; Carvalho, Félix; da Silva, Diana Dias; Silva, João Pedro (2023-01-20). "Synthetic Cannabinoids: A Pharmacological and Toxicological Overview". Annual Review of Pharmacology and Toxicology. 63 (1): 187–209. doi:10.1146/annurev-pharmtox-031122-113758. ISSN 0362-1642. PMID 35914767. S2CID 251255354.

External links edit

November 27, 2023
synthetic, cannabinoids, spice, drug, redirects, here, fictional, drug, frank, herbert, dune, novels, melange, fictional, drug, class, designer, drug, molecules, that, bind, same, receptors, which, cannabinoids, many, others, cannabis, plants, attach, these, n. Spice drug redirects here For the fictional drug in Frank Herbert s Dune novels see Melange fictional drug Synthetic cannabinoids are a class of designer drug molecules that bind to the same receptors to which cannabinoids THC CBD and many others in cannabis plants attach 1 These novel psychoactive substances should not be confused with synthetic phytocannabinoids obtained by chemical synthesis or synthetic endocannabinoids from which they are in many aspects distinct 2 3 4 Bag and contents of a well known early brand of synthetic cannabinoids named Spice that contains herbs covered with synthetic cannabinoids now illegal throughout much of the worldTypically 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 agonists of the cannabinoid receptors They have been designed to be similar to THC 9 the natural cannabinoid with the strongest binding affinity to the CB1 receptor which is linked to the psychoactive effects or high of marijuana 10 These synthetic analogs often have greater binding affinity and greater potency to the CB1 receptors There are several synthetic cannabinoid families e g AM xxx CP xx xxx HU xx JWH xxx which are classified by the creator of the substance e g JWH stands for John W Huffman which can include several substances with different base structures such as classical cannabinoids and unrelated naphthoylindoles 11 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 palpitations paranoia intense anxiety nausea vomiting confusion poor coordination and seizures There have also been reports of a strong compulsion to re dose withdrawal symptoms and persistent cravings 12 There have been several deaths linked to synthetic cannabinoids The Centers for Disease Control and Prevention CDC found that the number of deaths from synthetic cannabinoid use tripled between 2014 and 2015 13 14 In 2018 the United States Food and Drug Administration warned of significant health risks from synthetic cannabinoid products that contain the rat poison brodifacoum which is added because it is thought to extend the duration of the drugs effects 15 Severe illnesses and death have resulted from this contamination 15 Contents 1 Synthetic cannabinoid products 1 1 Counterfeit black market cannabis products 1 2 Counterfeit CBD products 1 3 Herb incense blends 1 3 1 Synthetic cannabinoids found in herb blends 1 3 2 Non cannabinoid chemicals found in herb blends 1 3 3 Herbs labeled on packages marketed as legal high 2 Naming synthetic cannabinoids 2 1 Common names 2 2 Neocannabinoids 3 Uses 4 Toxicity 4 1 Addiction 4 2 Psychosis 5 Structural classifications 5 1 Stereospecificity 5 2 Fluorination of terminal carbon 6 Detection in bodily fluids 7 Notable incidents 7 1 New Zealand 7 2 United States 8 Research 8 1 Vaping associated pulmonary injury 9 Legal restrictions and regional availability 9 1 Europe 9 1 1 Austria 9 1 2 Germany 9 1 3 France 9 1 4 Ireland 9 1 5 Latvia 9 1 6 Poland 9 1 7 Romania 9 1 8 Russia 9 1 9 Slovakia 9 1 10 Spain 9 1 11 Sweden 9 1 12 Switzerland 9 1 13 Turkey 9 1 14 United Kingdom 9 2 North America 9 2 1 Canada 9 2 2 United States 9 3 South America 9 3 1 Chile 9 4 Asia 9 4 1 South Korea 9 4 2 Indonesia 9 4 3 Japan 9 4 4 United Arab Emirates 9 5 Australasia 9 5 1 Australia 9 5 2 New Zealand 10 See also 11 References 12 Further reading 13 External linksSynthetic cannabinoid products editSynthetic cannabinoids reagent testing kits have recently become economical 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 cannabinoid s used differ between each synthetic cannabinoid product sold so do the other contents of the counterfeit product Counterfeit black market cannabis products edit See also Lacing drugs Cannabis nbsp Cannabis buds sold on the street may be adulterated 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 edit See also Lacing drugs CBD Synthetic cannabinoids appear in many CBD brands in products such as gummy bears and vape cartridges 36 Herb incense blends edit Synthetic cannabinoids found in herb blends edit Synthetic cannabinoid components of Spice a non exhaustive list 37 Compound TypeHU 210 Classic cannabinoidAM 694 BenzoylindoleRCS 4 BenzoylindoleWIN 48 098 BenzoylindoleCP 47 497 CyclohexylphenolJWH 018 NaphthoylindoleJWH 019 NaphthoylindoleJWH 073 NaphthoylindoleJWH 081 NaphthoylindoleJWH 122 NaphthoylindoleJWH 210 NaphthoylindoleAM 2201 NaphthoylindoleJWH 203 PhenylacetylindoleJWH 250 PhenylacetylindoleRCS 8 PhenylacetylindoleNon cannabinoid chemicals found in herb blends edit 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 m opioid agonist and analgesic drug and kratom an Asiatic medicinal plant containing mitragynine another m 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 edit 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 Common name Psychoactive alkaloids Species FamilyBeach bean Unknown Canavalia maritima syn C rosea FabaceaeBlue Sacred lotus Nuciferine and aporphine Nelumbo nucifera NelumbonaceaeDog rose Rosehip Unknown Rosa canina RoseceaeDwarf skullcap Unknown Scutellaria nana LamiacaeHoneyweed Siberian motherwort Leonurine Leonurus sibiricus LamiaceaeIndian warrior Unknown Pedicularis densiflora OrobanchaceaeLion s ear tail Wild dagga Leonurine Leonotis leonurus Lamiacae Maconha brava Genistein apigenin Zornia latifolia or Z diphylla FabaceaeMarshmallow Unknown Althaea officinalis MalvaceaeWhite and blue water lily Nupharine nymphaeine respectively aporphine Nymphaea alba and N caerulea NymphaeaceaeNaming synthetic cannabinoids editMany 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 Compounds InventorAM Alexandros MakriyannisCP Charles PfizerHU Hebrew UniversityJWH John W HuffmanSome 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 edit 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 edit 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 editSynthetic 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 53 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 editBecause 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 55 For example D9 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 8 Adverse effects observed due to synthetic cannabinoid use include acute kidney injury cardiac toxicity seizure stroke tremor hypokalemia and rhabdomyolysis 56 57 58 59 60 61 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 12 In addition while there are no fatal overdose cases linked to marijuana 62 there are deaths linked to synthetic cannabinoids each year 14 63 64 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 65 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 66 Secondly they may have other actions in the body in addition to activating cannabinoid receptors Some may work on NMDA glutamate receptors 60 Some may also work on serotonin either indirectly by inhibiting MAO 67 and increasing 5 HT1A receptor expression 68 or by directly binding to serotonin receptors including the 5 HT1A and 5 HT3 60 subtypes some researchers speculate that this activity may be because the indole moiety that some synthetic cannabinoids possess is similar to the structure of serotonin 69 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 70 Some metabolites even appear to be cannabinoid antagonists 71 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 70 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 edit 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 edit 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 editSee also Comparison of phytocannabinoids Table 1 Structural classifications of synthetic cannabinoids 81 Classification ExamplesAdamantoylindoles or indazole carboxamide 5F AKB 48 APICA STS 135Benzimidazoles AZ 11713908 AZD 1940Phenylacetylindoles JWH 250 RCS 8Cyclohexylphenols CP 47 947 CP 55 940Dibenzopyrans JWH 051 JWH 056Eicosanoids AM 883 AM 1346 O 585 O 689Naphtylindenes JWH 171 JWH 176Indazole carboxamides AB PINACA AB FUBINACAIndazole 3 carboxamides AB CHMINACA AB FUBINACA PX 2 PX 3Indole 3 carboxamides CUMYL BICA CUMYL CBMICA Org 28312 Org 28611Indole 3 carboxylates or aryloxycarbonylindole FDU PB 22 FUB PB 22Naphthoylindazoles THJ 018 THJ 2201Naphthoylindoles AM 1221 AM 2201 JWH 007 JWH 018 JWH 073 JWH 200 JWH 398 WIN 55 212 2Phenylacetylindoles JWH 167 JWH 203Pyrazolecarboxamides 5F AB FUPPYCA AB CHFUPYCAPyrrolobenzoxazines or naphtoylindole WIN 55 212 2Quinolinyl esters or aryloxycarbonylindole PB 22 5F PB 22Tetramethylcyclo propylcarbonylindazoles FAB 144Tetramethylcyclo propylcarbonylindoles A 796 260 A 834 735 UR 144 XLR 11 XLR 12 nbsp nbsp 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 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 83 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 5 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 82 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 lipid soluble non polar small molecules usually 20 26 carbon atoms that are fairly volatile making them smokable like THC 50 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 38 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 50 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 86 CB2 binding affinity nM 86 CB1 EC50 nM 8 CB2 EC50 nM 8 D9 THC control phytocannabinoid Classical cannabinoid nbsp 41 2 36 10 250 1157HU 210 2009 38 Classical cannabinoid nbsp 0 061 0 007 0 52 0 04 C8 CP 47 497 2008 8 Non classical cannabinoid cyclohexylphenol nbsp 2 20 0 47JWH 018 2008 8 Aminoalkylindole naphthoylindoles nbsp 9 0 5 0 8 2 94 2 65 8 102 133AM 2201 Fluorinated JWH 018 2011 8 Aminoalkylindole naphthoylindoles nbsp 1 0 2 6 38 58UR 144 2010 8 Tetramethylcyclopropylindoles nbsp 29 0 9 4 5 1 7 421 72XLR 11 Fluorinated UR 144 2012 8 Tetramethylcyclopropylindoles nbsp 24 4 6 2 1 0 6 98 83APICA 2012 citation needed Adamantoylindole nbsp 128 87 29 87 STS 135 Fluorinated APICA Adamantoylindole nbsp 51 13AB PINACA 2012 88 Indazole carboxamide nbsp 1 2 2 5PB 22 2013 8 Quinolinyl ester nbsp 5 1 375F PB 22 Fluorinated PB 22 Quinolinyl ester nbsp 0 468 89 0 633 89 2 8 11Stereospecificity edit 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 D8 THC DMH and a full agonist of the CB1 receptor 90 the enantiomer of 11 OH D8 THC DMH known as HU 211 is a NMDA receptor antagonist and is largely inactive as a cannabinoid 91 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 82 Fluorination of terminal carbon edit 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 8 as shown in table two Detection in bodily fluids editSynthetic 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 Serum concentrations of synthetic cannabinoids are generally in the 1 10 mg L range during the first few hours after recreational usage and the metabolites are usually present in urine at similar concentrations 96 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 7 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 97 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 84 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 98 99 100 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 95 Notable incidents editNew Zealand edit 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 are in critical condition in the Intensive Care Unit 101 United States edit 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 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 103 On July 12 2016 33 people were intoxicated by an herbal incense product called AK 47 24 Karat Gold 104 and dozens overdosed in Brooklyn 18 people were transported to local hospitals 105 The herbal incense product was determined to be a synthetic cannabinoid called AMB FUBINACA 104 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 106 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 107 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 108 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 109 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 110 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 111 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 112 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 113 114 115 2 deaths and over 41 hospitalizations have been directly linked to this specific outbreak as of December 16 2021 116 117 Research editVaping associated pulmonary injury edit Synthetic cannabinoids have been speculated to be involved in vaping associated pulmonary injury VAPI 118 Legal restrictions and regional availability editEurope edit Austria edit 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 119 120 121 Germany edit 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 122 123 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 124 France edit JWH 018 CP 47 497 and its homologues and HU 210 were all made illegal in France on February 24 2009 125 Ireland edit From June 2010 JWH 018 along with a variety of other designer drugs has been illegal 126 Latvia edit nbsp A store selling synthetic cannabinoids in Riga in 2012JWH 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 127 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 128 Poland edit 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 129 130 and Polish Senat 131 and was signed by the President 132 Romania edit Spice was made illegal in Romania on February 15 2010 As on 12 September 2018 Spice was made legal for personal use 133 A new law is being discussed to make spice illegal for personal use again 134 135 Russia edit 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 Yucatan 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 136 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 137 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 103 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 Slovakia edit 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 edit 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 edit 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 edit Spice has been banned in Switzerland 143 Turkey edit 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 edit 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 edit Canada edit 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 edit See also JWH 018 United StatesThe 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 156 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 157 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 158 159 160 161 The Drug Enforcement Administration DEA considered K2 to be a drug of concern 162 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 163 164 Several states independently passed acts making it illegal under state law including Kansas in March 2010 165 Georgia and Alabama in May 2010 166 167 Tennessee and Missouri in July 2010 168 169 Louisiana in August 2010 citation needed Mississippi in September 2010 citation needed and Iowa 170 An emergency order was passed in Arkansas in July 2010 banning the sale of synthetic cannabis mimics 171 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 172 According to the National Conference of State Legislatures several other states also considered legislation including New Jersey New York Florida and Ohio 169 Illinois passed a law on July 27 2010 banning all synthetic cannabinoids as of January 1 2011 173 Michigan banned synthetic cannabinoids in October 2010 174 and the South Dakota Legislature passed a ban on these products which was signed into law by Gov Dennis Daugaard on February 23 2012 and which took immediate effect under an emergency clause of the state constitution 175 Indiana banned synthetic cannabinoids in a law which became effective in March 2012 176 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 177 178 Following cases in Japan involving the use of synthetic cannabinoids by navy army and marine corps personnel they were officially banned 179 A punitive general order issued on January 4 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 180 On June 8 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 181 Usage among 8th 10th and 12th graders has been decreasing since 2011 while use of botanical marijuana has remained stable 182 There are important regional differences with large declines in the Western and Southern US and increases in the Northeast and Midwest 183 South America edit Chile edit The Chilean Ministry of Health on April 24 2009 declared the sale of synthetic cannabis mimics to be illegal 184 Asia edit South Korea edit South Korea officially added JWH 018 CP 47 497 and HU 210 to the controlled substance list on July 1 2009 effectively making these chemicals illegal 185 Indonesia edit Tembakau Gorilla Gorilla Tobacco a catch all term for synthetic cannabinoids blended in tobacco products were listed as Class I Narcotics with no therapeutic use in 2017 186 187 Japan edit Japan has banned JWH 018 CP 47 497 and homologues and HU 210 since October 2009 citation needed United Arab Emirates edit The United Arab Emirates had stated that Spice is an illegal substance and possession or intent to sell is a jailable offense 188 Australasia edit Australia edit On June 17 2011 the Western Australian government banned all of the synthetic cannabinoids found in already existing products including brands such as Kronic Kalma Voodoo Kaos and Mango Kush Western Australia was the first state in Australia to prohibit the sale of certain synthetic cannabinoids 189 190 On June 18 2013 an interim ban made a large list of product brands and synthetic substances illegal to sell anywhere in Australia 191 This ban lapsed on October 13 2013 and a permanent ban has not been imposed 192 Synthetic cannabinoids and related products remain illegal in NSW where a bill was passed on September 18 2013 that bans entire families of synthetic drugs instead of only banning existing compounds that have been identified 193 194 The introduction of this law makes NSW the first state in Australia to completely ban substances with psychoactive properties 194 New Zealand edit Synthetic Cannabinoids are illegal in New Zealand it is classified as a Class A controlled drug 195 The New Zealand Parliament passed a law in July 2013 banning the sale of legal highs in dairies and supermarkets but allowing some low risk drugs to continue to be sold through speciality licensed shops 196 Synthetic cannabinoids as well as all other legal highs were outlawed at midnight on 7 May 2014 after a law was passed a week prior by the New Zealand government 197 An analysis of 41 different synthetic cannabis mimic blends sold commercially in New Zealand conducted by the Institute of Environmental Science and Research and released in July 2011 found 11 different synthetic cannabinoid ingredients used including JWH 018 JWH 073 AM 694 AM 2201 RCS 4 RCS 4 butyl homologue JWH 210 JWH 081 JWH 250 or possibly JWH 302 isomer not determined JWH 203 and JWH 122 with between one and five different active ingredients though JWH 018 was present in 37 of the 41 blends tested In two brands the benzodiazepine anxiolytic drug phenazepam was also found which is classified as a prescription medicine in New Zealand and these brands were ordered to be removed from the market by emergency recall 198 199 Since this time a further 15 cannabinoid compounds have been detected as ingredients of synthetic cannabis mimicking blends in New Zealand and banned as temporary class drugs 200 In 2013 another hypnotic medication zaleplon was found to have been used as an active ingredient in a blend that had been sold in New Zealand during 2011 and 2012 201 See also editList of designer drugs Synthetic cannabinoids Endocannabinoid enhancer Endocannabinoid system Structural scheduling of synthetic cannabinoidsReferences edit UNODC Laboratory amp Scientific Service Details for Synthetic cannabinoids United Nations Office on Drugs and Crime Retrieved 2021 10 17 Mechoulam R Lander N Breuer A Zahalka J 1990 Synthesis of the individual pharmacologically distinct enantiomers of a tetrahydrocannabinol derivative Tetrahedron Asymmetry 1 5 315 318 doi 10 1016 S0957 4166 00 86322 3 Seely Kathryn A Lapoint Jeff Moran Jeffery H Fattore Liana 2012 12 03 Spice drugs are more than harmless herbal blends a review of the pharmacology and toxicology of synthetic cannabinoids Progress in Neuro Psychopharmacology amp Biological Psychiatry 39 2 234 243 doi 10 1016 j pnpbp 2012 04 017 ISSN 1878 4216 PMC 3936256 PMID 22561602 Riboulet Zemouli Kenzi 2020 Cannabis ontologies I Conceptual issues with Cannabis and cannabinoids terminology Drug Science Policy and Law 6 12 19 doi 10 1177 2050324520945797 ISSN 2050 3245 S2CID 234435350 a b c Macher R Burke TW Owen SS 2012 05 01 Synthetic Marijuana FBI Law Enforcement Bulletin Retrieved 2020 03 19 a b c d Science Live 2017 02 07 Synthetic Marijuana Linked To Seizures Psychosis And Death Huffington Post Retrieved 2018 05 04 a b c Diao X Huestis MA February 2017 Approaches Challenges and Advances in Metabolism of New Synthetic Cannabinoids and Identification of Optimal Urinary Marker Metabolites Clinical Pharmacology and Therapeutics 101 2 239 253 doi 10 1002 cpt 534 PMID 27727455 S2CID 10910467 a b c d e f g h i j k l m n o p q Banister SD Stuart J Kevin RC Edington A Longworth M Wilkinson SM et al August 2015 Effects of bioisosteric fluorine in synthetic cannabinoid designer drugs JWH 018 AM 2201 UR 144 XLR 11 PB 22 5F PB 22 APICA and STS 135 ACS Chemical Neuroscience 6 8 1445 58 doi 10 1021 acschemneuro 5b00107 PMID 25921407 Cannaert A Storme J Franz F Auwarter V Stove CP December 2016 Detection and Activity Profiling of Synthetic Cannabinoids and Their Metabolites with a Newly Developed Bioassay Analytical Chemistry 88 23 11476 11485 doi 10 1021 acs analchem 6b02600 PMID 27779402 Rapaka RS Makriyannis A eds 1987 Structure Activity Relationships of the Cannabinoids PDF NIDA Research Monograph 79 via U S Department of Health and Human Services K2 Scary Drug or Another Drug Scare Newsweek 2010 03 03 Retrieved 2018 05 04 a b c d Abouchedid R Ho JH Hudson S Dines A Archer JR Wood DM Dargan PI December 2016 Acute Toxicity Associated with Use of 5F Derivations of Synthetic Cannabinoid Receptor Agonists with Analytical Confirmation Journal of Medical Toxicology 12 4 396 401 doi 10 1007 s13181 016 0571 7 PMC 5135680 PMID 27456262 Notes from the Field Increase in Reported Adverse Health Effects Related to Synthetic Cannabinoid Use United States January May 2015 www cdc gov June 12 2015 Retrieved 2018 11 01 a b Frequently Asked Questions Marijuana CDC www cdc gov 2018 03 16 Retrieved 2018 05 04 10 How harmful is K2 Spice synthetic marijuana or synthetic cannabinoids a b Statement from FDA warning about significant health risks of contaminated illegal synthetic cannabinoid products that are being encountered by FDA Press release United States Food and Drug Administration July 19 2018 Angerer V Moosman B Franz F Auwarter V 2015 5F cumyl PINACA in e liquids for electronic cigarettes A new type of synthetic cannabinoid in a trendy product PDF Retrieved 14 June 2018 McLennan William 22 September 2018 Vapers tricked into buying synthetic cannabis laced product The Observer Health warning issued over fake THC vape that contains spice www christie nhs uk Eight pupils collapse after vaping Spice missold as THC vape Metro 17 December 2019 Day Rebecca 16 July 2019 Schoolchildren have collapsed after vaping Spice men Schoolchildren collapse after unknowingly inhaling spice vape The Independent 16 July 2019 Archived from the original on 2022 05 26 Tahsin Jamie 10 December 2019 If You Buy Weed Vapes in the UK Beware But Not for the Reason You Think Vice Health warning as nine young people collapse after using spice vape ITV News Health warning as nine youths collapse after using spice vape www lep co uk Health warning as nine youths collapse after using Spice vape www thestar co uk Cannabis 3 8 3 Vervuiling van cannabis Nationale Drug Monitor in Dutch 27 October 2020 Fake Hanf Ein Drogentrend schwappt in die Schweiz was du daruber wissen musst watson ch in German Fake Hanf Todliches Marihuana hat bereits 61 Menschen getotet watson ch in German Fake Hanf mit synthetischen Cannabinoiden bespruht drugcom www drugcom de Todlicher Fake Hanf Chemisch behandelte Hanfbluten niemand kann sie erkennen Schweizer Radio und Fernsehen SRF in German 14 August 2020 Harris Jenese 22 September 2020 Calls about poisonings from fake marijuana edibles candy triple WJXT EcstasyData org DrugsData org Erowid DrugsData org formerly EcstasyData Test Details Result 6905 Synthetisches Haschisch 6905 www drugsdata org EcstasyData org DrugsData org Erowid DrugsData org formerly EcstasyData Test Details Result 8111 Haschish 8111 www drugsdata org EcstasyData org DrugsData org Erowid DrugsData org formerly EcstasyData Test Details Result 8255 Fake Hash 8255 www drugsdata org EcstasyData org DrugsData org Erowid DrugsData org formerly EcstasyData Test Details Result 8672 Adulterated Hash 8672 www drugsdata org How the Associated Press collected information on CBD vapes AP NEWS 16 September 2019 Spaderna M Addy PH D Souza DC August 2013 Spicing things up Synthetic cannabinoids Psychopharmacology 228 4 525 40 doi 10 1007 s00213 013 3188 4 PMC 3799955 PMID 23836028 a b c d e Fattore L Fratta W 2011 09 21 Beyond THC The New Generation of Cannabinoid Designer Drugs Frontiers in Behavioral Neuroscience 5 60 doi 10 3389 fnbeh 2011 00060 PMC 3187647 PMID 22007163 Uchiyama N Matsuda S Kawamura M Kikura Hanajiri R Goda Y 2013 07 01 Two new type cannabimimetic quinolinyl carboxylates QUPIC and QUCHIC two new cannabimimetic carboxamide derivatives ADB FUBINACA and ADBICA and five synthetic cannabinoids detected with a thiophene derivative a PVT and an opioid receptor agonist AH 7921 identified in illegal products Forensic Toxicology 31 2 223 240 doi 10 1007 s11419 013 0182 9 ISSN 1860 8965 S2CID 1279637 Zolot J March 2019 Life Threatening Bleeding and Deaths from Synthetic Cannabinoids The American Journal of Nursing 119 3 15 doi 10 1097 01 NAJ 0000554023 28593 fd PMID 30801303 Fattore Liana Fratta Walter 21 September 2011 Beyond THC The New Generation of Cannabinoid Designer Drugs Frontiers in Behavioral Neuroscience 5 60 doi 10 3389 fnbeh 2011 00060 PMC 3187647 PMID 22007163 Uchiyama Nahoko Kikura Hanajiri Ruri Ogata Jun Goda Yukihiro May 2010 Chemical analysis of synthetic cannabinoids as designer drugs in herbal products Forensic Science International 198 1 3 31 38 doi 10 1016 j forsciint 2010 01 004 PMID 20117892 Kikura Hanajiri R Uchiyama N Goda Y May 2011 Survey of current trends in the abuse of psychotropic substances and plants in Japan Legal Medicine 13 3 109 15 doi 10 1016 j legalmed 2011 02 003 PMID 21377397 Uchiyama N Kawamura M Kikura Hanajiri R Goda Y April 2013 URB 754 a new class of designer drug and 12 synthetic cannabinoids detected in illegal products Forensic Science International 227 1 3 21 32 doi 10 1016 j forsciint 2012 08 047 PMID 23063179 European Monitoring Centre for Drugs Drug Addiction 2009 Understanding the Spice phenomenon PDF European Monitoring Centre for Drugs and Drug Addiction doi 10 2810 27063 ISBN 9789291684113 ISSN 1725 5767 Retrieved 2 October 2021 Synthetic cannabinoids in Europe www emcdda europa eu www emcdda europa eu Retrieved 2018 05 04 New York Bans Synthetic Marijuana NPR org Retrieved 2018 05 04 Synthetic Cannabinoids The Newest Almost Illicit Drug of Abuse www mdedge com Retrieved 2018 05 04 Support Spice Addiction 1 March 2017 700 Street Names for Synthetic Marijuana Spice K2 etc Spice Addiction Support a b c d European Monitoring Centre for Drugs and Drug Addiction 2009 Understanding the Spice Phenomenon PDF EMCDDA 2009 Thematic Paper Cesarone Travis 2021 06 30 One dollar THC threatens the future of the cannabis farmer here s why Latest Cannabis News Today Headlines Videos amp Stocks Retrieved 2021 10 17 a b Riboulet Zemouli Kenzi 2020 Cannabis ontologies I Conceptual issues with Cannabis and cannabinoids terminology Drug Science Policy and Law 6 25 29 doi 10 1177 2050324520945797 ISSN 2050 3245 S2CID 234435350 Pertwee RG January 2006 Cannabinoid pharmacology the first 66 years British Journal of Pharmacology 147 Suppl 1 S1 S163 71 doi 10 1038 sj bjp 0706406 PMC 1760722 PMID 16402100 Crowther SM Reynolds LA Tansey EM eds 2010 The Medicalization of Cannabis PDF Wellcome Witnesses to Twentieth Century Medicine 40 via Wellcome Trust Centre for the History of Medicine at UCL Law R Schier J Martin C Chang A Wolkin A June 2015 Notes from the Field Increase in Reported Adverse Health Effects Related to Synthetic Cannabinoid Use United States January May 2015 MMWR Morbidity and Mortality Weekly Report 64 22 618 9 PMC 4584925 PMID 26068566 Khullar V Jain A Sattari M August 2014 Emergence of new classes of recreational drugs synthetic cannabinoids and cathinones Journal of General Internal Medicine 29 8 1200 4 doi 10 1007 s11606 014 2802 4 PMC 4099455 PMID 24553958 Buser GL Gerona RR Horowitz BZ Vian KP Troxell ML Hendrickson RG et al August 2014 Acute kidney injury associated with smoking synthetic cannabinoid Clinical Toxicology 52 7 664 73 doi 10 3109 15563650 2014 932365 PMID 25089722 S2CID 5175567 Hermanns Clausen M Kneisel S Szabo B Auwarter V March 2013 Acute toxicity due to the confirmed consumption of synthetic cannabinoids clinical and laboratory findings Addiction 108 3 534 44 doi 10 1111 j 1360 0443 2012 04078 x PMID 22971158 Young AC Schwarz E Medina G Obafemi A Feng SY Kane C Kleinschmidt K September 2012 Cardiotoxicity associated with the synthetic cannabinoid K9 with laboratory confirmation The American Journal of Emergency Medicine 30 7 1320 e5 7 doi 10 1016 j ajem 2011 05 013 PMID 21802885 a b c Fattore L April 2016 Synthetic Cannabinoids Further Evidence Supporting the Relationship Between Cannabinoids and Psychosis Biological Psychiatry 79 7 539 48 doi 10 1016 j biopsych 2016 02 001 PMID 26970364 S2CID 36165555 Freeman MJ Rose DZ Myers MA Gooch CL Bozeman AC Burgin WS December 2013 Ischemic stroke after use of the synthetic marijuana spice Neurology 81 24 2090 3 doi 10 1212 01 wnl 0000437297 05570 a2 PMC 3863350 PMID 24212384 Drug Fact Sheet Marijuana PDF Drug Enforcement Administration Synthetic Marijuana Deaths Tripled This Year Newsweek 2015 06 11 Retrieved 2018 05 05 Huge jump in synthetic cannabis deaths coroner 2018 07 27 Retrieved 2020 05 30 Giorgetti A Busardo FP Tittarelli R Auwarter V Giorgetti R 2020 05 25 Post Mortem Toxicology A Systematic Review of Death Cases Involving Synthetic Cannabinoid Receptor Agonists Frontiers in Psychiatry 11 464 doi 10 3389 fpsyt 2020 00464 PMC 7261860 PMID 32523555 Fantegrossi WE Moran JH Radominska Pandya A Prather PL February 2014 Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to D 9 THC mechanism underlying greater toxicity Life Sciences 97 1 45 54 doi 10 1016 j lfs 2013 09 017 PMC 3945037 PMID 24084047 Fisar Z June 2010 Inhibition of monoamine oxidase activity by cannabinoids Naunyn Schmiedeberg s Archives of Pharmacology 381 6 563 72 doi 10 1007 s00210 010 0517 6 PMID 20401651 S2CID 8198770 Zavitsanou K Wang H Dalton VS Nguyen V August 2010 Cannabinoid administration increases 5HT1A receptor binding and mRNA expression in the hippocampus of adult but not adolescent rats Neuroscience 169 1 315 24 doi 10 1016 j neuroscience 2010 04 005 PMID 20438810 S2CID 44510611 Yano H Adhikari P Naing S Hoffman AF Baumann MH Lupica CR Shi L May 2020 1A Receptor by Indole Based Synthetic Cannabinoids Abused by Humans ACS Chemical Neuroscience 11 10 1400 1405 doi 10 1021 acschemneuro 0c00034 PMC 8275447 PMID 32324370 a b Le Boisselier R Alexandre J Lelong Boulouard V Debruyne D February 2017 Focus on cannabinoids and synthetic cannabinoids Clinical Pharmacology and Therapeutics 101 2 220 229 doi 10 1002 cpt 563 PMID 27861784 S2CID 42697638 Brents LK Gallus Zawada A Radominska Pandya A Vasiljevik T Prisinzano TE Fantegrossi WE et al April 2012 Monohydroxylated metabolites of the K2 synthetic cannabinoid JWH 073 retain intermediate to high cannabinoid 1 receptor CB1R affinity and exhibit neutral antagonist to partial agonist activity Biochemical Pharmacology 83 7 952 61 doi 10 1016 j bcp 2012 01 004 PMC 3288656 PMID 22266354 Fake pot that acts real stymies law enforcement msnbc com 2010 02 17 Retrieved 2018 05 05 Riederer AM Campleman SL Carlson RG Boyer EW Manini AF Wax PM Brent JA July 2016 Acute Poisonings from Synthetic Cannabinoids 50 U S Toxicology Investigators Consortium Registry Sites 2010 2015 MMWR Morbidity and Mortality Weekly Report 65 27 692 5 doi 10 15585 mmwr mm6527a2 PMC 4972329 PMID 27413997 Behonick G Shanks KG Firchau DJ Mathur G Lynch CF Nashelsky M et al October 2014 Four postmortem case reports with quantitative detection of the synthetic cannabinoid 5F PB 22 Journal of Analytical Toxicology 38 8 559 62 doi 10 1093 jat bku048 PMC 4334789 PMID 24876364 Malheiro Rui F Gomes Telma M Carmo Helena Carvalho Felix Silva Joao P 2021 Cannabinoids and psychosis current challenges of mechanistic toxicology Toxicological Risk Assessment and Multi System Health Impacts from Exposure Elsevier pp 601 615 doi 10 1016 b978 0 323 85215 9 00020 9 ISBN 9780323852159 S2CID 238921214 retrieved 2021 09 07 Shalit N Barzilay R Shoval G Shlosberg D Mor N Zweigenhaft N et al August 2016 Characteristics of Synthetic Cannabinoid and Cannabis Users Admitted to a Psychiatric Hospital A Comparative Study The Journal of Clinical Psychiatry 77 8 e989 95 doi 10 4088 jcp 15m09938 PMID 27379411 Hurst D Loeffler G McLay R October 2011 Psychosis associated with synthetic cannabinoid agonists a case series The American Journal of Psychiatry 168 10 1119 doi 10 1176 appi ajp 2011 11010176 PMID 21969050 Pierre JM September 2011 Cannabis synthetic cannabinoids and psychosis risk What the evidence says PDF Current Psychiatry 10 Every Palmer S September 2011 Synthetic cannabinoid JWH 018 and psychosis an explorative study Drug and Alcohol Dependence 117 2 3 152 7 doi 10 1016 j drugalcdep 2011 01 012 PMID 21316162 Muller H Sperling W Kohrmann M Huttner HB Kornhuber J Maler JM May 2010 The synthetic cannabinoid Spice as a trigger for an acute exacerbation of cannabis induced recurrent psychotic episodes Schizophrenia Research 118 1 3 309 10 doi 10 1016 j schres 2009 12 001 PMID 20056392 S2CID 205066297 a b Wohlfarth A Gandhi AS Pang S Zhu M Scheidweiler KB Huestis MA February 2014 Metabolism of synthetic cannabinoids PB 22 and its 5 fluoro analog 5F PB 22 by human hepatocyte incubation and high resolution mass spectrometry Analytical and Bioanalytical Chemistry 406 6 1763 80 doi 10 1007 s00216 014 7668 0 PMID 24518903 S2CID 32240644 a b c d Synthetic Cannabinoids in Herbal Products PDF United Nations Office on Drugs and Crime a b c d Details for Synthetic cannabinoids www unodc org Retrieved 2018 05 04 a b Synthetic Cannabinoids AACC org www aacc org Retrieved 2018 05 04 Cannabinoids Abood Mary Ellen 1958 Pertwee R G Roger G Berlin Springer 2005 ISBN 978 3540225652 OCLC 65169431 a href Template Cite book html title Template Cite book cite book a CS1 maint others link a b Gurney SM Scott KS Kacinko SL Presley BC Logan BK January 2014 Pharmacology Toxicology and Adverse Effects of Synthetic Cannabinoid Drugs PDF Forensic Science Review 26 1 53 78 PMID 26226970 a b Banister SD Moir M Stuart J Kevin RC Wood KE Longworth M et al September 2015 Pharmacology of Indole and Indazole Synthetic Cannabinoid Designer Drugs AB FUBINACA ADB FUBINACA AB PINACA ADB PINACA 5F AB PINACA 5F ADB PINACA ADBICA and 5F ADBICA ACS Chemical Neuroscience 6 9 1546 59 doi 10 1021 acschemneuro 5b00112 PMID 26134475 Uchiyama N Matsuda S Wakana D Kikura Hanajiri R Goda Y 2013 01 01 New cannabimimetic indazole derivatives N 1 amino 3 methyl 1 oxobutan 2 yl 1 pentyl 1H indazole 3 carboxamide AB PINACA and N 1 amino 3 methyl 1 oxobutan 2 yl 1 4 fluorobenzyl 1H indazole 3 carboxamide AB FUBINACA identified as designer drugs in illegal products Forensic Toxicology 31 1 93 100 doi 10 1007 s11419 012 0171 4 ISSN 1860 8965 S2CID 25242453 a b Hess C Schoeder CT Pillaiyar T Madea B Muller CE 2016 07 01 Pharmacological evaluation of synthetic cannabinoids identified as constituents of spice Forensic Toxicology 34 2 329 343 doi 10 1007 s11419 016 0320 2 PMC 4929166 PMID 27429655 Howlett AC Champion TM Wilken GH Mechoulam R February 1990 Stereochemical effects of 11 OH delta 8 tetrahydrocannabinol dimethylheptyl to inhibit adenylate cyclase and bind to the cannabinoid receptor Neuropharmacology 29 2 161 5 doi 10 1016 0028 3908 90 90056 W PMID 2158635 S2CID 28602221 Shohami E Mechoulam R 2000 07 01 Dexanabinol HU 211 A nonpsychotropic cannabinoid with neuroprotective properties Drug Development Research 50 3 4 211 215 doi 10 1002 1098 2299 200007 08 50 3 4 lt 211 aid ddr3 gt 3 0 co 2 g ISSN 1098 2299 S2CID 73340207 Zimmermann US Winkelmann PR Pilhatsch M Nees JA Spanagel R Schulz K July 2009 Withdrawal phenomena and dependence syndrome after the consumption of spice gold Deutsches Arzteblatt International in German 106 27 464 7 doi 10 3238 arztebl 2009 0464 PMC 2719097 PMID 19652769 Auwarter V Dresen S Weinmann W Muller M Putz M Ferreiros N May 2009 Spice and other herbal blends harmless incense or cannabinoid designer drugs Journal of Mass Spectrometry 44 5 832 7 Bibcode 2009JMSp 44 832A doi 10 1002 jms 1558 PMID 19189348 Milone MC 2012 Analytical Techniques used in Therapeutic Drug Monitoring Therapeutic Drug Monitoring Elsevier pp 49 73 doi 10 1016 b978 0 12 385467 4 00003 8 ISBN 9780123854674 a b Znaleziona J Ginterova P Petr J Ondra P Valka I Sevcik J et al May 2015 Determination and identification of synthetic cannabinoids and their metabolites in different matrices by modern analytical techniques a review Analytica Chimica Acta 874 11 25 doi 10 1016 j aca 2014 12 055 PMID 25910441 Spinelli E Barnes AJ Young S Castaneto MS Martin TM Klette KL Huestis MA June 2015 Performance characteristics of an ELISA screening assay for urinary synthetic cannabinoids Drug Testing and Analysis 7 6 467 74 doi 10 1002 dta 1702 PMID 25167963 Sobolevsky T Prasolov I Rodchenkov G July 2010 Detection of JWH 018 metabolites in smoking mixture post administration urine Forensic Science International 200 1 3 141 7 doi 10 1016 j forsciint 2010 04 003 PMID 20430547 Huppertz LM Kneisel S Auwarter V Kempf J February 2014 A comprehensive library based automated screening procedure for 46 synthetic cannabinoids in serum employing liquid chromatography quadrupole ion trap mass spectrometry with high temperature electrospray ionization Journal of Mass Spectrometry 49 2 117 27 Bibcode 2014JMSp 49 117H doi 10 1002 jms 3328 PMID 24677304 Scheidweiler KB Jarvis MJ Huestis MA January 2015 Nontargeted SWATH acquisition for identifying 47 synthetic cannabinoid metabolites in human urine by liquid chromatography high resolution tandem mass spectrometry Analytical and Bioanalytical Chemistry 407 3 883 97 doi 10 1007 s00216 014 8118 8 PMID 25224637 S2CID 45574713 Baselt RC 2014 Disposition of toxic drugs and chemicals in man Tenth ed Seal Beach California Biomedical Publications ISBN 9780962652394 OCLC 883367655 New Zealand City Has 10 Synthetic Cannabis Overdoses in 48 Hours High Times 2018 09 21 Retrieved 2018 09 25 Schlabach M October 20 2011 Sources LSU players had positive tests ESPN com Retrieved November 4 2011 a b FSKN ot otravleniya spajsami v rossijskih regionah pogibli bolee 40 chelovek FSKN more than 40 people died from spice poisoning in Russian regions TASS 29 October 2014 Retrieved 13 December 2014 a b Adams AJ Banister SD Irizarry L Trecki J Schwartz M Gerona R January 2017 Zombie Outbreak Caused by the Synthetic Cannabinoid AMB FUBINACA in New York The New England Journal of Medicine 376 3 235 242 doi 10 1056 nejmoa1610300 PMID 27973993 Santora Marc 14 December 2016 Drug 85 Times as Potent as Marijuana Caused a Zombielike State in Brooklyn The New York Times Retrieved 2018 09 25 Wisconsinites are smoking rat poison How did we get here Milwaukee Journal Sentinel Retrieved 2018 09 25 Outbreak Alert Potential Life Threatening Vitamin K Dependent Antagonist Coagulopathy Associated With Synthetic Cannabinoids Use Centers for Disease Control and Prevention CDC Retrieved 2018 05 04 Synthetic Cannabinoids IDPH www dph illinois gov Retrieved 2018 05 04 More Cases of Severe Bleeding in Wisconsin Linked to Synthetic Cannabinoids Wisconsin Department of Health Services 2018 09 18 Retrieved 2018 09 25 Bad Batch Of K2 Is Suspected In Dozens Of Overdoses In Connecticut NPR org Retrieved 2018 08 28 Whelan A Two dead dozens sickened from weekend overdoses in Philly www2 philly com Retrieved 2018 09 25 Synthetic marijuana detected in drug sample from Philly overdose spike Health WHYY WHYY Retrieved 2018 09 25 DOH Investigating Synthetic Marijuana Illnesses Florida Department of Health in Hillsborough Authorities say batch of spice laced with rat poison circulating in Hillsborough County 41 hospitalized and 2 dead after using spice in Hillsborough County poison center says 13 December 2021 2 dead 41 hospitalized in Hillsborough from poisonous batch of Spice Family mourns former JROTC member who died after using poisoned spice 15 December 2021 Project CBD Releases Special Report on Vaping Related Lung Injuries Project CBD www projectcbd org Krautermischung Spice Gesundheitsministerium stoppt Handel December 18 2008 Herbal Blend Spice Ministry of Health Stops Trading December 18 2008 Derstandard at December 19 2008 Retrieved June 19 2010 AFP December 18 2008 Austria bans herbal incense Spice Archived from the original on March 10 2010 Retrieved June 19 2010 Gesundheitsministerium setzt Massnahme zum Verbot von Spice Ministry of Health takes action to ban Spice Bmgfj gv at December 18 2008 Archived from the original on November 21 2009 Retrieved June 19 2010 BGBl I Nr 3 vom January 21 2009 22 BtMAndV vom 19 Jan 2009 S 49 50 BGBl I No 3 of January 21 2009 22nd BtMAndV of January 19 2009 pp 49 50 PDF in German Archived from the original PDF on 2009 02 05 Betaubungsmittelrecht Modedroge Spice wird per Eilverordnung verboten Narcotics law the fashion drug Spice is banned by an emergency ordinance Spiegel Online 2009 01 21 Retrieved June 19 2010 Neue psychoaktive Stoffe Gesetz NpSG tritt in Kraft New Psychoactive Substances Act NpSG comes into force Bundesgesundheitsministerium Retrieved 29 October 2017 Arrete du 24 fevrier 2009 modifiant l arrete du 22 fevrier 1990 fixant la liste des substances classees comme stupefiants Decree of February 24 2009 amending the Decree of February 22 1990 establishing the list of substances classified as narcotic drugs Journal Officiel De La Republique Francaise February 27 2009 Retrieved June 19 2010 Move on head shops not enough The Irish Times March 3 2010 Retrieved August 24 2010 Regulations Regarding Narcotic Substances Psychotropic Substances and Precursors to be Controlled in Latvia likumi lv Retrieved June 19 2010 Saeima steidzami nosaka kriminalatbildibu par spaisa paveidu tirgosanas aizlieguma parkapumu The Saeima urgently establishes criminal liability for violation of the ban on the sale of spais in Latvian Diena lv Retrieved November 12 2014 Archived copy Archived from the original on 2009 03 25 Retrieved 2009 04 06 a href Template Cite web html title Template Cite web cite web a CS1 maint archived copy as title link mm PAP February 12 2009 Sejm za delegalizacja dopalaczy Sejm to ban legal highs Wiadomosci gazeta pl Retrieved June 19 2010 Senat poparl ustawe zakazujaca handlu dopalaczami Wiadomosci WP PL The Senate backed the bill banning the trade in legal highs Wiadomosci Wiadomosci wp pl Retrieved June 19 2010 Oficjalna strona Prezydenta Rzeczypospolitej Polskiej The official website of the President of the Republic of Poland Archived from the original on July 31 2009 Retrieved February 20 2015 OUG 6 2010 pentru modificarea si completarea Legii nr 143 2000 privind prevenirea si combaterea traficului si consumului ilicit de droguri si pentru completarea Legii nr 339 2005 privind regimul juridic al plantelor substantelor si preparatelor stupefiante si psihotrope Ordonanta de urgenta nr 6 2010 GEO 6 2010 for the amendment and completion of Law no 143 2000 on preventing and combating illicit drug trafficking and consumption and for completing Law no 339 2005 regarding the legal regime of narcotic and psychotropic plants substances and preparations Emergency Ordinance no 6 2010 Dreptonline ro August 3 2000 Retrieved June 19 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exposure from January 2016 to September 2019 in the United States Drug and Alcohol Dependence 207 107810 doi 10 1016 j drugalcdep 2019 107810 PMC 9590641 PMID 31862557 S2CID 209433979 Chile prohibe uso de Spice La Nacion 24 de Abril 2009 Chile prohibits the use of Spice La Nacion April 24 2009 Lanacion cl Retrieved June 19 2010 최연희 July 2 2009 1일부터 5 메오 밉트 등 향정신성의약품 지정 Designated as a psychotropic drug such as 5 Meo Mip from Japan in Korean 헬스코리아뉴스 Health Korea News Retrieved February 18 2010 Kompasiana com 2017 01 23 Tembakau Gorilla Dinyatakan sebagai Narkotika Golongan 1 Gorilla Tobacco Declared Narcotics Category 1 KOMPASIANA in Indonesian Retrieved 2020 07 02 Liputan6 com 2017 01 12 Tembakau Gorila Masuk Narkotika Golongan I Gorilla Tobacco Enters Class I Narcotics liputan6 com in Indonesian Retrieved 2020 07 02 a href Template Cite web html title Template Cite web cite web a CS1 maint numeric names authors list link Dubai Customs foil 126 attempts to smuggle narcotic Gulfnews com Retrieved February 20 2015 Jerga J June 13 2011 Fake cannabis to be outlawed in WA The Sydney Morning Herald Retrieved June 15 2011 O Brien A April 11 2011 Miners working high on synthetic grass The Australian Retrieved April 17 2011 Bradbury D June 18 2013 Competition and Consumer Act 2010 Consumer Protection Notice No 3 of 2013 Imposition of Interim Ban on Certain Consumer Goods Containing Synthetic Drug Substances Retrieved October 28 2013 Synthetic drug substances national interim ban ACCC Retrieved October 28 2013 NSW law to ban synthetic drugs passed September 18 2013 Retrieved October 28 2013 a b Coultan M September 10 2013 NSW law to ban synthetic drugs to stop legal highs The Australian Retrieved October 28 2013 Misuse of Drugs Act 1975 New Zealand Legislation Website December 7 2021 Retrieved May 29 2022 Heather B October 6 2013 Kronic king gets the green light Retrieved October 28 2013 Ryan S May 7 2014 Legal highs banned from midnight NZ Herald Retrieved May 8 2014 Whitworth Chris July 7 2011 Kronic ingredients secret to stop industry cowboys 3 News Retrieved November 16 2011 Herbal High synthetic Cannabinoid composition released by ESR July 2011 PDF Retrieved on August 7 2011 Temporary Class Drug Notices Ministry of Health NZ Retrieved February 20 2015 Conviction for sale of herbal smoking material containing a prescription medicine Ministry of Health NZ Retrieved February 20 2015 Further reading editRoque Bravo Rita Silva Rafaela Sofia Malheiro Rui F Carmo Helena Carvalho Felix da Silva Diana Dias Silva Joao Pedro 2023 01 20 Synthetic Cannabinoids A Pharmacological and Toxicological Overview Annual Review of Pharmacology and Toxicology 63 1 187 209 doi 10 1146 annurev pharmtox 031122 113758 ISSN 0362 1642 PMID 35914767 S2CID 251255354 External links editErowid Synthetic cannabinoid profile at the European Monitoring Centre for Drugs and Drug Addiction Interactive model to help understand the structures of synthetic cannabinoids Retrieved from https en wikipedia org w index php title Synthetic cannabinoids amp oldid 1186078462, wikipedia, wiki, book, books, library,

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