Synthetic cannabis

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A bag of Spice brand herbal incense

Commercially known as Synthetic cannabis (synthetic marijuana), or technically cannabinoid research chemicals, is any designer drug that mimics the effects of cannabis.[1] There are several psychoactive artificial cannabinoid families (eg AM-xxx, HU-xxx, JWH-xxx, CP xx) that are used as designer drugs sprayed on herbs and sold as natural highs under brand names like K2[2] and Spice,[3] both of which are genericized trademarks used for any synthetic cannabis product. Synthetic cannabis is often termed spice product.

When synthetic cannabis blends first went on sale in the early 2000s, it was thought that they achieved an effect through a mixture of natural herbs. Laboratory analysis in 2008 showed that this is not the case, and that they in fact contain synthetic cannabinoids that act on the body in a similar way to cannabinoids naturally found in cannabis, such as THC. A large and complex variety of synthetic cannabinoids, most often cannabicyclohexanol, JWH-018, JWH-073, or HU-210, are used in an attempt to avoid the laws that make cannabis illegal, making synthetic cannabis a designer drug. It has been sold under various brand names, online, in head shops, and at some gas stations.

It is often marketed as "herbal incense"; however, some brands market their products as "herbal smoking blends". In either case, the products are usually smoked by users. Although synthetic cannabis does not produce positive results in drug tests for cannabis, it is possible to detect its metabolites in human urine. The synthetic cannabinoids contained in synthetic cannabis products have been made illegal in many European countries. On November 24, 2010, the US Drug Enforcement Administration announced it would use emergency powers to ban many synthetic cannabinoids within a month.[4] Prior to the announcement, several US states had already made them illegal under state law. In the US, as of March 1, 2011, five cannabinoids, JWH-018, JWH-073, CP-47,497, JWH-200, and cannabicyclohexanol have been placed on Schedule I of the Controlled Substances Act (and are therefore illegal to possess or use in the US); the Drug Enforcement Administration claims that said action is "to avoid an imminent hazard to the public safety."[5][6] In July 2012, the Synthetic Drug Abuse Prevention Act of 2012 was signed into law. It banned synthetic compounds commonly found in synthetic cannabis, placing them under Schedule I of the Controlled Substances Act.[7]

Misnomer

There is controversy about calling Spice and K2 synthetic cannabis. Synthetic marijuana is a misnomer according to Lewis Nelson, MD, a medical toxicologist at the NYU School of Medicine. "It's really quite different, and the effects are much more unpredictable. It's dangerous, and there is no quality control in what you are getting."[8] Since the term synthetic does not apply to the plant but rather to the chemical that the plant contains (tetrahydrocannabinol), the term synthetic cannabinoid is more appropriate.[9] Research on the safety of synthetic cannabinoids is now becoming available. Initial studies are focused on the role of synthetic cannabinoids in psychosis. Synthetic cannabis may precipitate psychosis and in some cases it may be prolonged. Some studies suggest that synthetic cannabinoid intoxication is associated with acute psychosis, worsening of previously stable psychotic disorders, and it may trigger a chronic (long-term) psychotic disorder among vulnerable individuals such as those with a family history of mental illness.[10][11]

Ingredients

Synthetic cannabis is claimed by the manufacturers to contain a mixture of traditionally used medicinal herbs, each of which producing mild effects, with the overall blend resulting in the cannabis-like intoxication produced by the product. Herbs listed on the packaging of Spice include Canavalia maritima (Coastal Jack-bean), Nymphaea caerulea (Blue Egyptian water lily), Scutellaria nana (dwarf skullcap), Pedicularis densiflora (Indian warrior), Leonotis leonurus (lion's tail), Zornia latifolia (maconha brava), Nelumbo nucifera (lotus), and Leonurus sibiricus (honeyweed). However, when the product was analyzed by laboratories in Germany and elsewhere, it was found that many of the characteristic "fingerprint" molecules expected to be present from the claimed plant ingredients were not present. There were also large amounts of synthetic tocopherol present. This suggested that the actual ingredients might not be the same as those listed on the packet, and a German government risk assessment of the product conducted in November 2008 concluded that it was unclear as to what the actual plant ingredients were, where the synthetic tocopherol had come from, and whether the subjective cannabis-like effects were actually produced by any of the claimed plant ingredients or instead caused by a synthetic cannabinoid drug.

Artificial cannabinoids

In January 2009, researchers at the University of Freiburg in Germany announced that an active substance in Spice was an undisclosed analogue of the synthetic cannabinoid CP 47,497.[12] Later that month, CP 47,497 along with its dimethylhexyl, dimethyloctyl and dimethylnonyl homologues, were added to the German controlled drug schedules.[13][14] In May the analogue of CP 47,497 was named cannabicyclohexanol.[15]

In July 2010, it was announced that JWH-018 is one of the active components in at least three versions of Spice, which had been sold in a number of countries around the world since 2002, often marketed as incense.[16][17][18][19] Another potent synthetic cannabinoid, HU-210, has been reported to have been found in Spice seized by U.S. Customs and Border Protection.[20] An analysis of samples acquired four weeks after the German prohibition of JWH-018 took place found that the compound had been replaced with JWH-073.[21]

Different ratios of JWH-018 and CP 47,497 and their analogues have been found in different brands of synthetic cannabis[22] and manufacturers constantly change the composition of their products.[23] The amount of JWH-018 in Spice has been found to vary from 0.2% to 3%.[24]

Other non-cannabinoid ingredients have also been found in synthetic cannabis blends around the world, but they do not produce classical cannabis intoxication effects. This includes substituted cathinone derived stimulant drugs such as 4-methylbuphedrone and 4-methyl-alpha-PPP, and psychedelic tryptamine derivatives such as 4-HO-DET.[25][26] In 2013 a designer opioid drug AH-7921 was detected in smoking blends in Japan, along with several novel cannabinoids and a cathinone analogue.[27]

New Zealand

An analysis of 41 different synthetic cannabis 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 so these brands were ordered to be removed from the market by emergency recall.[28][29] Since this time, a further 15 cannabinoid compounds have been detected as ingredients of synthetic cannabis blends in New Zealand and banned as temporary class drugs.[30] 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 2011-2012.[31]

Pharmacological properties of cannabinoids identified in synthetic cannabis, with THC for comparison
Name Structure Binding affinity for the CB1 receptor Binding affinity for the CB2 receptor
THC
Tetrahydrocannabinol.svg
Ki = 40.7±1.7 nM[32] Ki = 36.4±10 nM[32]
HU-210
HU-210 structure.png
Ki = 234 pM (100–800 times more potent)[33]
Cannabicyclohexanol
Cannabicyclohexanol.png
Ki = unknown. Reported to be 5 times more potent than THC, based on physiological responses in rats[34]
JWH-073
JWH073.svg
Ki = 8.90±1.80 nM[32] Ki = 38.0±24.0 nM[32]
JWH-018
JWH018.svg
Ki = 9.00±5.00 nM[32] Ki = 2.94±2.65 nM[32]
AM-2201
AM-2201 structure.png
Ki = 1.0 nM[35] Ki = 2.6 nM[35]

Safety

No official studies have been conducted on the effects of synthetic cannabinoids on humans (as is usually the case with known toxic and/or illegal compounds).[36] However, reports describing effects seen in patients seeking medical care after taking synthetic cannabinoids have been published. Compared to cannabis and its active cannabinoid THC, the adverse effects are often much more severe and can include hypertension, tachycardia, myocardial infarction,[37] agitation, vomiting, hallucinations, psychoses, seizures, convulsions[38] and panic attacks.[39][40][41][42][43] Among individuals who need emergency treatment after using synthetic cannabis, the most common symptoms are accelerated heartbeat, high blood pressure, nausea, blurred vision, hallucination and agitation.[44] Other symptoms included epileptic seizures, acute psychosis, and heart attacks.[44]

At least one death has been linked to overdose of synthetic cannabinoids[45] and in Colorado three deaths in September 2013 have been investigated for being linked to synthetic cannabinoids.[46] In December 2012, after two weeks of daily synthetic cannabis use, a 17-year old girl suffered multiple strokes and subsequent brain damage, leaving her blind and paralyzed.[47]

These more severe adverse effects in contrast to use of marijuana are believed to stem from the fact that many of the synthetic cannabinoids are full agonists to the cannabinoid receptors, CB1R and CB2R, compared to THC which is only a partial agonist and thus not able to saturate and activate all of the receptor population no matter of dose and resulting concentration.[48] It has also been seen that phase 1 metabolism of JWH-018 results in at least nine monohydroxylated metabolites and with at least three of the metabolites shown to have full agonistic effect on CB1R which compared to metabolism of THC only results in one psychoactive monohydroxylated metabolite. This may further explain the increased toxicity of synthetic cannabinoids compared to THC.[45]

Professor John W. Huffman, who first synthesised many of the cannabinoids used in synthetic cannabis, is quoted as saying, "People who use it are idiots."[36] "You don't know what it's going to do to you."[49] A user who consumed 3 g of Spice Gold every day for several months showed withdrawal symptoms, similar to those associated with withdrawing from the use of narcotics. Doctors treating the user also noted that his use of the product showed signs associated with addiction.[50] One case has been reported wherein a user, who had previously suffered from cannabis-induced recurrent psychotic episodes, suffered reactivation of his symptoms after using Spice. Psychiatrists treating him have suggested that the lack of an antipsychotic chemical, similar to cannabidiol found in natural cannabis, may make synthetic cannabis more likely to induce psychosis than natural cannabis.[51]

Studies are currently available which suggest an association between synthetic cannabinoids and psychosis. Physicians should be aware that the use of synthetic cannabinoids can be associated with psychosis and investigate possible use of synthetic cannabinoids in patients with inexplicable psychotic symptoms. 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.[52] Individuals with risk factors for psychotic disorders should be counseled against using synthetic cannabinoids.[53]

Synthetic cannabis may be more dangerous than real cannabis.[54][55][56] If cannabis had been legal, there would have been little incentive to develop or use synthetic cannabis. These casualties are an indirect result of the War on Drugs.[57][58][59][60][61]

Drug testing

Spice does not cause a positive drug test for cannabis or other illegal drugs using GC-MS-screening with library search, multi-target screening by LC-MS/MS, or immunological screening procedures.[22][50] A study has been conducted into the detection of metabolites of JWH-018 in urine; the metabolites are mainly conjugates with glucuronic acid and can be reliably detected by GC–MS/MS and LC–MS/MS.[62]

Legal status

Europe

Austria
The Austrian Ministry of Health announced on December 18, 2008 that Spice would be controlled under Paragraph 78 of their drug law on the grounds that it contains an active substance that affects the functions of the body, and the legality of JWH-018 is under review.[63][64][65]
Germany
JWH-018, CP 47,497 and the C6, C8 and C9 homologues of CP 47,497 are illegal in Germany since January 22, 2009.[14][66]
Finland
Spice blends are classified as a medicine in Finland, and, therefore, it is illegal to order them without a prescription. In practice, it is not possible to get a prescription.[citation needed]
France
JWH-018, CP 47,497 (and its homologues) and HU-210 were all made illegal in France on February 24, 2009.[67]
Ireland
From June 2010, JWH-018, along with a variety of other designer drugs, is illegal.[68]
Latvia
JWH-018, JWH-073, CP 47,497 (and its homologues) and HU-210 are all banned in Latvia as well as leonotis leonurus.[69]
Poland
JWH-018 and many of the herbs mentioned on the ingredient lists of Spice and similar preparations were made illegal in May 2009. The bill was passed by Polish Sejm,[70][71] Polish Senat[72] and was signed by the President.[73]
Romania
Spice was made illegal in Romania on February 15, 2010.[74]
Russia
On April 9, 2009, the Chief Medical Officer of the Russian Federation issued a resolution on reinforcing control over the sales of smoking blends. These blends, marketed under the trade names AM-HI-CO, Dream, Spice (Gold, Diamond), Zoom, Ex-ses, Yucatán Fire and others, have been declared to contain Salvia divinorum, Hawaiian Wood Rose, and Blue Lotus, and are prohibited to be sold. These substances have been found to have "psychotropic, narcotic effects, contain poisonous components and represent potential threat for humans". The resolution does not mention JWH-018 or other synthetic cannabinoids.[75] 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. Thus, all of these plants and compounds are now illegal in the Russian Federation.[76]
Slovakia
Spice is legal in Slovakia. The National Anti-Drug Unit is considering adding it to the list of controlled substances.[77] The latest anti-drug law version (468/2009) valid since January 2010 still does not mention active compounds of Spice.[78]
Sweden
CP 47,497-C6, CP 47,497-C7, CP 47,497-C8, CP 47,497-C9, JWH-018, JWH-073 and HU-210 were all made illegal in Sweden on September 15, 2009. The bill was accepted on July 30, 2009 and was put in effect on September 15, 2009.[79]
Switzerland
Spice has been banned in Switzerland.[80]
Turkey
Spice a.k.a Bonzai added to the list of drugs and psychotropic substances in 07.01.2011 by the law which numbered as 2011/1310 B.K.K. (February 13, 2011 and the Official Gazette No. 27845) [81]
United Kingdom
Spice was legal in the United Kingdom until December 2009, when it was classified as a Class B drug.[82]

South America

Chile
The Chilean Ministry of Health on April 24, 2009 declared the sale of synthetic cannabis to be illegal.[83]

Asia

South Korea
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.[84]
Japan
Japan has banned JWH-018, CP 47, 497, and homologues, and HU-210 since October 2009[citation needed]
United Arab Emirates
The United Arab Emirates had stated that Spice was an illegal substance and possession or intent to sell would be a jailable offense.[85]

Australasia

Australia
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.[86][87] On June 18, 2013, an interim ban made a large list of product brands and synthetic substances illegal to sell anywhere in Australia.[88] This ban lapsed on October 13, 2013, and a permanent ban has not been imposed.[89] Synthetic cannabis remains 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.[90][91] The introduction of this law makes NSW the first state in Australia to completely ban substances with psychoactive properties.[91]
New Zealand
Spice is illegal in New Zealand, it is classified as a Class C controlled drug.[92] 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.[93] 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.[94]

North America

Canada

Spice and specific forms of JWHxxx are not specifically prohibited in Canada, but synthetic cannabis is listed as a schedule II drug.[95][96] Health Canada is debating on the subject.[97][98]

United States

The case of David Mitchell Rozga, an American teenager from Indianola, Iowa, United States, brought international attention to K2. Rozga shot himself in the head with a family owned hunting rifle in an apparent suicide in 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, had led investigators to believe that it was likely Rozga was under the influence of a mind-altering substance, at the time of his death. The death of Rozga has been used as a face of political lobbying against the continuation of K2, and other legal synthetic drugs, such as bath salts.[99]

Following the incident, an act to ban the use and distribution of the drug was proposed by the US Senator Chuck Grassley of Iowa as the David Mitchell Rozga Act. It was approved into legislation by the United States Congress in June 2011.[100] 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.[7]

Prior to that, some compounds within synthetic cannabis (HU-210) were scheduled in the USA under federal law, while others (JWH-073) have been temporarily scheduled until final determination of their status can be made.[101][102][103][104] The Drug Enforcement Administration (DEA) considers it to be a "drug of concern",[105] 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."[106][107]

Several states independently passed acts making it illegal under state law, including Kansas in March 2010,[108] Georgia and Alabama in May 2010,[109][110] Tennessee and Missouri in July 2010,[111][112] Louisiana in August 2010,[citation needed] Mississippi in September 2010,[citation needed] and Iowa.[113] An emergency order was passed in Arkansas in July 2010 banning the sale of synthetic cannabis.[114] 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.[115] According to the National Conference of State Legislatures, several other states are also considering legislation, including New Jersey, New York, Florida, and Ohio.[112] Illinois passed a law on July 27, 2010 banning all synthetic cannabinoids that goes into effect January 1, 2011.[116] Michigan banned synthetic cannabinoids in October 2010,[117] 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).[118] Indiana banned synthetic cannabinoids in a law which became effective in March 2012.[119] North Carolina banned synthetic cannabis by a unanimous vote of the state senate, due to concerns that its contents and effects are reasonably similar to natural cannabis, and may cause equal effects in terms of psychological dependency.[120][121]

Following cases in Japan involving the use of synthetic cannabis by Navy, Army and Marine Corps personnel resulted in the official banning of it,[122] 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 or manufacture of synthetic cannabis as well as any derivative, analogue or variant of it.[123] On June 8, 2010, the U.S. 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.[124]

On November 24, 2010, the DEA announced that it would make JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol, which are often found in synthetic cannabis, illegal using emergency powers.[125] They will be placed in Schedule I of the Controlled Substances Act, within a month of the announcement, and the ban will last for at least a year.[126][127] The temporary ban, for at least a year, came into effect on March 1, 2011.[128]

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 cannabis.[129]

History

According to the Psychonaut Web Mapping Research Project, synthetic cannabis products, sold under the brand name Spice, first appeared in Europe in 2004.[130] The brand "Spice" was released in 2004 by the now-dormant company The Psyche Deli in London, UK. 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.[131] The EMCDDA[clarification needed] reported in 2009 that 'Spice' products were identified in 21 of the 30 participating countries. Because 'Spice' was the dominant brand until 2009, the competing brands that started to appear from 2008 on were also dubbed 'Spice'. Spice can, therefore, refer to both the brand 'Spice', as to all herbal blends with synthetic cannabinoids added.

A survey of readers of Mixmag in the UK in 2009 found that one in eight respondents had used synthetic cannabis, compared to 85% who had used cannabis.[132]

Slang terms

In addition to K2 and Spice, other street names include Black Mamba (Turnera diffusa), Bombay Blue, Genie, and Zohai.[7] According to Partnership at Drugfree.org, other names also include Bliss, Blaze, JWH -018, -073, -250, Yucatan Fire, Skunk, Moon Rocks[133] and Bonzai (esp. in Turkey)[81]

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