Synthetic cannabis

A bag of Spice brand herbal incense

Synthetic cannabis (synthetic marijuana), or technically synthetic cannabinoid receptor agonists are designer drugs that mimic the effects of cannabis sprayed onto a herbal base material.[1] There are several psychoactive artificial cannabinoid families (e.g. 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 was 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 other stores.

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.

Relationship to cannabis

Main article: Cannabis (drug)

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."[4] 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.[5] 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.[6][7] Synthetic Cannabis is stated to be more toxic to the brain and more addictive than regular cannabis.[8]

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 have been 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.[9] Later that month, CP 47,497 along with its dimethylhexyl, dimethyloctyl and dimethylnonyl homologues, were added to the German controlled drug schedules.[10][11] In May, the analogue of CP 47,497 was named "cannabicyclohexanol".[12]

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.[13][14][15][16] Another potent synthetic cannabinoid, HU-210, has been reported to have been found in Spice seized by U.S. Customs and Border Protection.[17] 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.[18]

Different ratios of JWH-018 and CP 47,497 and their analogues have been found in different brands of synthetic cannabis[19] and manufacturers constantly change the composition of their products.[20] The amount of JWH-018 in Spice has been found to vary from 0.2% to 3%.[21]

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.[22][23] In 2013, a designer opioid drug, AH-7921, was detected in smoking blends in Japan, along with several novel cannabinoids and a cathinone analogue.[24]

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 these brands were ordered to be removed from the market by emergency recall.[25][26] 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.[27] 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.[28]

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
Ki = 40.7±1.7 nM[29] Ki = 36.4±10 nM[29]
HU-210
Ki = 234 pM (100–800 times more potent)[30]
Cannabicyclohexanol
Ki = unknown. Reported to be five times more potent than THC, based on physiological responses in rats[31]
JWH-073
Ki = 8.90±1.80 nM[29] Ki = 38.0±24.0 nM[29]
JWH-018
Ki = 9.00±5.00 nM[29] Ki = 2.94±2.65 nM[29]
AM-2201
Ki = 1.0 nM[32] Ki = 2.6 nM[32]

Legal herbs

Main article: Herbal smoking blend

Unlike Herbal smoking blends synthetic cannabis may use chemicals on their herbs, but both use legal psychotropic herbs.[33] Some herbs used may be salvia divinorum or other mildly psychoactive herbs that can be sold legally. In some cases the herbs have no effect on humans or are overpowered by the chemicals on them.

Safety

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).[34] 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,[35] agitation, vomiting, hallucinations, psychoses, seizures, convulsions[36] and panic attacks.[37][38][39][40][41] 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.[42] Other symptoms included epileptic seizures, acute psychosis, and heart attacks.[42]

At least one death has been linked to overdose of synthetic cannabinoids[43] and in Colorado three deaths in September 2013 have been investigated for being linked to synthetic cannabinoids.[44]

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.[45] 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.[43]

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.[34] You don't know what it's going to do to you."[46] 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.[47] 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.[48]

Studies are currently available which suggest an association between synthetic cannabinoids and psychosis. The use of synthetic cannabinoids can be associated with psychosis and physicians are beginning to 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.[49] Individuals with risk factors for psychotic disorders are often counseled against using synthetic cannabinoids.[50]

Detection in body fluids

Synthetic cannabis consumption does not cause a positive urine drug test for THC, its metabolites or other cannabinoids present in marijuana using standard immunological screening procedures, library search GC-MS-screening, or multi-target screening by LC-MS/MS.[19][47] Serum concentrations of the chemicals present in synthetic cannabis are generally in the 1–10 μg/L range during the first few hours after recreational usage. The major urinary metabolites, in most cases formed by oxidation of the alkyl side-chain to an alcohol and carboxylic acid followed by glucuronide conjugation, but also by N-dealkylation and aromatic hydroxylation, are usually present in urine at similar concentrations. The presence of synthetic cannabinoids or their metabolites in biofluids may be determined using specifically-targeted commercially available immunoassay screening methods, while liquid chromatography-mass spectrometry is most often used for confirmation and quantitation.[51][52][53][54][55]

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.[56][57][58]
Germany
JWH-018, CP 47,497 and the C6, C8 and C9 homologues of CP 47,497 have been illegal in Germany since January 22, 2009.[11][59]
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.
France
JWH-018, CP 47,497 (and its homologues) and HU-210 were all made illegal in France on February 24, 2009.[60]
Ireland
from June 2010, JWH-018, along with a variety of other designer drugs, has been illegal.[61]
Latvia
JWH-018, JWH-073, CP 47,497 (and its homologues) and HU-210 as well as leonotis leonurus have been all banned in Latvia since 2005.[62] 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 offence.[63]
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,[64][65] Polish Senat[66] and was signed by the President.[67]
Romania
Spice was made illegal in Romania on February 15, 2010.[68]
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.[69] 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.[70]
About 780 new psychoactive substances were added to the list from 2011 to 2014. The drugmakers 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[71] On October 30, 2014, President Vladimir Putin brought in a bill that would ban the turnover of any type of smoking blends and introduce administrative sanctions and criminal responsibility for it.[72]
Slovakia
Spice is legal in Slovakia. The National Anti-Drug Unit is considering adding it to the list of controlled substances.[73] The latest anti-drug law version (468/2009) valid since January 2010 does not mention active compounds of Spice.[74]
Spain
Spice is unregulated in Spain. For this reason, spice is available in grow shop stores or cannabis related stores, and it can be bought and shipped online without any legal impediment from those kind of stores.[75] But only a few people know about the existence of spice and it's not widely consumed. This happens due to the lax laws of Spain against cannabis; because in Spain is not illegal to have up to 2 cannabis plants per house and it's completely legal the consumption and possession in a private propierty, and all related actions to cannabis unless the sell/trade are decriminalized.[76]
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.[77]
Switzerland
Spice has been banned in Switzerland.[78]
Turkey
Spice, which is colloquially called bonzai in Turkey, was 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) [79]
United Kingdom
Many cannabinoids were legal in the United Kingdom until December 2009, when they were classified as a Class B drugs.[80] The UK has continued to ban new synthetic cannabinoids as they come to market but they are typically replaced instantly by novel alternatives.

South America

Chile
the Chilean Ministry of Health on April 24, 2009, declared the sale of synthetic cannabis to be illegal.[81]

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.[82]
Japan
Japan has banned JWH-018, CP 47, 497, and homologues, and HU-210 since October 2009
United Arab Emirates
the United Arab Emirates had stated that Spice is an illegal substance and possession or intent to sell is a jailable offense.[83]

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.[84][85] On June 18, 2013, an interim ban made a large list of product brands and synthetic substances illegal to sell anywhere in Australia.[86] This ban lapsed on October 13, 2013, and a permanent ban has not been imposed.[87] 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.[88][89] The introduction of this law makes NSW the first state in Australia to completely ban substances with psychoactive properties.[89]
New Zealand
Spice is illegal in New Zealand, it is classified as a Class C controlled drug.[90] 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.[91] 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.[92]

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.[93][94] Health Canada is debating the subject.[95][96]

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 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.[97]

Following the incident, an act to ban the use and distribution of the drug was proposed by 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.[98] 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.[99]

Prior to that, some compounds within synthetic cannabis (HU-210) were scheduled in the US under federal law, while others (JWH-073) have been temporarily scheduled until final determination of their status can be made.[100][101][102][103] The Drug Enforcement Administration (DEA) considers it to be a "drug of concern",[104] 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."[105][106]

Several states independently passed acts making it illegal under state law, including Kansas in March 2010,[107] Georgia and Alabama in May 2010,[108][109] Tennessee and Missouri in July 2010,[110][111] Louisiana in August 2010, Mississippi in September 2010, and Iowa.[112] An emergency order was passed in Arkansas in July 2010 banning the sale of synthetic cannabis.[113] 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.[114] According to the National Conference of State Legislatures, several other states are also considering legislation, including New Jersey, New York, Florida, and Ohio.[111] Illinois passed a law on July 27, 2010 banning all synthetic cannabinoids that goes into effect January 1, 2011.[115] Michigan banned synthetic cannabinoids in October 2010,[116] 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).[117] Indiana banned synthetic cannabinoids in a law which became effective in March 2012.[118] 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.[119][120]

Following cases in Japan involving the use of synthetic cannabis by navy, army and marine corps personnel resulted in the official banning of it,[121] 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 as well as any derivative, analogue or variant of it.[122] 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.[123]

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.[124] 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.[125][126] The temporary ban, for at least a year, came into effect on March 1, 2011.[127]

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.[128]

History

According to the Psychonaut Web Mapping Research Project, synthetic cannabis products, sold under the brand name Spice, first appeared in Europe in 2004.[129] 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.[130] The EMCDDA 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.[131]

Slang terms

In addition to synthetic marijuana, K2 and Spice, other brand names include Black Mamba, Bombay Blue, Genie, and Zohai.[99] According to Partnership at Drugfree.org, other names also include Bliss.[132]

See also

References

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  2. ↑ Mary Carmichael (March 4, 2010). "K2: Scary Drug or Another Drug Scare?". Newsweek. Retrieved November 24, 2010.
  3. ↑ "What's the buzz?: Synthetic marijuana, K2, Spice, JWH-018 : Terra Sigillata". Scienceblogs.com. Retrieved November 24, 2010.
  4. ↑ "New York Bans 'Synthetic Marijuana'". NPR.org. March 30, 2012. Retrieved February 20, 2015.
  5. ↑ www.emed-journal.com Lapoint J, Nelson LS. Synthetic Cannabinoids: The Newest, Almost Illicit Drug of Abuse. Emergency Medicine 2011;43(2):26-28
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