k2 spice japan Synthetic cannabinoids

Synthetic cannabinoids, or neocannabinoids, 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 distinct in many aspects. k2 spice japan Synthetic cannabinoids

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 United States and United Kingdom since 2016.^[7] They have been marketed as herbal incense, or “herbal smoking blends”,^[6] and sold under common names such as 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]

• 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]}

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

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

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”.

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-HO-DET.

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]

Many of the early synthetic cannabinoids that were synthesized for use in research were named after either the scientist who first synthesized them or the institution or company where they originated.

Some of the names of synthetic cannabinoids synthesized for recreational use were given names to help market the products. For example, AKB-48 (also known as APINACA) is also the name of a popular Japanese girl band; 2NE1 (also known as APICA) is also a South Korean girl band; and XLR-11 was named after the first US-developed liquid fuel rocket for aircraft. Now many synthetic cannabinoids are assigned names derived from their four main structural components, core, tail, linker, and linked group, where the name is formatted as LinkedGroup-TailCoreLinker. For example, in 5F-MDMB-PINACA (also known as 5F-ADB), 5F stands for the terminal fluorine or “fluorine on carbon 5” of the pentyl chain; MDMB stands for “methyl-3,3-dimethyl butanoate”, the linked group; and PINACA stands for “pentyl chain (tail) indazole (core) carboxamide (linker)”.

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.

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.

Because of these controversies,^[51] and in particular the difficulty of distinguishing natural cannabinoids obtained in laboratory (for example, CBD or synthetic THC) from artificial novel synthetic cannabinoid analog compounds not present in nature (like nabilone, Spice, the HU, JWH series, etc.), the term “neocannabinoid” has been proposed to name the latter.

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.^[55] Unlike nabilone, the synthetic cannabinoids found being used for recreational use did not have any documented therapeutic effects.^[38]

Critics of drug prohibition point to laws against marijuana as a cause for the popularity of synthetic products, and argue that cannabis legalization reduces demand for substitutes.^[56][57][58] The drug is most commonly used in populations that cannot easily acquire or consume marijuana, such as teenagers, inmates,^[59][60] people on probation or parole, and members of the armed forces subjected to regular drug testing.^{[56][61][55] k2 spice japan Synthetic cannabinoids}

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.^[62] 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.

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] While there are no fatal overdose cases linked to marijuana,^[69] there are deaths linked to synthetic cannabinoids each year.^[14][70][71] The most common mechanisms leading to death following synthetic cannabinoid use include behavioral risks, such as self-harm and suicide, falling from a height, and wandering into traffic; cardiovascular effects; and central nervous system depression.

Researchers have pointed out a few ways that synthetic cannabinoids differ from marijuana, and therefore may be more dangerous. First, they often have greater intrinsic activity. Many of the synthetic cannabinoids are full agonists of the cannabinoids receptors, CB₁ and CB₂, compared to THC, which is only a partial agonist.^[73] Secondly, they may have other actions in the body, in addition to activating cannabinoid receptors. Some may work on NMDA glutamate receptors.^[67] Some may also work on serotonin, either indirectly by inhibiting MAO^[74] and increasing 5-HT_1A expression,^[75] or by directly binding to serotonin receptors, including the 5-HT_1A and 5-HT₃^[67] 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.^{[76] k2 spice japan Synthetic cannabinoids}

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.^[77] Some metabolites even appear to be cannabinoid antagonists.^[78] 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).

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);^[79] 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.^[80]

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.^{[81] k2 spice japan Synthetic cannabinoids}

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]

Studies have strongly linked particular synthetic cannabinoids with psychosis.^{[82][83][84][85]} 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.^{[86] k2 spice japan Synthetic cannabinoids}

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.^[87] Individuals with risk factors for psychotic disorders are often counseled against using synthetic cannabinoids.^[88] 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.