Synthetic Marijuana
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Synthetic cannabinoids, or neocannabinoids, are a class of
designer drug A designer drug is a structural or functional analog of a controlled substance that has been designed to mimic the pharmacological effects of the original drug, while avoiding classification as illegal and/or detection in standard drug tests. ...
molecules that
bind BIND () is a suite of software for interacting with the Domain Name System (DNS). Its most prominent component, named (pronounced ''name-dee'': , short for ''name Daemon (computing), daemon''), performs both of the main DNS server roles, acting ...
to the same receptors to which
cannabinoid Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...
s ( THC, CBD and many others) in
cannabis ''Cannabis'' () is a genus of flowering plants in the family Cannabaceae that is widely accepted as being indigenous to and originating from the continent of Asia. However, the number of species is disputed, with as many as three species be ...
plants attach. These novel psychoactive substances should not be confused with synthetic
phytocannabinoids Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...
(obtained by
chemical synthesis Chemical synthesis (chemical combination) is the artificial execution of chemical reactions to obtain one or several products. This occurs by physical and chemical manipulations usually involving one or more reactions. In modern laboratory uses ...
) or synthetic
endocannabinoids Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...
from which they are distinct in many aspects. Typically, synthetic cannabinoids are sprayed onto plant matter and are usually smoked, although they have also been ingested as a concentrated liquid form in the United States and United Kingdom since 2016. They have been marketed as herbal incense, or "herbal smoking blends", and sold under common names such as K2, spice, and synthetic marijuana. They are often labeled "not for human consumption" for liability defense. A large and complex variety of synthetic cannabinoids are designed in an attempt to avoid legal restrictions on
cannabis ''Cannabis'' () is a genus of flowering plants in the family Cannabaceae that is widely accepted as being indigenous to and originating from the continent of Asia. However, the number of species is disputed, with as many as three species be ...
, making synthetic cannabinoids
designer drug A designer drug is a structural or functional analog of a controlled substance that has been designed to mimic the pharmacological effects of the original drug, while avoiding classification as illegal and/or detection in standard drug tests. ...
s. Most synthetic cannabinoids are
agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
s of the cannabinoid receptors. They have been designed to be similar to THC, the natural
cannabinoid Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...
with the strongest binding affinity to the CB1 receptor, which is linked to the
psychoactive A psychoactive drug, psychopharmaceutical, mind-altering drug, consciousness-altering drug, psychoactive substance, or psychotropic substance is a chemical substance that alters psychological functioning by modulating central nervous system acti ...
effects or "high" of
marijuana Cannabis (), commonly known as marijuana (), weed, pot, and ganja, List of slang names for cannabis, among other names, is a non-chemically uniform psychoactive drug from the ''Cannabis'' plant. Native to Central or South Asia, cannabis has ...
. These synthetic analogs often have greater
binding affinity In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from Latin ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usuall ...
and greater potency to the CB1 receptors. There are several synthetic cannabinoid families (e.g., AM-''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. Synthetic marijuana compounds began to be manufactured and sold in the early 2000s. From 2008 to 2014, 142 synthetic cannabinoid receptor agonists were reported to the European Monitoring-Center for Drugs and Drug Addiction (EMCDDA). Reported user negative effects include
palpitations Palpitations occur when a person becomes aware of their heartbeat. The heartbeat may feel hard, fast, or uneven in their chest. Symptoms include a very fast or irregular heartbeat. Palpitations are a sensory symptom. They are often described as ...
,
paranoia Paranoia is an instinct or thought process that is believed to be heavily influenced by anxiety, suspicion, or fear, often to the point of delusion and irrationality. Paranoid thinking typically includes persecutory beliefs, or beliefs of co ...
, intense
anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...
,
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...
, vomiting, confusion, poor coordination, and seizures. There have also been reports of a strong compulsion to re-dose, withdrawal symptoms, and persistent cravings. There have been several deaths linked to synthetic cannabinoids. The
Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the National public health institutes, national public health agency of the United States. It is a Federal agencies of the United States, United States federal agency under the United S ...
(CDC) found that the number of deaths from synthetic cannabinoid use tripled between 2014 and 2015.10. How harmful is K2/Spice (synthetic marijuana or synthetic cannabinoids)?
/ref> In 2018, the
United States Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
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. Severe illnesses and death have resulted from this contamination.


Synthetic cannabinoid products

It is often difficult to determine what is in these products without reagent testing because masking agents, such as
tocopherol Tocopherols (; TCP) are a class of organic compounds comprising various methylated phenols, many of which have vitamin E activity. Because the vitamin activity was first identified in 1936 from a dietary fertility factor in rats, it was named ''t ...
(or vitamin E acetate that causes vaping-associated pulmonary injury),
eugenol Eugenol is an allyl chain-substituted guaiacol, a member of the allylbenzene class of chemical compounds. It is a colorless to pale yellow, aromatic oily liquid extracted from certain essential oils especially from clove, nutmeg, cinnamon, ...
, and
fatty acid In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an ...
s, are added to confound identification. Just as the synthetic used differ between each synthetic cannabinoid product sold, so do the other contents of the counterfeit product.


Counterfeit black market cannabis products

* Counterfeit cannabis-liquid (c-liquid) for e-cigarettes: Synthetic cannabinoids are increasingly offered in e-cigarette form as "c-liquid". Several schoolchildren in
Greater Manchester Greater Manchester is a ceremonial county in North West England. It borders Lancashire to the north, Derbyshire and West Yorkshire to the east, Cheshire to the south, and Merseyside to the west. Its largest settlement is the city of Manchester. ...
collapsed after vaping synthetic cannabinoids mis-sold as THC e-liquid. * Counterfeit
cannabis ''Cannabis'' () is a genus of flowering plants in the family Cannabaceae that is widely accepted as being indigenous to and originating from the continent of Asia. However, the number of species is disputed, with as many as three species be ...
buds: Hemp buds (or low-potency cannabis buds) laced with synthetic cannabinoids. * Counterfeit
cannabis edible A cannabis edible, also known as a cannabis-infused food or simply an edible, is a food item (either homemade or produced commercially) that contains decarboxylated cannabinoids (cannabinoid acids converted to their orally bioactive form) fro ...
: 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. * Counterfeit
hashish Hashish (; ), usually abbreviated as hash, is a Compression (physics), compressed form of resin (trichomes) derived from the cannabis flowers. European Monitoring Centre for Drugs and Drug Addiction, Lisbon, As a Psychoactive drug, psychoactive ...
: From December 2018, different samples of hashish have been found to contain synthetic cannabinoids.


Counterfeit CBD products

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


"Herb/incense" blends


Synthetic cannabinoids found in herb blends

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


Non-cannabinoid chemicals found in herb blends

Most blends consist of synthetic cannabinoids sprayed onto inert vegetable matter, but some contain other psychoactive substances, including psychoactive herbs, e.g., wild dagga and indian warrior, and psychoactive
alkaloid Alkaloids are a broad class of natural product, naturally occurring organic compounds that contain at least one nitrogen atom. Some synthetic compounds of similar structure may also be termed alkaloids. Alkaloids are produced by a large varie ...
s, e.g., betonicine, aporphine, leonurine, nuciferine, and
nicotine Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...
. Some synthetic cannabinoids products have also been found to contain
synthetic opioids Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...
. For example, in 2010, nine people died due to the combination of ''O''-desmethyltramadol, a μ- opioid agonist and
analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...
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. In 2018, there was an outbreak of synthetic cannabinoids contaminated with
anticoagulant An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which ...
s, mainly brodifacoum, in at least 11 states in the US that caused
coagulopathy Coagulopathy (also called a bleeding disorder) is a condition in which the blood's ability to coagulate (form clots) is impaired. This condition can cause a tendency toward prolonged or excessive bleeding ( bleeding diathesis), which may occur s ...
(prolonged or excessive bleeding) and resulted in the treatment of over 300 people and at least eight deaths. One of the most common non-cannabinoid ingredients in these products is oleamide, a
fatty acid In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an ...
derivative that acts similarly to a
cannabinoid Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...
and has
hypnotic A hypnotic (from Ancient Greek, Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to sleep induction, induce sleep and to trea ...
properties. Analysis of 44 products synthetic cannabinoid revealed oleamide in 7 of the products tested. Other non-cannabinoid ingredients that have been found in synthetic cannabinoid blends include harmine and harmaline, reversible
monoamine oxidase inhibitor Monoamine oxidase inhibitors (MAOIs) are a drug class, class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressa ...
s, which have been found with myristicin and asarone;
substituted cathinone Substituted cathinones, or simply cathinones, which include some stimulants and Empathogen-entactogen, entactogens, are chemical derivative, derivatives of cathinone. They feature a substituted phenethylamine, phenethylamine core with an alkyl ...
derived stimulant drugs such as 4-methylbuphedrone and 4'-methyl-alpha-PPP; and psychedelic
tryptamine Tryptamine is an indolamine metabolite of the essential amino acid tryptophan. The chemical structure is defined by an indole—a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon (third aromatic atom, with the firs ...
derivatives such as 4-HO-DET.


Herbs labeled on packages marketed as legal high

Packages of synthetic cannabinoid products can claim to contain a wide array of plants. However, oftentimes, none of the listed ingredients have been detectable. Herbal components of 'Spice' (a non-exhaustive list):


Naming synthetic cannabinoids

Many of the early synthetic cannabinoids that were synthesized for use in research were named after either the scientist who first synthesized them or the institution or company where they originated. Some of the names of synthetic cannabinoids synthesized for recreational use were given names to help market the products. For example, AKB-48 (also known as APINACA) is also the name of a popular Japanese girl band;
2NE1 2NE1 (, ) is a South Korean girl group formed by YG Entertainment in 2009. The group consists of Park Bom, Bom, CL (rapper), CL, Sandara Park, Dara, and Minzy. Known for their Experimental music, musical experimentation, fashion, and stage pre ...
(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)".


Common names

Use of the term "synthetic marijuana" to describe products containing synthetic cannabinoids is controversial and, according to Lewis Nelson, a medical toxicologist at the NYU School of Medicine, a mistake. Nelson claims that relative to
marijuana Cannabis (), commonly known as marijuana (), weed, pot, and ganja, List of slang names for cannabis, among other names, is a non-chemically uniform psychoactive drug from the ''Cannabis'' plant. Native to Central or South Asia, cannabis has ...
, products containing synthetic cannabinoids "are really quite different, and the effects are much more unpredictable. It's dangerous". Since the term ''synthetic'' does not apply to the plant, but rather to the
cannabinoid Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...
that the
plant Plants are the eukaryotes that form the Kingdom (biology), kingdom Plantae; they are predominantly Photosynthesis, photosynthetic. This means that they obtain their energy from sunlight, using chloroplasts derived from endosymbiosis with c ...
contains ( THC), the term ''synthetic cannabinoid'' is more appropriate. Nearly 700 "herbal incense" blends exist. They are often called "synthetic marijuana", "natural herbs", "herbal incense", or "herbal smoking blends" and often labeled "not for human consumption". In some Spanish-speaking countries, such as Chile and Argentina, such preparations are often referred to as . 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 ''Financial Times'' (''FT'') is a British daily newspaper printed in broadsheet and also published digitally that focuses on business and economic Current affairs (news format), current affairs. Based in London, the paper is owned by a Jap ...
'', 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.


Neocannabinoids

Because of these controversies, 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.


Uses

Synthetic
cannabinoids Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoa ...
were made for cannabinoid research focusing on
tetrahydrocannabinol Tetrahydrocannabinol (THC) is a cannabinoid found in cannabis. It is the principal psychoactive constituent of ''Cannabis'' and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) de ...
(THC), cannabinoid receptors, and the
endocannabinoids Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...
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 Tritium () or hydrogen-3 (symbol T or H) is a rare and radioactive isotope of hydrogen with a half-life of ~12.33 years. The tritium nucleus (t, sometimes called a ''triton'') contains one proton and two neutrons, whereas the nucleus of the ...
-labelled cannabinoids such as CP-55,940 were instrumental in discovering the cannabinoid receptors in the early 1990s. Some early synthetic cannabinoids were also used clinically. Nabilone, a first generation synthetic THC analog, has been used as an
antiemetic An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They may ...
to combat vomiting and nausea since 1981. Synthetic THC (marinol,
dronabinol Dronabinol (), sold under the brand names Marinol and Syndros, is the generic name for the molecule of (−)-trans-Δ9-tetrahydrocannabinol (THC) in the pharmaceutical context. It has indications as an appetite stimulant, antiemetic, and sleep ...
) has been used as an antiemetic since 1985, and an appetite stimulant since 1991, although synthetic THC is often not listed among the "synthetic cannabinoids" but as a "synthetic phytocannabinoid". In the early 2000s, synthetic cannabinoids began to be used for
recreational drug use Recreational drug use is the use of one or more psychoactive drugs to induce an altered state of consciousness, either for pleasure or for some other casual purpose or pastime. When a psychoactive drug enters the user's body, it induces an Sub ...
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. 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. The drug is most commonly used in populations that cannot easily acquire or consume marijuana, such as teenagers, inmates, people on
probation Probation in criminal law is a period of supervision over an offence (law), offender, ordered by the court often in lieu of incarceration. In some jurisdictions, the term ''probation'' applies only to community sentences (alternatives to incar ...
or
parole Parole, also known as provisional release, supervised release, or being on paper, is a form of early release of a prisoner, prison inmate where the prisoner agrees to abide by behavioral conditions, including checking-in with their designated ...
, and members of the armed forces subjected to regular drug testing.


Toxicity

Because they activate the
cannabinoid Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...
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. 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. Adverse effects observed due to synthetic cannabinoid use include
acute kidney injury Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in renal function, kidney function that develops within seven days, as shown by an increase in serum creatinine or a decrease in urine output, or both. ...
, cardiac toxicity,
seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...
,
stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...
,
tremor A tremor is an involuntary, somewhat rhythmic muscle contraction and relaxation involving neural oscillations, oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the h ...
,
hypokalemia Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an a ...
, and rhabdomyolysis. Some negative effects of 5F-PB-22 reported by users included
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...
,
vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...
,
confusion In psychology, confusion is the quality or emotional state of being bewildered or unclear. The term "acute mental confusion"
, poor coordination,
anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...
, and seizures. Some of the negative effects of 5F-AKB-48 reported by users included
palpitations Palpitations occur when a person becomes aware of their heartbeat. The heartbeat may feel hard, fast, or uneven in their chest. Symptoms include a very fast or irregular heartbeat. Palpitations are a sensory symptom. They are often described as ...
,
paranoia Paranoia is an instinct or thought process that is believed to be heavily influenced by anxiety, suspicion, or fear, often to the point of delusion and irrationality. Paranoid thinking typically includes persecutory beliefs, or beliefs of co ...
, intense anxiety, and a taste like burned plastic. While there are no fatal
overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014.
cases linked to
marijuana Cannabis (), commonly known as marijuana (), weed, pot, and ganja, List of slang names for cannabis, among other names, is a non-chemically uniform psychoactive drug from the ''Cannabis'' plant. Native to Central or South Asia, cannabis has ...
, there are deaths linked to synthetic cannabinoids each year. The most common mechanisms leading to death following synthetic cannabinoid use include behavioral risks, such as self-harm and
suicide Suicide is the act of intentionally causing one's own death. Risk factors for suicide include mental disorders, physical disorders, and substance abuse. Some suicides are impulsive acts driven by stress (such as from financial or ac ...
, falling from a height, and wandering into traffic;
cardiovascular In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...
effects; and
central nervous system depression Central nervous system depression (or CNS depression) is a nervous system disorder characterized by a severely impaired physiological state in which patients may exhibit decreased rate of breathing, decreased heart rate, and loss of consciousnes ...
. 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
agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
s of the cannabinoids receptors, CB1 and CB2, compared to THC, which is only a
partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...
. Secondly, they may have other actions in the body, in addition to activating cannabinoid receptors. Some may work on NMDA
glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...
receptors. Some may also work on
serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...
, either indirectly by inhibiting MAO and increasing 5-HT1A expression, or by directly binding to serotonin receptors, including the 5-HT1A and 5-HT3 subtypes; some researchers speculate that this activity may be because the
indole Indole is an organic compound with the formula . Indole is classified as an aromatic heterocycle. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indoles are derivatives of indole ...
moiety that some synthetic cannabinoids possess is similar to the structure of serotonin. 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 JWH-018 (1-pentyl-3-(1-naphthoyl)indole, NA-PIMO or AM-678) is an analgesic chemical from the naphthoylindole family that acts as a full agonist at both the CB1 and CB2 cannabinoid receptors, with some selectivity for CB2. It produces effe ...
results in at least nine monohydroxylated
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
s, three of which have been shown to be full
agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
s of the CB1 receptors, compared to the
metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
of THC, which only results in one
psychoactive A psychoactive drug, psychopharmaceutical, mind-altering drug, consciousness-altering drug, psychoactive substance, or psychotropic substance is a chemical substance that alters psychological functioning by modulating central nervous system acti ...
monohydroxylated metabolite. The metabolite N-(3-hydroxypentyl) JWH-018 was found to have toxic effects that its parent compound does not. Some metabolites even appear to be cannabinoid
antagonists An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. No official studies have been conducted on the effects of synthetic cannabinoids on humans (as is often the case with illegal and potentially
toxic Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...
compounds); 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 The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency under the Department of Health and Human Services (HHS), and is headquartered in Atlanta, ...
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 The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
(e.g., agitation,
coma A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to Nociception, respond normally to Pain, painful stimuli, light, or sound, lacks a normal Circadian rhythm, sleep-wake cycle and does not initiate ...
, toxic psychosis), 17% reported
cardiovascular In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...
problems (e.g.,
tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ...
,
bradycardia Bradycardia, also called bradyarrhythmia, is a resting heart rate under 60 beats per minute (BPM). While bradycardia can result from various pathological processes, it is commonly a physiological response to cardiovascular conditioning or due ...
), 7.6% reported pulmonary problems (5.4% of which had respiratory depression), and 4% reported
acute kidney injury Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in renal function, kidney function that develops within seven days, as shown by an increase in serum creatinine or a decrease in urine output, or both. ...
. 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 Pulmonary edema (British English: oedema), also known as pulmonary congestion, is excessive fluid accumulation in the tissue or air spaces (usually alveoli) of the lungs. This leads to impaired gas exchange, most often leading to shortness ...
; 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 The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animals and plants. The anatomy and physiology that make this happen varies gr ...
,
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
, and
renal failure Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...
.


Addiction

There have been reports of a strong compulsion to re-dose, withdrawal symptoms, and persistent cravings lasting up to a week after taking synthetic cannabinoids, indicating that synthetic cannabinoids may be more addictive than
marijuana Cannabis (), commonly known as marijuana (), weed, pot, and ganja, List of slang names for cannabis, among other names, is a non-chemically uniform psychoactive drug from the ''Cannabis'' plant. Native to Central or South Asia, cannabis has ...
.


Psychosis

Studies have strongly linked particular synthetic cannabinoids with
psychosis In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...
. 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 Recreation is an activity of leisure, leisure being discretionary time. The "need to do something for recreation" is an essential element of human biology and psychology. Recreational activities are often done for enjoyment, amusement, or plea ...
, 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. Some studies suggest that not only can synthetic cannabinoids induce psychosis, but they can worsen previously stable
psychotic disorders In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or incoh ...
and might trigger a chronic (long-term) psychotic disorder among vulnerable individuals such as those with a family history of
mental illness A mental disorder, also referred to as a mental illness, a mental health condition, or a psychiatric disability, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. A mental disorder is ...
. Individuals with
risk factor In epidemiology, a risk factor or determinant is a variable associated with an increased risk of disease or infection. Due to a lack of harmonization across disciplines, determinant, in its more widely accepted scientific meaning, is often use ...
s for psychotic disorders are often counseled against using synthetic cannabinoids. Psychiatrists have suggested that the lack of an
antipsychotic Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), p ...
chemical, like CBD in natural
cannabis ''Cannabis'' () is a genus of flowering plants in the family Cannabaceae that is widely accepted as being indigenous to and originating from the continent of Asia. However, the number of species is disputed, with as many as three species be ...
, may make synthetic cannabinoids more likely to induce psychosis than natural cannabis.


Structural classifications

There are five major categories for synthetic cannabinoids: classical cannabinoids, non-classical cannabinoids, hybrid cannabinoids, aminoalkylindoles, and eicosanoids. Classical cannabinoids are analogs of THC that are based on a dibenzopyran ring. They were developed starting in the 1960s, following the isolation of THC, and were originally the only cannabinoids synthesized. Classical cannabinoids include nabilone and
dronabinol Dronabinol (), sold under the brand names Marinol and Syndros, is the generic name for the molecule of (−)-trans-Δ9-tetrahydrocannabinol (THC) in the pharmaceutical context. It has indications as an appetite stimulant, antiemetic, and sleep ...
, and one of the best known synthetic classical cannabinoids is HU-210. HU-210 is a chiral compound first synthesized by Raphael Mechoulam at Hebrew University of Jerusalem, 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. Non-classical cannabinoids include cyclohexylphenols (CP), which were first synthesized in the late 1970s to 1980s by Pfizer as potential
analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...
s. The C8 homologue of CP 47,497, CP-47,497 (Cannabicyclohexanol, CP-47,497-C8) was one of the first synthetic cannabinoids being used recreationally. Cannabicyclohexanol, CP-47,497-C8 is made by extending the dimethylheptyl side chain of CP 47,497, 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 JWH-018 (1-pentyl-3-(1-naphthoyl)indole, NA-PIMO or AM-678) is an analgesic chemical from the naphthoylindole family that acts as a full agonist at both the CB1 and CB2 cannabinoid receptors, with some selectivity for CB2. It produces effe ...
, an aminoalkylindole. Hybrid cannabinoids have a combination of classical and non-classical cannabinoid structural features. 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. Aminoalkylindoles are structurally dissimilar to THC and include naphthoylindoles (
JWH-018 JWH-018 (1-pentyl-3-(1-naphthoyl)indole, NA-PIMO or AM-678) is an analgesic chemical from the naphthoylindole family that acts as a full agonist at both the CB1 and CB2 cannabinoid receptors, with some selectivity for CB2. It produces effe ...
), 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. The Federal Bureau of Investigation, 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. Eicosanoid synthetic cannabinoids are analogs of
endocannabinoids Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...
, such as anandamide. Endocannabinoids are cannabinoids naturally occurring in the body. One of the best known synthetic analogs of anandamide is methanandamide. Some synthetic cannabinoids 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 Structural scheduling of synthetic cannabinoids, 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. 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; however, one group that was unprecedented when discovered by forensic scientists in 2013, was the quinolinyl ester synthetic cannabinoids. PB-22 and 5F-PB-22 were the first synthetic cannabinoids to include a quinoline substructure and an Ester, ester linkage. These compounds are thought to have been synthesized with the intention of making a synthetic cannabinoid prodrug, which might improve Absorption (pharmacology), absorption and confound detection. Ester bonds are easily Biodegradation, biodegradable through spontaneous or Endogeny (biology), 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 Controlled Substances Act, US scheduling laws. Although most synthetic cannabinoids are not direct analogs of THC, they share many common features with THC. Most are Lipophilicity, lipid-soluble, Chemical polarity, non-polar, small molecules (usually 20–26 carbon atoms) that are fairly Volatile organic compound, volatile, making them "smokable", like THC. 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 Psychoactive drug, psychotropic activity from binding CB1 receptors. Also, most synthetic cannabinoids are
agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
s of both cannabinoid receptors, CB1 and CB2, like THC; however, they often have greater
binding affinity In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from Latin ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usuall ...
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.


Stereospecificity

Most classical, non-classical, and hybrid synthetic cannabinoids have stereospecificity (one stereoisomer is usually much more potent than the ). For example, HU-210 is the (–) enantiomer of 11-OH-Δ8-THC-DMH and a full
agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
of the CB1 receptor; the (+) enantiomer of 11-OH-D8-THC-DMH, known as HU-211, is a NMDA receptor antagonist and is largely inactive as a
cannabinoid Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...
. 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.


Fluorination of terminal carbon

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, as shown in table two.


Detection in bodily fluids

Synthetic cannabinoids are typically not identified by the standard marijuana drug tests including the immunoassay test (Enzyme multiplied immunoassay technique, EMIT), Gas chromatography–mass spectrometry, GC-MS screening, and multi-target screening by LC-GC/MS because those tests only detect the presence of THC and its metabolites. Although most synthetic cannabinoids are analogs of THC, they are structurally different enough that, for example, the specific Antibody, antibodies in the Enzyme multiplied immunoassay technique, EMIT for
marijuana Cannabis (), commonly known as marijuana (), weed, pot, and ganja, List of slang names for cannabis, among other names, is a non-chemically uniform psychoactive drug from the ''Cannabis'' plant. Native to Central or South Asia, cannabis has ...
do not bind to them. Due to their high potency, a very small dose of synthetic cannabinoids is used. 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. Serology, 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. 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. 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, glucuronide conjugation and also by N-dealkylation and aromatic hydroxylation. For example, the main metabolites of
JWH-018 JWH-018 (1-pentyl-3-(1-naphthoyl)indole, NA-PIMO or AM-678) is an analgesic chemical from the naphthoylindole family that acts as a full agonist at both the CB1 and CB2 cannabinoid receptors, with some selectivity for CB2. It produces effe ...
, of which there are over 20, include carboxylated, monohydroxylated, dihydroxylated, and trihydroxylated metabolites, but they are mostly excreted in urine as glucuronide conjugates. The presence of synthetic cannabinoids or their metabolites in bodily fluids may be determined using specifically targeted commercially available Enzyme multiplied immunoassay technique, immunoassay screening methods (EMIT), while Liquid chromatography–mass spectrometry, liquid chromatography-mass spectrometry is most often used for confirmation and quantitation. There are commercially available EMIT kits for the screening of the synthetic cannabinoids
JWH-018 JWH-018 (1-pentyl-3-(1-naphthoyl)indole, NA-PIMO or AM-678) is an analgesic chemical from the naphthoylindole family that acts as a full agonist at both the CB1 and CB2 cannabinoid receptors, with some selectivity for CB2. It produces effe ...
, JWH-073, JWH-398, JWH-200, JWH-019, JWH-122, JWH-081, JWH-250, JWH-203, CP 47,497, CP-47,497, Cannabicyclohexanol, 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.


Notable incidents


New Zealand

In September 2018, at least 10 people overdosed on a synthetic cannabinoid, either AMB-FUBINACA or AB, in Christchurch over two days. Some of the people were in critical condition in the Intensive care unit, Intensive Care Unit.


United States

In October 2011, the LSU Tigers football, Louisiana State University football program announced that it had suspended three players, including star cornerback Tyrann Mathieu, who tested positive for synthetic cannabinoids. On July 12, 2016, 33 people were intoxicated by an herbal "incense" product called "AK-47 24 Karat Gold", and dozens Drug overdose, overdosed, in Brooklyn. Eighteen people were transported to local hospitals. The herbal "incense" product was determined to be a synthetic cannabinoid called AMB-FUBINACA. Since March 2018, Illinois, Wisconsin, Maryland, and eight 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 and on April 5, 2018, the
CDC The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency under the Department of Health and Human Services (HHS), and is headquartered in Atlanta, ...
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. 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. 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. 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 Drug Enforcement Administration, DEA. From September 21–22, 2018, almost 50 people overdosed and two people died in the Kensington, Philadelphia, Kensington area of Philadelphia. Officials believed the cause to be a combination of heroin or fentanyl and a synthetic cannabinoid. 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." 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. Two deaths and over 41 hospitalizations have been directly linked to this specific outbreak as of December 16, 2021.


Research


Vaping-associated pulmonary injury

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


Legal restrictions and regional availability


Europe


Austria

The Austrian Ministry of Health announced in December 2008, that Spice would be controlled under 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.


Germany

JWH-018, CP 47,497 and the C6, C8, and C9 homologues of CP 47,497 have been illegal in Germany since January 2009. Since November 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.


France

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


Ireland

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


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. 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. In April 2014, parliament made selling of the temporarily banned substances a criminal offense.


Poland

JWH-018 JWH-018 (1-pentyl-3-(1-naphthoyl)indole, NA-PIMO or AM-678) is an analgesic chemical from the naphthoylindole family that acts as a full agonist at both the CB1 and CB2 cannabinoid receptors, with some selectivity for CB2. It produces effe ...
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 and Polish Senat and was signed by the President.


Romania

Spice was made illegal in Romania in February 2010. In September 2018, Spice was made legal for personal use. A new law is being discussed to make spice illegal for personal use again.


Russia

In April 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. In January 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. 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 2000 Spice consumers in Russia sought medical attention, 1000 were admitted to hospitals, and 40 people died. In October 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.


Slovakia

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


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.


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 in September 2009.


Switzerland

Spice has been banned in Switzerland.


Turkey

Spice, which is colloquially called ''bonzai'' in Turkey, was added to the list of drugs and psychotropic substances in July 2011.


United Kingdom

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


North America


Canada

Spice is not specifically prohibited in Canada, but synthetic cannabis mimics are listed as a schedule II drug. Schedule II to the Controlled Drugs and Substances Act makes reference to specific synthetic compounds JWH-XXX and AM-XXXX, although is not limiting to those identified. Health Canada is debating the subject. 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

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 Rifle, hunting rifle in an apparent
suicide Suicide is the act of intentionally causing one's own death. Risk factors for suicide include mental disorders, physical disorders, and substance abuse. Some suicides are impulsive acts driven by stress (such as from financial or ac ...
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 (drug), 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. 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 controlled substance, Schedule I of the Controlled Substances Act. Prior to that, some synthetic cannabis compounds (HU-210) were Controlled Substances Act, scheduled in the US under federal law, while others (JWH-073) were temporarily scheduled until final determination of their status could be made. The Drug Enforcement Administration (DEA) considered K2 to be a "drug of concern", 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." Several states independently passed acts making it illegal under state law, including Kansas in March 2010,The Associated Press. How major issues fared in Kansas Legislature. CNBC. May 23, 2010. Accessed: May 23, 2010
/ref> Georgia (U.S. state), Georgia and Alabama in May 2010, Tennessee and Missouri in July 2010,Gay, Malcolm. (2010-07-10
Synthetic Marijuana Spurs State Bans
''The New York Times''. Retrieved on August 7, 2011.
Louisiana in August 2010, Mississippi in September 2010, and Iowa. An emergency order was passed in Arkansas in July 2010 banning the sale of synthetic cannabis mimics. 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. According to the National Conference of State Legislatures, several other states also considered legislation, including New Jersey, New York, Florida, and Ohio. Illinois banned all synthetic cannabinoids in January 2011. Michigan banned synthetic cannabinoids in October 2010. The South Dakota banned these products in February 2012. Indiana banned synthetic cannabinoids in March 2012. 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 Addiction, psychological dependency. Following cases in Japan involving the use of synthetic cannabinoids by navy, army and marine corps personnel, they were officially banned. A punitive general order issued in January 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. In June 2010, the US Air Force issued a memorandum that banned the possession and use of Spice, or any other mood-altering substance except alcohol (drug), alcohol or tobacco, among its service members. Usage among 8th, 10th, and 12th graders has been decreasing since 2011, while use of botanical marijuana has remained stable. There are important regional differences, with large declines in the Western and Southern US, and increases in the Northeast and Midwest.


= Dronabinol

= Exceptional are synthetic ∆9-THC (
dronabinol Dronabinol (), sold under the brand names Marinol and Syndros, is the generic name for the molecule of (−)-trans-Δ9-tetrahydrocannabinol (THC) in the pharmaceutical context. It has indications as an appetite stimulant, antiemetic, and sleep ...
) -containing FDA-approved drug products with a currently accepted medical use in treatment in the United States, such as Syndros and Marinol, which are, respectively, under Schedule II and Schedule III of the CSA.


South America


Chile

The Ministry of Health (Chile), Chilean Ministry of Health in April 2009, declared the sale of synthetic cannabis mimics to be illegal.


Asia


South Korea

South Korea added JWH-018, CP 47,497 and HU-210 to the controlled substance list in July 2009, effectively making these chemicals illegal.


Indonesia

''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.


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.


Australasia


Australia

In June 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. In June 2013, an interim ban made a large list of product brands and synthetic substances illegal to sell anywhere in Australia. This ban lapsed on October 13, 2013, and a permanent ban has not been imposed. Synthetic cannabinoids and related products remain illegal in NSW, where a bill was passed in September 2013, that bans entire families of synthetic drugs instead of only banning existing compounds that have been identified. The introduction of this law makes NSW the first state in Australia to completely ban substances with psychoactive properties.


New Zealand

Synthetic Cannabinoids are illegal in New Zealand, it is classified as a Class A controlled drug. The New Zealand Parliament passed a law in July 2013 banning the sale of legal highs in Convenience store, dairies and supermarkets, but allowing some "low risk" drugs to continue to be sold through speciality licensed shops. Synthetic cannabinoids, as well as all other legal highs were outlawed in May 2014. 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-018 (1-pentyl-3-(1-naphthoyl)indole, NA-PIMO or AM-678) is an analgesic chemical from the naphthoylindole family that acts as a full agonist at both the CB1 and CB2 cannabinoid receptors, with some selectivity for CB2. It produces effe ...
, 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. 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. 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.


See also

*Chimique *List of designer drugs#Synthetic cannabinoids, List of designer drugs § Synthetic cannabinoids *Endocannabinoid enhancer *Endocannabinoid system *Structural scheduling of synthetic cannabinoids *Synthetic Cannabinoid Use Disorder


References


Further reading

*


External links

* {{DEFAULTSORT:Spice (Drug) Cannabinoids, * Designer drugs Drug culture