Synthetic cannabinoids are a class of molecules that bind to the same receptors to which cannabinoids in cannabis plants THC and CBD attach. They are designer drugs , commonly sprayed onto plant matter  and are usually smoked,  although they have also been ingested as a concentrated liquid form in the US and UK since Most synthetic cannabinoids are agonists of the cannabinoid receptors.
They have been designed to be similar to THC ,  the natural cannabinoid with the strongest binding affinity to the CB 1 receptor , which is linked to the psychoactive effects or "high" of marijuana. There are several synthetic cannabinoid families e. When the herbal blends went on sale in the early s, it was thought [ by whom? Laboratory analysis in showed instead that many contained synthetic cannabinoids. 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. The Centers for Disease Control and Prevention CDC found that the number of deaths from synthetic cannabinoid use tripled between and Just as the synthetic cannabinoid s used differ between each synthetic cannabinoid product sold, so do the other contents of the "herbal blends.
Oftentimes, none of the listed ingredients have been detectable. It is often difficult to determine what is in these products because masking agents , such as tocopherol vitamin E , eugenol , and fatty acids , are added to confound identification.
Most products consist of synthetic cannabinoids sprayed onto inert vegetable matter, but some contain other psychoactive substances , including psychoactive herbs, e. Some synthetic cannabinoids products have also been found to contain synthetic opioids including O -desmethyltramadol and AH 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.
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 ;  substituted cathinone derived stimulant drugs such as 4-methylbuphedrone and 4'-methyl-alpha-PPP ; and psychedelic tryptamine derivatives such as 4-OH-DET. 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.
Huffman and AM compounds are named after Alexandros Makriyannis , the scientists who first synthesized those cannabinoids. HU compounds are named after Hebrew University in Jerusalem, the institution where they were first synthesized, and CP compounds are named after Charles Pfizer , the company where they were first synthesized.
Some of the names of synthetic cannabinoids synthesized for recreational use were given names to help market the products. 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.
Use of the term "synthetic marijuana" to describe products containing synthetic cannabinoids is controversial and, according to Dr. Nelson claims that relative to marijuana , products containing synthetic cannabinoids "are really quite different, and the effects are much more unpredictable.
It's dangerous. They are often called "synthetic marijuana", "natural herbs", "herbal incense", or "herbal smoking blends" and often labeled "not for human consumption".
In , the brand gained popularity. 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.
Tritium -labelled cannabinoids such as CP, were instrumental in discovering the cannabinoid receptors in the early s. 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 Synthetic THC marinol, dronabinol has been used as an antiemetic since , and an appetite stimulant since In the early s, 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 , 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. 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. Some of the negative effects of 5F-AKB reported by users included palpitations , paranoia , intense anxiety, and a taste like burned plastic.
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 , CB 1 and CB 2 , compared to THC , which is only a partial agonist. Some may work on NMDA glutamate receptors.
Phase 1 metabolism of JWH results in at least nine monohydroxylated metabolites , three of which have been shown to be full agonists of the CB 1 receptors , compared to the metabolism of THC , which only results in one psychoactive monohydroxylated metabolite.
The metabolite N- 3-hydroxypentyl JWH was found to have toxic effects that its parent compound does not. 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 ;  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 and and of drug overdose patients who reported synthetic cannabinoid as the sole agent, Four postmortem cases linked to the synthetic cannabinoids 5F-PB have been reviewed.
The postmortem blood specimens contained a range of 1. 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. Studies are currently available that suggest an association between synthetic cannabinoids and psychosis.
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. JWH , AM ,. 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 s, following the isolation of THC ,  and were originally the only cannabinoids synthesized. It was discovered in herbal incense products by the U. Customs and Border Protection in January ; 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 s to s by Pfizer as potential analgesics.
CP,C8 is made by extending the dimethylheptyl side chain of CP, to a dimethyloctyl side chain. It was discovered by forensic scientists in an herbal blend known as "Spice" in , along with JWH , an aminoalkylindole. Hybrid cannabinoids have a combination of classical and non-classical cannabinoid structural features.
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. Huffman's research, people searching for a " marijuana-like-high " would follow his recipes and methods.
Eicosanoid synthetic cannabinoids are analogs of endocannabinoids , such as anandamide. Endocannabinoids are cannabinoids naturally occurring in the body. One of the best known synthetic analogs of anandamide is methanandamide. The synthetic cannabinoids that have emerged recently have even greater structural diversity, possibly to subvert legal regulations on earlier generations of synthetic cannabinoids.
There are a few different structural classifications of synthetic cannabinoids that include many of the new structures, some of which are shown in Table 1. PB and 5F-PB were the first synthetic cannabinoids to include a quinoline substructure and an ester linkage. These compounds are thought to have been synthesized with the intention of making a synthetic cannabinoid prodrug , which might improve absorption and confound detection.
Ester bonds are easily biodegradable through spontaneous or endogenous , nonspecific esterase hydrolysis, which has been commonly used in medicinal chemistry to make ester prodrugs. The reason for the change to the quinolone substructure is unknown, but it may have been found to be a suitable replacement for the naphthoyl moiety that is currently regulated by US scheduling laws. Most are lipid-soluble , non-polar , small molecules usually carbon atoms that are fairly volatile , making them "smokable," like THC.
It has been found that this chain of carbons is required for optimal psychotropic activity from binding CB 1 receptors. Most classical, non-classical, and hybrid synthetic cannabinoids have stereospecificity one stereoisomer is usually much more potent than the other s. Recently there has been an increase in the emergence of terminally fluorinated synthetic cannabinoids, such as 5F-PB fluorinated version of PB and XLR fluorinated version of UR On October 20, , the Louisiana State University football program announced that it had suspended three players, including star cornerback Tyrann Mathieu , who tested positive for synthetic cannabinoids.
In the autumn of , more than two-thousand Spice consumers in Russia sought medical attention, one-thousand were admitted to hospitals, and 40 people died. On July 12, , 33 people were intoxicated by an herbal "incense" product called "AK 24 Karat Gold,"  and dozens overdosed , in Brooklyn. Since March , Illinois, Wisconsin, Maryland, and 8 other states in the United States have had an outbreak of severe bleeding caused by a synthetic cannabinoid contaminated with brodifacoum , a rat poison that causes bleeding.
Illinois was hit the hardest  and on April 5, , the CDC issued a Clinical Action alert to health care providers across the United States advising of 89 confirmed cases of "serious unexplained bleeding" in Illinois. The cases are still being studied; however, 63 of the patients reported synthetic cannabinoid use, and laboratory analysis confirmed brodifacoum was present in at least 18 patients.
In August , there were almost one hundred overdose cases reported over two days in New Haven, Connecticut from a bad batch of K2. The synthetic cannabinoid was believed to have been mixed with fentanyl , although no fentanyl was identified in samples of the drug tested by the DEA. Some of the people are in critical condition in the Intensive Care Unit. From September 21—22, , almost 50 people overdosed and two people died in the Kensington area of Philadelphia. Tests are still in progress, but officials believe the cause to be a combination of heroin or fentanyl and a synthetic cannabinoid.
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. The Austrian Ministry of Health announced on December 18, 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 is under review. From June , JWH, along with a variety of other designer drugs, has been illegal. On April 3, , parliament made selling of the temporarily banned substances a criminal offense.
JWH and many of the herbs mentioned on the ingredient lists of Spice and similar preparations were made illegal in May Spice was made illegal in Romania on February 15, As on 12 September Spice was made legal for personal use.