Synthetic Cannabinoids: A 2.5 Minute Primer

What are synthetic cannabinoid receptor agonists and how do they work in the body?

Synthetic cannabinoid receptor agonists (also called SCRAs or synthetic cannabinoids) are laboratory developed chemicals that bind to the cannabinoid receptors 1 and 2 (CB₁ and CB₂) in the body. CB₁ receptors are primarily located in the central nervous system (the brain and spinal cord) and are responsible for mediating the psychoactive effects of cannabis. The CB₂ receptors are primarily located in the peripheral nervous system, as well as the spleen and immune system, and are thought to be involved in pain perception mediation and immunosuppression. While delta-9-tetrahydrocannabinol (THC), the primary psychoactive component found in marijuana, is a partial agonist of both the CB₁ and CB₂ receptors, SCRAs are considered to act as full agonists of the same receptors.

Are these substances the same as marijuana?

No. The media loves to use the words synthetic marijuana or synthetic weed or synthetic pot to describe SCRA containing products. This description could not be further from reality. SCRAs and related products are not marijuana. 

From where did these compounds originate?

Many compounds have originated in academic research on new drug targets and the cannabinoid receptor systems. The JWH series (JWH-018, JWH-019, JWH-122, etc.) of SCRAs were developed at Clemson University under Dr. John W. Huffman. AM-2201 was developed at Northeastern University under Alexandros Makriyannis. Another SCRA, UR-144, was developed by Abbott Labs. XLR-11, a 5-fluorinated derivative of UR-144, was covered under an Abbott Labs patent, but never synthesized. The indazole carboxamide ADB-FUBINACA was synthesized by Pfizer as a possible therapeutic drug. Some compounds on the market today have no formal academic or industry history and are the product of clandestine chemists using rational drug design.

Are these chemicals considered “controlled substances” in the USA?

In the USA, SCRAs have been sold as ingredients in herbal incense, herbal potpourri, or smoking blends since approximately 2009 and have become popular as a cannabis alternative. The powders are also available via the Internet. Throughout the last several years in the USA, various waves of legislation have been passed by the Federal government classifying several synthetic cannabinoids as Schedule I controlled substances. Schedule I controlled substances are those substances that are considered to have a high potential for abuse, a potential for severe psychological or physical dependence, and have no currently accepted medical use in the USA. These substances are illegal to possess, manufacture, and distribute. As this legislation is enacted, manufacturers and vendors of these substances and resulting mass-produced retail products vary the active ingredient(s) to now uncontrolled (and quasi-legal) substances. Currently there are thirty eight (38) synthetic cannabinoids explicitly controlled by the Federal government as Schedule I controlled substances.

These are:

4-CN-CUMYL-BUTINACA, 5F-AB-PINACA, 5F-ADB, 5F-AKB48, 5F-AMB, 5F-CUMYL-P7AICA, 5F-PB-22, AB-CHMINACA, AB-FUBINACA, AB-PINACA, ADB-FUBINACA, ADB-PINACA, AKB48/APINACA, AM694, AM2201, CP-47,497, CP-47,497-C8 homologue, FUB-AMB, JWH-018/AM678, JWH-019, JWH-073, JWH-081, JWH-122, JWH-200, JWH-203, JWH-250, JWH-398, MAB-CHMINACA, MDMB-CHMICA, MDMB-FUBINACA, MMB-CHMICA, NM2201, PB-22, RCS-4/SR-19, RCS-8/SR-18, THJ-2201, UR-144, and XLR-11

Each state in the USA has its own controlled substance laws. As there is considerable variation in inter-state laws – some states have blanket bans on chemical structure classes and other states only explicitly list substances by name while other states use a combinatorial approach – please consult those specific laws for a list of scheduled substances.

How are these products made?

Common plant material, such as marshmallow leaf, mullein, or damiana can be easily purchased over the internet in bulk and used as the base for the herbal incense product. The drug material can also be purchased over the Internet and is then dissolved in acetone or high proof ethanol and sprayed on the plant material. The plant material is dried and packaged for distribution. The laboratories in which these products are made do not possess stringent quality assurance/quality control (QA/QC) policies, so there tends to be much cross contamination of product as well as intra-product variation in actual synthetic cannabinoids used. Also, due to the lack of QA/QC procedures, there may be ‘hot spots’ of drug in certain section of the plant material, which essentially means that the drug is not uniformly applied to the substrate leading to extreme variation in dosages across a batch of product.

How are these substances or products consumed?

The plant material products can be rolled up in a cigarette or joint and smoked like tobacco or marijuana. The chemical powder can also be smoked. SCRAs are also available in liquid form for vaping via electronic cigarettes (e-cigarettes).

What are some commonly reported effects of these substances?

Common cognitive and psychomotor effects attributed to SCRAs include poor coordination, instability, slowed movements, sedation, sway, balance issues, slowed or slurred speech, agitation, irritability, delusions, paranoia, hallucinations, and psychosis. Other adverse effects that have been observed include nausea, vomiting, tachycardia, hypertension, hyperthermia, and acute kidney injury. Several fatalities have occurred after use of these substances. As with any drug, effects seem to be very dose-dependent. Lower doses will elicit the more common effects while larger doses or repeated dosing will lead to the more exaggerated adverse effects.

What are a forensic toxicologist’s thoughts on SCRAs?

In the laboratory, we’ve been dealing with synthetic cannabinoids for approximately the last 6 years. In 2009-2010, there were only 1-2 synthetic cannabinoids detected in casework. Via different forces on the market (in my opinion, not the only factor, but primarily legislation) the market exploded in sheer number of compounds and continues to change with the ever-evolving controlled substance laws. The USA has legislated itself into a public health nightmare. By continually outlawing substances, we have allowed compounds with completely unknown pharmacological and toxicological profile to find their way to the grey-market. We are only seeing the beginnings of this nightmare through mass hospitalizations and outbreaks of illnesses (and a noted increase in phone calls to poison centers) after use of synthetic cannabinoid-containing products. The vast majority of people using these substances and products are consuming substances of unknown identity with unknown pharmacological and toxicological profiles in unknown combinations at unknown dosages. This is reckless behavior. This is dangerous behavior. It will result in serious adverse health effects for the individual.

The chemical diversity in structure of these compounds is amazing. Take a bit of substance A and mix it with this bit from substance B and add it all together with this group from substance C. Voila! We have new alphabet soup synthetic cannabinoid compound D! I’ve coined the phrase “diverse chemical grab bag o’ death” to describe these substances. We know very little of the true acute effects of individual synthetic cannabinoids. We know nothing of the long-term or chronic effects of synthetic cannabinoid use (and we will not for quite some time). We do not know if they act on other receptors or mediate other effects downstream. It is thought that they do not, but who knows. And therein is the important part of this - we know nothing about these compounds. Nothing. And that is what makes them dangerous.