Designer Drug Exposé: Cannabinoids
Cannabinoids are any compound (natural or synthetic) that interact with the endocannabinoid system. There are hundreds of them, with new, structurally unique substances being discovered all the time.
Humans have been consuming cannabis for its medicinal, nutritional, and psychoactive qualities since at least 3000 BCE. It was used as a medicine by ancient Egyptians, Chinese, Indians, and virtually every other culture to come into contact with it — yet it remains strictly prohibited in almost every country on Earth.
For the past 75 years, cannabis use has been relegated to the underground. The only option was to grow the plant ourselves (illegally) or buy it from someone who did. Getting caught could result in a double-digit jail sentence.
Everything changed in the late 2000s with the emergence of designer cannabinoids.
New and untested psychoactive cannabinoids like HU-210, JWH-018, and AM-2201 were sprayed onto dried leaves and shipped to headshops around the world. They were sold under names like Spice, K2, or Black Mamba.
They were sold as "legal weed" alternatives that could be smoked the same way one would smoke marijuana. These products didn’t contain anything that was actually derived from the illegal cannabis plant — so, as per the law at the time, they were completely legal to buy and sell.
Today, the number of synthetic cannabinoids in existence reaches into the triple digits. Our database contains a total of 313 individual cannabinoids, but new ones are created all the time.
Designer cannabinoids reached peak popularity in the early 2010s before regulators started taking steps to ban them. Legislation is slow, so by the time these loopholes were closed, designer cannabinoids had already flooded the market — you could find them at headshops, gas stations, and online marketplaces the world over.
It was rare to find products that actually listed what was contained inside. Most were designed purely to intoxicate, with no regard for risk or harmful side effects (which were many).
Starting in 2012, sweeping bans on synthetic cannabinoids were implemented by federal agencies like the DEA and FDA. However, as with all designer drugs, the moment one compound was banned, 3 new ones would appear to take its place.
As of 2024, a total of 78 individual cannabinoids are now listed as banned Schedule I drugs in the United States — but there are many others that have yet to appear on the radar of regulators.
The Evolution of the Designer Cannabinoid Market
Despite the bans, the designer cannabis market has grown substantially in recent years.
The synthetic cannabinoid market was valued at around $3 billion USD in 2023 and is projected to reach $20.1 billion by 2032.
This goes in parallel to a new trend in the legal cannabis space, which involves pushing a new set of alternative cannabinoids like delta-8-THC and HHC (hexahydrocanabinol), which are technically found in the cannabis plant but require sophisticated chemical conversion to obtain in any useable amounts.
Research by Brightfield Group suggests the legal delta-8-THC and other alt-cannabinoid market is believed to have grown 1,283% from $200.5 million in 2020 to $2.8 billion at the end of 2023.
This new market was initiated by the surprising update of the Farm Bill in 2018 — which, for the first time, set official distinctions between legal and illegal types of cannabis plants.
More specifically, the bill established a clear difference between Cannabis sativa plants that produce lots of THC (more than 0.3% of dried flowers) and Cannabis sativa plants that produce very little (less than 0.3%).
Plants with more than 0.3% THC are considered “marijuana” and are illegal according to federal law.
Plants that produce less than 0.3% THC are considered hemp and are perfectly legal to grow and sell.
Today’s designer cannabinoids — that is, compounds developed as a way to circumvent bans on marijuana and delta-9 THC — are largely centered around a loophole in this bill.
Psychoactive cannabinoids like delta-8-THC, delta-10-THC, THCP, and HHC are chemically converted from CBD — which was extracted from legal hemp plants.
They’re considered “legal” because they don’t contain delta-9-THC (which is explicitly banned), are made exclusively from hemp (not marijuana), and are naturally occurring (even though commercial versions are actually manufactured through a synthetic isomerization process).
The debate as to whether these compounds count as designer drugs or not is ongoing.
An even more recent development is the reframing of THCA — which is the raw form of delta-9-THC found in unprocessed cannabis plants. Because the law is so specific towards delta-9-THC as the “illegal” component of cannabis, vendors argue that plants producing high levels of THCA, but not delta-9 THC are exempt.
This loophole essentially reframes plants that were previously labeled "marijuana" as "hemp."
To nobody's surprise, the DEA disagrees with this interpretation but has yet to take any specific action against it.
As soon as THCA is exposed to heat (such as through smoking, vaping, or baking), the carboxyl (acid) group is ripped off — yielding pure delta-9 THC. This means the effects of THCA are identical to that of THC — there is no difference.
Now, on to the good stuff.
Designer Cannabinoid Families
Cannabinoids can be split into three key groups based on their general chemical structure:
Classical cannabinoids — the cannabinoids found in the cannabis plant or share the same base structure.
Eicosanoids — a new and emerging group of complex, hormone-like molecules that resemble our endogenous cannabinoids.
Non-classical cannabinoids — anything else that binds to cannabinoid receptors (this group is HUGE).
Let’s explore each class more closely, along with some of the most prominent members of each group.
1. Classical Cannabinoids
All naturally occurring cannabinoids from the cannabis plant are considered classical cannabinoids. They’re defined as “ABC-tricyclics incorporating a benzopyran moiety.”
Classical cannabinoids can be further categorized according to their backbone structures, which determine much of their chemical and biological behavior:
Orchinoids (Delta-9 THC, Delta-8 THC) — Psychoactive.
Varinoids (THCV, CBDV) — Inactive or low psychoactivity.
Olivetoids (THCP, THCB) — Typically very potent.
Bibenzyls (Canniprene, Perrottetinene) — Inactive or low psychoactivity.
In the context of designer drugs, there are three main groups we can use to breakdown this family based on how close to nature each compound is:
Enzymatically-produced (Delta-9-THC, THCV, CBG, CBD, CBC) — These are the cannabinoids made on purpose by the plant using specialized enzymes.
Spontaneously-produced (HHC, Delta-8-THC, CBN) — These compounds form spontaneously as cannabinoids are exposed to the air, heat, pH changes, or UV radiation.
Synthetically-produced (THC-O, HU-210, AM-2201) — These compounds can only be manufactured synthetically and do not exist in nature.
Experts disagree on whether we can include naturally occurring spontaneous cannabinoids under the designation of “designer” cannabinoids or not. Compounds like delta-8 THC and HHC are technically found in the plant in trace amounts, but they aren't made on purpose. They form as a rare byproduct as other cannabinoids break down.
For example, to make a single dose of delta-8-THC (around 20 mg), we would need to extract roughly 250–500 pounds of dried marijuana. This compound forms as delta-9-THC breaks down, so hemp plants, which naturally produce low concentrations of delta-9-THC, require significantly more to get the same dose — closer to 10,000 or 15,000 pounds.
If the companies selling these substances were to rely on extracting delta-8-THC directly from hemp, as most claim, the cost would be prohibitively high. Instead, they apply a process called isomerization to convert CBD into delta-8-THC, HHC, and others. Whether this is illegal or not has been under debate for the past three years (is this considered synthetic? How does this ruling apply to substances that are technically also found in nature?)
Examples of naturally occurring “designer” cannabinoids in this class include HHC (hexahydrocannabinol), THCV (tetrahydrocannabivarin), THCP (tetrahydrocannabiphorol), delta-8-THC, delta-10-THC, THCB (tetrahydrocannabutol), and the active metabolite of THC, delta-11 (11-Hydroxy-THC).
Examples of synthetic designer cannabinoids in this class include HU-210, 9-ketocannabinoid (Nabilone), AM-2389, AM-993, AM-994, AM-7499, and THC-O-Acetate.
HU-210 stands out here. It's the strongest classical cannabinoid ever discovered — estimated to be somewhere between 100 and 800 times more potent than delta-9 THC (depending on study design). It was invented by a research group at the Hebrew University (hence the abbreviation “HU”) in 1988 while under the leadership of the infamous organic chemist Raphael Mechoulam — otherwise known as "the godfather of cannabis research." Mechoulam is also credited with the isolation of THC and the discovery of the endocannabinoid system.
2. Synthetic Eicosanoids
The endocannabinoid system is one of the oldest biological signaling systems — believed to have first appeared in the nervous system of the hydra — a species of simple aquatic animals that evolved more than 600 million years ago.
All vertebrates on Earth have an endocannabinoid system, which is involved with regulating everything from appetite to mood.
There are two naturally occurring endocannabinoids, which are types of eicosanoids (signaling lipids). These are 2-AG and anandamide.
Designer cannabinoids can theoretically be made in the likeness of these naturally occurring messenger molecules. However, to date, most of the synthetics in this class have proven either inactive or toxic. It remains a theoretical class for chemists to explore in the future.
There are only noteworthy examples in this class — methanandamide (which acts as a more stable analog of anandamide) and 2-AG Ether (which is a modified version of 2-AG with a longer half-life).
3. Non-Classical Cannabinoids
This group contains the vast majority of designer cannabinoids.
Basically, anything that activates the endocannabinoid system or provides effect profiles similar to those of THC but doesn't fit the basic description for a classical cannabinoid is considered a non-classical cannabinoid.
This group is massive and can be further subdivided into 8 subgroups:
Adamantoylindoles
These synthetic cannabinoids feature a structural modification that typically enhances lipophilicity (the ability of the molecule to dissolve in fat). This enhancement gives them a stronger binding capacity to the cannabinoid receptors, thus increasing their potency.
A few examples in this group known to be used as designer cannabinoids include AB-001 and AM-1248.
Aminoalkylindoles
This class was first developed by the pharmaceutical company Sterling-Winthrop in the early 1990s as a new class of non-steroidal anti-inflammatory drugs (NSAIDs). None of these drugs ever made it to market after clinical studies reported unusually high incidences of acute kidney damage and other harsh side effects.
A few of these drugs are still used today in synthetic cannabis products but are generally less favored than other classes.
The main members of this group include Pravadoline (WIN 48098), WIN 55,212-2, and EAM-2201.
Benzoylindoles
Not much is known about this group. Several of these compounds were first reported by the American biochemist, Alexandros Makriyannis (these drugs maintain the “AM” abbreviation).
Benzoylindole cannabinoids have been reported in drug detection agencies in Europe and the United States, but none appear to be very popular today.
A few members of this group are either inactive or completely block the CB1 or CB2 receptors. Examples include AM-630 and 6-Bromopravadoline.
Examples of psychoactive members of this group include AM-679, AM-694, AM-2233, GW-405,833, 3-(4-Hydroxymethylbenzoyl)-1-pentylindole, RCS-4 (E-4), and AM-1241 (weak).
Cyclohexylphenols
There are only 3 prominent members in this group that interact with the cannabinoids system.
CP 47,497 (cannabicyclohexanol) and CP55,940 were both invented by the pharmaceutical company, Pfizer (1982 and 1974, respectively) but were never marketed.
These compounds are exceptionally strong; Cannabicyclohexanol is roughly 5 times more potent than delta-9 THC, and CP55,940 is nearly 45 times as strong. Both compounds are well-known for their inclusion in Spice and other synthetic cannabinoid products and are officially banned throughout the US, Canada, and most of Europe.
The third compound is O-1871, which was invented by Billy R Martin and Raj K Razdan at Organix Inc. in 2002. It’s unknown whether this compound has hit the designer drug market yet.
Indazole Carboxamides
The indazole carboxamide cannabinoids are exceptionally potent. Because of this, they’re also some of the most common substances found in fake weed products.
Carboxamide groups are often added to molecules during pharmaceutical drug development because they have a tendency to dramatically alter the pharmacological properties of the original molecule — sometimes making them weaker but often enhancing their effects. Carboxamide additions are used in cancer medications such as Niraparib (Zejula), Olaparib (Lynparza), and Rucaparib (Rubraca), as well as analgesics like Tapentadol.
The indazole carbamoxide cannabinoids are some of the most common ingredients in herbal smoke blends today.
A study in China found that over 36 random samples of herb blends contained as least one of the following isazole carboxamides in every sample: 4F-MDMB-BUTINACA, 4F-MDMB-PUTICA, 5F-ADB, 5F-EDMB-PICA, 5F-MDMB-PICA, ADB-BUTINACA, ADB-FUTINACA, AMB-CHMICA, AMB-FUBINACA, and MDMB-4en-PINACA.
Several members of this group are also well-known to induce severe psychotic symptoms in humans — such as 5F-ADB and MDMB-FUBINACA. There are likely many other synthetic cannabinoids with this side effect that share either an indazole or indole core.
Other compounds found in this group include: 4F-MDMB-BINACA, 4F-MDMB-BICA, 5F-APINACA, 5F-AB-PICA, 5F-AB-PINACA, 5F-AMB, MMB-2201 (5F-AMB-PICA), 5F-CUMYL-PINACA (SGT-25), 5F-EMB-PICA, and more.
Naphthoylindoles
The naphthoyl group present in all these compounds enhances the lipophilicity and potency of the core structure, making them exceptionally potent at binding with cannabinoid receptors. This class is well-studied and was the most abundant class in the early days of the designer cannabinoid craze.
JWH-018 was the first to enter the market. It was invented in the early 1990s and has been on the public market since at least 2004 (now banned worldwide).
JWH stands for “John W. Huffman” — one of the lead chemists to have discovered this new class of synthetic cannabinoids.
He’s quoted as saying:
“It bothers me that people are so stupid as to use this stuff."
Others in this group are named after Alex Makryannis (AM) — a group of potent bicyclic cannabinoids.
Most of the compounds in this class are exceptionally strong. In the right dose, the effects are similar to THC, but just a little too much leads to a collection of notoriously harsh side effects, including seizures, psychosis, and, in some cases, death.
The naphthoylindole cannabinoid group is very large, but the most predominant include JWH-018, JWH-073, JWH-200, and AM-2201.
Others include AM-1220, AM-1221, AM-1235, AM-2232, CBL-018, JWH-007, JWH-015, JWH-019, JWH-022, JWH-080, JWH-081, JWH-098, JWH-116, JWH-122, JWH-149, JWH-182, JWH-193, JWH-198, JWH-210, JWH-267, JWH-398, JWH-424, MAM-2201, NE-CHMIMO, and NM-2201.
Phenylacetylindoles
This group of indole-based synthetic cannabinoids look a lot like the naphthoylindole class, only instead of a naphthoyl group, these compounds feature a phenylacetyl group. This change doesn’t appear to have much difference in the potency but may have some impact on the quality of effects.
For example, JWH-250 is described as being more “psychedelic” than the other JWH cannabinoids and JWH-250 is often described as “dissociative.”
Common phenylacetylindole cannabinoids include JWH-167, JWH-203, JWH-249, JWH-250, JWH-251, JWH-302, JWH-320, and RCS-8.
Tetramethylcyclopropylindoles
This small group consists of just 5 known substances (so far) — UR-144, XLR-11, FUB-144, A-796,260, and A-834,735.
This indole-based cannabinoid group shares similarities in structure and effects as the benzoylindoles, naphtyoylindoles, and pheylacetylindoles.
All but XLR-11 were invented by Abbott Laboratories in the 2000s but failed clinical testing and never made it to market.
XLR-11 and UR-144 were picked up by vendors selling designer cannabinoids around 2008 and both remain relatively common today. Both substances have a rapid onset and short duration of effects. UR-144 is milder (considered to be roughly half as potent as delta-9 THC) compared to XLR-11 (roughly 2X as potent).
A-796,260 is completely inactive (selective to the CB2 receptors), and A-834,735 never seemed to have caught on despite being roughly 3X stronger than delta-9 THC.
What Are The Most Potent Cannabinoids?
Using delta-9 THC as the baseline, researchers have mapped out the relative potency of hundreds of individual cannabinoids.
These values are based on the ability for cannabinoids to bind to the CB1 or CB2 endocannabinoid receptors (binding affinity). While this is a useful metric, it doesn’t do a perfect job of comparing the relative potency of cannabinoids. Some compounds bind more strongly but exert less effect on the receptor.
An example of this is LY320135, which has roughly 21 times the binding affinity to the CB1 receptor but causes no effect whatsoever.
Potency also depends on individual factors, such as body chemistry or tolerance.
List of Top 10 Most Potent Known Cannabinoids (CB1 Receptors):
HU-210 (Classical Cannabinoid) — This is the strongest cannabinoid known. Placed somewhere between 100 and 800 times more potent than delta-9 THC.
5F-ADB (Indazole Carbamoxide) — Estimated to be more than 290 times more potent then delta-9 THC.
MDMB-CHMICA — A highly potent synthetic cannabinoid with strong agonistic effects on CB1 receptors, estimated to be up to 286X stronger than delta-9 THC.
ADB-PINACA — A potent synthetic cannabinoid, showing around 68X stronger than delta-9 THC in its ability to activate cannabinoid receptors.
AM-2201 — Estimated to be roughly 40 times stronger than delta-9 THC.
CP55,940 — Estimated to be around 45X stronger than delta-9 THC.
THCP (Delta-9 Tetrahydrocannabiphorol) — A naturally occurring trace cannabinoid with roughly 33x stronger binding affinity for the CB1 receptors as delta-9 THC.
WIN 55,212-2 — A synthetic aminoalkylindole derivative estimated to be around 10X stronger than delta-9 THC.
FUB-AMB (AMB-FUBINACA) — This potent compound has been found to have roughly 5X binding affinity compared to delta-9 THC.
JWH-018 — Studies suggest this cannabinoid is roughly 4–5 times stronger than delta-9 THC.
It's important to note that higher potency also means higher chances of side effects — and more severe side effects when they do appear.
Potent, synthetic cannabinoids frequently cause side effects like nausea, dizziness, anxiety, heart palpitations, and seizures. In some cases, they’ve even been known to cause cardiac events, psychosis, and death.
Designer Drug Series
This has been part 7 in a 10-part series on designer drugs.
Read some of our past series using the link below, or subscribe to receive new posts as they’re released in upcoming weeks:
Part 7: Cannabinoids
Part 8: Sedative Hypnotics & Opioids (Subscribe)
Part 9: Deliriants (Subscribe)
Part 10: Atypical Designer Drugs (Subscribe)
Enjoying Tripsitter? 🍄❤️
Don’t Journey Alone! Tripsitter was built by a community of psychedelic advocates — but it’s people like you that enable us to thrive.
If you found this newsletter insightful, share the love ❤️ using the link below.