Synthetic Pot: Not Your Grandfather's Marijuana

Abstract

In the early 2000s in Europe and shortly thereafter in the USA, it was reported that 'legal' forms of marijuana were being sold under the name K2 and/or Spice. Active ingredients in K2/Spice products were determined to be synthetic cannabinoids (SCBs), producing psychotropic actions via CB₁ cannabinoid receptors, similar to those of Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the primary active constituent in marijuana. Often abused by adolescents and military personnel to elude detection in drug tests due to their lack of structural similarity to Δ⁹-THC, SCBs are falsely marketed as safe marijuana substitutes. Instead, SCBs are a highly structural diverse group of compounds, easily synthesized, which produce very dangerous adverse effects occurring by, as of yet, unknown mechanisms. Therefore, available evidence indicates that K2/Spice products are clearly not safe marijuana alternatives.

Figure 1. Structural evolution and legislative scheduling of SCBs between 2010 and 2014

Schematic illustration shows the prevalent SCB structural classes and corresponding compounds available in K2/Spice products. In 2010, naphthoylindoles, such as JWH-018 and JWH-073, and cyclohexylphenols, like CP-47,497, were the primary SCBs found in seized K2/Spice products. Use of these SCBs continued throughout 2011, with the addition of the flouroalkyl derivative of JWH-018, AM-2201. On March 1, 2011 legislation under the 76 FR 11075 act temporarily scheduled numerous SCBs (many not shown) that were structurally similar to naphthoylindole and cyclohexylphenol classes. Although numerous SCB analogues within these two classes were permanently scheduled July 9, 2012 under the 152 FDASIA act, new, structurally diverse classes of SCBs were subsequently identified in K2/Spice products. These novel classes included the tetramethylcyclopropylindoles, e.g., UR-144 and its fluorinated analogue XLR-11, as well as adamantoylindoles, e.g., AKB48. Because these structurally distinct SCBs were not included in section the 1152 of FDASIA scheduling act in 2012, May 6, 2013, legislation temporarily scheduled compounds associated with the tetramethylcyclopropylindole and adamantoylindole classes under the 78 FR 28735 act. As previous trends suggested, before completion of the 78 FR 28735 scheduling act, new SCBs had once again emerged in K2/Spice products that were also not included in section the 1152 of FDASIA scheduling act. The new classes of SCBs were the indazole carboximides, AB-PINACA and AB-FUBNACA, and quinolinyl esters, PB-22 and its fluorinated analogue 5F-PB-22 (not shown). Although, most of the compounds in these classes (excluding AB-PINACA) were temporarily scheduled on February 10, 2014 under the 78 FR 28735 act, it can only be assumed that new classes of SCBs will emerge in the future [2].

Figure 2. The SCB JWH-018 is a full agonist at CB₁ cannabinoid receptors when compared to Δ⁹-THC at the cellular level

In panel A, Δ⁹-THC (green circles) binds and stabilizes the active confirmation of CB₁ cannabinoid receptors with high affinity. Δ⁹-THC induces amplification that results in highly potent, and moderately efficacious coupling to G_i/o proteins, that then proceed to inhibit activity of the downstream intracellular effector, adenylyl cyclase [–140]. Δ⁹-THC in marijuana is classified as a partial CB₁ cannabinoid receptor agonist due to its sub-maximal recruitment of G_i/o proteins and inhibition of adenylyl cyclase. Comparatively, in panel B, the SCB, JWH-018 (blue diamonds) also binds to CB₁ cannabinoid receptors with a very high affinity and couples G_i/o proteins to inhibit adenylyl cyclase. The major distinction between Δ⁹-THC and JWH-018 is the efficacy of JWH-018-induced G_i/o coupling and adenylyl cyclase inhibition. As depicted, binding of JWH-018 to CB₁ cannabinoid receptors results in marked increases in G_i/o protein coupling and inhibition of adenylyl cyclase when compared to the partial agonist Δ⁹-THC. As such, JWH-018 present in K2/Spice products can be classified as a full CB₁ cannabinoid receptor agonist [136].

Figure 3. Chronic administration of JWH-018 results in cellular desensitization and down-regulation of CB₁ cannabinoid receptors, as well as tolerance to SCB-induced behavioral responses in animals

In panel A, the SCB JWH-018 (blue diamonds) is administered to a naïve rodent. JWH-018 binds CB₁ cannabinoid receptors on pre-synaptic neurons and mediates full agonist G_i/o protein coupling, adenylyl cyclase inhibition and modulation of other effectors including ion channels (not depicted). A single behavioral end-point demonstrates that acute administration of JWH-018 also results in a marked, time-dependent decrease in core body temperature in a SCB-naïve rodent. In panel B, JWH-018 is administered chronically. Complex molecular signaling reveals significant desensitization of CB₁ cannabinoid receptors by phosphorylation and recruitment of β-arrestin 2 (purple rectangles), marked down-regulation and internalization of the receptor, and finally dis-inhibition of quantal release of neurotransmitter by the pre-synaptic neuron. Attenuation of CB₁ cannabinoid receptor signaling via desensitization, down-regulation and receptor internalization contributes to the blunting of JWH-018-induced hypothermia. The complexity of these cellular mechanisms and how they translate to reduced behavioral responses (such as hypothermia) is indicative of tolerance in the rodent following chronic administration of JWH-018 [187].

Key Figure 4. SCBs present in K2/Spice products are not safe alternatives to marijuana

SCBs in K2/Spice products are structurally diverse psychoactive compounds, exhibiting distinct pharmacodynamic, pharmacokinetic and clinical effects when compared to Δ⁹-THC in marijuana. The studies reviewed here clearly demonstrate that SCBs are neither similar, nor suitable, substitutes for marijuana and that use of these compounds can result in tolerance and dependence, as well as numerous other documented adverse, toxic and potentially fatal effects.