Marijuana-based drugs: innovative therapeutics or designer drugs of abuse?

Abstract

The principal psychoactive component of marijuana, Δ(9)-tetrahydrocannabinol (THC), activates CB1 cannabinoid receptors (CB1Rs). Unfortunately, pharmacological research into the design of effective THC analogs has been hampered by psychiatric side effects. THC-based drug design of a less academic nature, however, has led to the marketing of "synthetic marijuana," labeled as K2 or "Spice," among other terms, which elicits psychotropic actions via CB1R activation. Because of structural dissimilarity to THC, the active ingredients of K2/Spice preparations are widely unregulated. The K2/Spice "phenomenon" provides a context for considering whether marijuana-based drugs will truly provide innovative therapeutics or merely perpetuate drug abuse.

Figure 1

Timeline of ancient cannabis use to modern day banning of K2 products.

Figure 2. Synthesis, binding, signaling, and degradation of endocannabinoids in neurons

Endocannabinoids are produced on demand in post-synaptic neurons by stimuli that result in elevations of intracellular Ca²⁺ levels, activating synthetic enzymes such as diacylglycerol lipase (DAG-lipase). Synthesized endocannabinoids such as 2-arachidonyl glycerol (2-AG) then diffuse into the synaptic space, travel in a retrograde manner, and bind to CB1Rs on presynaptic neurons. Retrograde signaling produced by endocannabinoid binding to presynaptic CB1Rs results in inhibition of adenylyl cyclase and activation of mitogen-activated protein kinase (MAPK) activity. However, the inhibitory actions of cannabinoids on neurotransmission result primarily from hyperpolarization of presynaptic neurons resulting from inhibition of Ca²⁺ influx via voltage-gated Ca²⁺-channels and loss of intracellular K⁺ ions via opening of inwardly rectifying cannels. Hyperpolarized presynaptic neurons produce less exocytosis of neurotransmitter, such as γ–aminobutyric acid (GABA), resulting in decreased neurotransmission. Endocannabinoid actions are finally terminated by hydrolysis due to action of presynaptically located metabolizing enzymes such as monoacylglycerol lipase (MAG-lipase).

Figure 3. Structural classes of cannabinoid ligands

Ligands that bind to CBRs are derived from four basic structural classes: (A) classical cannabinoids, (B) nonclassical cannabinoids, (C) aminoalkylindoles, and (D) eicosanoids.

Figure 4

An example of K2 packaging.