In previous blog posts we’ve looked at the psychedelic effects of Salvia, the pharmacology of Salvia and the use of Salvia in animal research. Several times I’ve mentioned that Salvia holds much research potential. Here I’ll discuss just one of the ways in which the scientific study of Salvia could benefit society: by improving our understanding and treatment of cocaine addiction.

Cocaine is a highly addictive drug that works by increasing the amount of dopamine available to neurons in the brain (Thompson et al., 2000). Cocaine addicts show a long-term deterioration of mind and body (Maraj et al., 2010; Spronk et al., 2013), and the hospitalization and treatment of addicts is a large burden to society. At the moment there are no successful pharmacological treatments for cocaine addiction (Kivell et al., 2014). Salvinorin A, the main psychoactive compound of Salvia and a kappa-opioid receptor (KOR) activator, may hold the answer.

The KOR and cocaine addiction

The KOR is one of three receptors in the opioid receptor family, the other two being the mu- and delta-opioid receptors (MOR and DOR).  The MOR is particularly well studied due to its role in natural pain-killing, and its activation by opioids such as morphine and heroin. It’s thought that the KOR may have the potential to form complexes with MORs and DORs (Al-Hasani and Bruchas, 2011), and when MORs are activated by cocaine, ethanol or heroin, KORs are activated at the same time (Shippenberg et al., 2007; Wee and Koob, 2010).

As I mentioned in the previous blog, KOR activation causes a drop in dopamine levels. Dopamine is the brain’s ‘reward’ neurotransmitter thought to be highly involved in mechanisms of addiction. The drop in dopamine levels caused by KORs has been demonstrated during cocaine use (Trifilieff and Martinez, 2013), suggesting that the KOR may be part of a regulatory system that buffers dopamine levels. This presents KOR agonists (drugs that activate the KOR) as an important area of investigation in addiction research.

KOR agonists and cocaine addiction

Synthetic KOR agonists, drugs that have been created by scientists to specifically activate the KOR, have been shown to reduce the rewarding effects of cocaine (Shippenberg et al., 2007). However, KOR agonists can also cause re-addiction to cocaine, by creating extra stress during withdrawal (Wee and Koob, 2010). So the KOR system seems to have a complex and potentially contradictory role in addiction.

But what about Salvinorin A, the natural and potent KOR agonist found in Salvia? Several studies have shown that Salvinorin A reduces the addictive effects of cocaine; here I’ll summarize one of the best. Morani et al. (2009) trained rats to self-administer cocaine through an intravenous drip by pressing a lever. After several sessions the rats had learned to press the lever fairly frequently, as you might guess (reinforcement). Then, with the rats thoroughly enjoying themselves, the experimenters removed the cocaine. Now, pressing the lever only gave the rats a saline solution. The rats were obviously dismayed that their cocaine supply had stopped, and kept pressing the lever in the hope it would return, eventually giving up (extinction). The experimenters then injected all of the rats with cocaine, and this made the rats start pressing the lever again; the cocaine had re-started their addiction (reinstatement). Here’s the important part: some of the rats were also injected with Salvinorin A (a dose of either 0.3 or 1mg/kg) just before this final cocaine injection. These rats pressed the lever a lot less than the rats that had just received cocaine (figure 1). This suggests that Salvinorin A was reducing the addictive potential of cocaine for these rats (Morani et al., 2009).

Figure 1: Salvinorin A reduces cocaine-induced reinstatement of cocaine self-administration. Rats were trained to associate pushing a lever with receiving a dose of cocaine (Reinforcement). The cocaine was then replaced with saline so rats eventually stopped pressing the lever (Extinction). Then rats were injected with cocaine, or cocaine with a dose of Salvinorin A, creating a craving for more cocaine, which made them press the lever again (Reinstatement). The number of lever pushes was recorded over an hour after the injection, and the results are shown in the graph: administering Salvinorin A with cocaine seemed to reduce the rats’ craving for cocaine. Adapted from Morani et al., (2009).

Conclusions

Salvinorin A has a high affinity for the KOR and has reduced side effects compared to many synthetic KOR agonists, as well as other unique pharmacological properties (Wang et al., 2005). Finding a form a Salvinorin A that does not exhibit psychoactive properties is important if a therapeutic form of the drug is to be developed. However, Salvinorin A has been shown to have anti-addictive effects even at low doses, before psychedelic side-effects appear (Kivell et al., 2014), so this may not even be necessary.  

Many things need to be taken into consideration before Salvinorin A or potential non-psychoactive versions of it can be given to addicts as a treatment. Since KOR agonists reduce dopamine levels, they have the potential to increase the chance of re-addiction to cocaine by producing worse withdrawal symptoms (Kreek et al., 2012). The current literature suggests that KOR activators (like Salvinorin A) taken together with cocaine, can buffer the initial dopaminergic effects; but that KOR activation during withdrawal will only make things worse by increasing the craving for cocaine. The solution might be a therapy that activates KORs during cocaine use, and blocks KORs during withdrawal (figure 2).

Figure 2: Potential KOR therapy for cocaine addiction. Since KOR agonists decrease dopamine levels, and KOR antagonists increase dopamine levels, a joint therapy could be developed that prevents dopamine levels from becoming too high or too low. This graph is entirely hypothetical for illustrative purposes only and as such should not be considered accurate.

In any case, the study of Salvinorin A is uncovering the mechanism of addiction and its regulation in the brain. Even if Salvinorin A itself does not produce a treatment for addiction, the knowledge it provides us about how the KOR system works will be a crucial part of developing addiction therapies.

References

Al-Hasani R, Bruchas MR (2011) Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology 115:1363-1381.

Kivell BM, Ewald AW, Prisinzano TE (2014) Salvinorin A analogs and other kappa-opioid receptor compounds as treatments for cocaine abuse. Advances in pharmacology 69:481-511.

Kreek MJ, Levran O, Reed B, Schlussman SD, Zhou Y, Butelman ER (2012) Opiate addiction and cocaine addiction: underlying molecular neurobiology and genetics. The Journal of clinical investigation 122:3387-3393.

Maraj S, Figueredo VM, Lynn Morris D (2010) Cocaine and the heart. Clinical cardiology 33:264-269.

Morani AS, Kivell B, Prisinzano TE, Schenk S (2009) Effect of kappa-opioid receptor agonists U69593, U50488H, spiradoline and salvinorin A on cocaine-induced drug-seeking in rats. Pharmacology, biochemistry, and behavior 94:244-249.

Shippenberg TS, Zapata A, Chefer VI (2007) Dynorphin and the pathophysiology of drug addiction. Pharmacology & therapeutics 116:306-321.

Spronk DB, van Wel JH, Ramaekers JG, Verkes RJ (2013) Characterizing the cognitive effects of cocaine: a comprehensive review. Neuroscience and biobehavioral reviews 37:1838-1859.

Thompson AC, Zapata A, Justice JB, Jr., Vaughan RA, Sharpe LG, Shippenberg TS (2000) Kappa-opioid receptor activation modifies dopamine uptake in the nucleus accumbens and opposes the effects of cocaine. The Journal of neuroscience : the official journal of the Society for Neuroscience 20:9333-9340.

Trifilieff P, Martinez D (2013) Kappa-opioid receptor signaling in the striatum as a potential modulator of dopamine transmission in cocaine dependence. Frontiers in psychiatry 4:44.

Wang Y, Tang K, Inan S, Siebert D, Holzgrabe U, Lee DY, Huang P, Li JG, Cowan A, Liu-Chen LY (2005) Comparison of pharmacological activities of three distinct kappa ligands (Salvinorin A, TRK-820 and 3FLB) on kappa opioid receptors in vitro and their antipruritic and antinociceptive activities in vivo. The Journal of pharmacology and experimental therapeutics 312:220-230.

Wee S, Koob GF (2010) The role of the dynorphin-kappa opioid system in the reinforcing effects of drugs of abuse. Psychopharmacology 210:121-135.