The very recent publication of a draft of the Cannabis sativa genome has inspired me to briefly review why it’s so hard to do research on weed, and to highlight studies that have shown the benefits that can come from considering marijuana as more than just an abused substance.

Some would say our brains were made for marijuana, or vice versa, because of the abundant cannabinoid receptors that are directly activated by the primary psychoactive chemical in marijuana — a cannabinoid called delta-9-tetrahydrocannabinol (THC). The human body even produces its own endocannabinoids, which activate the same cannabinoid receptors. These receptors are known to have a role in everything from pain sensation to mood to appetite, and more, with some functions perhaps yet to be discovered.

 But about that medical research: much of what’s difficult in drug trials is establishing how toxic the test drug is and what its side effects are. Well, I think it’s generally accepted that there’s no documented human fatality from THC overdose, and as for side effects…well, just watch any one of the myriad “stoner movies” out there (e.g. 1, 2, 3, 4, 5, 6, 7, and 8). Many of the side effects are known quite well.

So what’s the big deal? Well, it all comes down to the fact that the Drug Enforcement Agency (DEA) classifies marijuana as a Schedule 1 drug, where it joins such baddies as heroin, LSD, and ecstasy. Schedule 1 drugs are defined as those that “have no currently accepted medical use in treatment in the United States.” The fact that marijuana is listed among these drugs can be perplexing, what with medical marijuana being legal in at least 16 states and our nation’s capitol.

"No medical use"? Let science decide.

So let’s say you’re a medical researcher, and you want to study the efficacy of marijuana in treating disease X; here are the three hurdles you have to jump: 1) applying for and receiving a license from the DEA, who fears Schedule 1 drugs getting into the wrong hands; 2) getting express approval from your research institution, who just might not want the stigma that comes with your research; and 3) securing funding, which, for Schedule 1 drugs, mostly comes from the National Institute on Drug Abuse (NIDA). NIDA has a government-sanctioned monopoly as the only legal source of marijuana for research in the U.S., and word on the street is that they don’t like to fund research that could conflict with their interest in, well, drug abuse.

To make a long story short, the debate over legalizing marijuana for medical research has a lot to it. Even if this legalization did occur, there would need to be firm oversight to make sure everyone and their mom didn’t run to sign up for studies just to get some reefer. But, in hopes of tilting the balance of this plant’s reputation, I am featuring a list of research studies in which THC, marijuana’s main active compound, appears to have done some good:

1. Cannabinoid Neuroimmune Modulation of SIV Disease. Monkeys with simian immunodeficiency virus (SIV, the monkey version of HIV) were given THC and experienced slowed disease progression, decreased amounts of virus, and milder tissue inflammation.

2. Chronic administration of THC prevents the behavioral effects of intermittent adolescent MDMA administration and attenuates MDMA-induced hyperthermia and neurotoxicity in rats. THC protected rats from ecstasy-induced hyperthermia and neurotoxicity, as well as prevented ecstasy’s behavioral effects.

3. Cannabinoids mediate opposing effects on inflammation-induced intestinal permeability. In inflammatory bowl diseases (IBD) like Crohn’s disease and ulcerative colitis, the intestines are inflamed; in this study, THC accelerated recovery from induced inflammation in human colorectal cells.

4. Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington’s disease. A THC-based treatment delayed the progression of Huntington’s Disease in rats.

5. Targeting cannabinoid receptors as a novel approach in the treatment of graft-versus-host disease: evidence from an experimental murine model. Mice with graft-versus-host disease were given THC and had increased numbers of immune cells, less tissue injury, less weight loss, and better overall survival.

6. Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy. THC reduced the viability of human hepatocellular carcinoma (liver cancer) cells and of tumors grown from human cancer cells implanted in mice.

7. The cannabinoid receptor agonist THC attenuates weight loss in a rodent model of activity-based anorexia. THC caused anorexic rats to gain weight.

8. Pre- and post-conditioning treatment with an ultra-low dose of Δ9-tetrahydrocannabinol (THC) protects against pentylenetetrazole (PTZ)-induced cognitive damage. Mice given THC before or after induced epilepsy (a model of brain injury) were protected from long-lasting deficits in learning and memory.

9. A combined preclinical therapy of cannabinoids and temozolomide against glioma. THC had anti-tumor effects against gliomas (brain tumors) that were resistant to temozolomide, the standard treatment for gliomas; the gliomas in the studies were grown by implanting human glioma cells in mice.

10. Acute and chronic cannabinoid extracts administration affects motor function in a CREAE model of multiple sclerosis. In a mouse model of multiple sclerosis, injection with a THC-rich Cannabis sativa extract reduced neurological deficits.

…And that’s all just from this year.

van Bakel H, Stout JM, Cote AG, Tallon CM, Sharpe AG, Hughes TR, & Page JE (2011). The draft genome and transcriptome of Cannabis sativa. Genome biology, 12 (10) PMID: 22014239

These researchers exploit this tryptophan-neurodegeneration link to make headway in finding better treatments for neurodegenerative diseases.

Title: Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration

Authors: Daniel Zwilling, Shao-Yi Huang, Korrapati V. Sathyasaikumar, Francesca M. Notarangelo, Paolo Guidetti, Hui-Qiu Wu, Jason Lee, Jennifer Truong, Yaisa Andrews-Zwilling, Eric W. Hsieh, Jamie Y. Louie, Tiffany Wu, Kimberly Scearce-Levie, Christina Patrick, Anthony Adame, Flaviano Giorgini, Saliha Moussaoui, Grit Laue, Arash Rassoulpour, Gunnar Flik, Yadong Huang, Joseph M. Muchowski, Eliezer Masliah, Robert Schwarcz and Paul J. Muchowski

Date of publication: June 6, 2011

Direct link: http://www.sciencedirect.com/science/article/pii/S0092867411005812

PMID: 21640374

Abstract: When the amino acid tryptophan is broken down by the body, a metabolite called kynurenine is produced, and this metabolite also goes on to be broken down into other products. One of the products of kynurenine breakdown is kynurenic acid, which is thought to have a protective effect on the brain and is decreased in those with neurodegenerative disease. The authors of this paper synthesized a drug called JM6 that inhibits the enzyme responsible for breaking down kynurenic acid – theoretically this drug would allow kynurenic acid levels to remain high and provide continued neuroprotection. In mouse models of Alzheimer’s and Huntington’s, administration of JM6 led to fewer memory deficits and longer lifespans, among other improvements in brain function.

Methods: These researchers first developed “slow release” versions of a drug already known to increase kynurenic acid levels by inhibiting the enzyme responsible for kynurenic acid breakdown. Slow-release drugs remain in blood circulation for an extended time and are thought to be more effective for that reason; the slow-release drug tested in this paper is called JM6. In mice known to have Alzheimer’s or Huntington’s like conditions, JM6 was given daily before the onset of disease symptoms. At 6-7 months of age, mice were behaviorally assessed (e.g. by time spent completing a maze) and some mice were sacrificed in order to study changes in brain tissue.

Results: In short, the drug JM6 works quite well in mouse models of both Alzheimer’s and Huntington’s Diseases, as evidenced by better spatial memory and longer lives in mice treated with the drug compared to mice that did not receive treatment. Alzheimer’s mice that were receiving JM6 were about 10% better at performing maze tasks than mice who did not receive the drug, which was a statistically significant difference. These mice also showed a more appropriate response to anxiety-inducing situations, which is important because in human Alzheimer’s cases, patients often display social and/or sexual “disinhibition” stemming from a loss of anxiety responses. Lastly, the mice modeling Huntington’s Disease lived significantly longer (on the order of a few weeks) with JM6 treatment than without. Both the Alzheimer’s and the Huntington’s mice treated with JM6 showed healthier brain tissue, e.g. an undiminished number of synapses, which are responsible for sending messages between cells in the brain.

Bottom line: In mice (not humans!) fated to develop Alzheimer’s and Huntington’s-like symptoms, the drug JM6 worked convincingly well to improve mental condition. Whether or not this drug could work in humans remains to be seen, but this research is powerful because the authors know that the drug JM6 works by increasing the amount of kynurenine in the blood (recall: kynurenine is a product of breaking down the amino acid tryptophan). This means that a potentially new approach to finding treatments for Alzheimer’s and/or Huntington’s could be to develop more drugs that act by increasing the body’s levels of kynurenine; and knowing what to target with a drug is often the first step to creating an effective treatment.

Zwilling D, Huang SY, Sathyasaikumar KV, Notarangelo FM, Guidetti P, Wu HQ, Lee J, Truong J, Andrews-Zwilling Y, Hsieh EW, Louie JY, Wu T, Scearce-Levie K, Patrick C, Adame A, Giorgini F, Moussaoui S, Laue G, Rassoulpour A, Flik G, Huang Y, Muchowski JM, Masliah E, Schwarcz R, & Muchowski PJ (2011). Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell, 145 (6), 863-74 PMID: 21640374