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

I will be interested to watch the trends in Pfizer stocks in the coming days, because it’s their injectable long-acting contraceptive, Depo-Provera, that is at the heart of a controversial new study in Lancet Infectious Diseases. A team based at the University of Washington in Seattle assessed nearly 4,000 couples in seven sub-Saharan African countries for rates of HIV acquisition and transmission, and the findings were pretty clear cut: women using long-acting progesterone-based birth control or low-dose combination hormonal oral contraceptives were twice as likely to acquire HIV, and their male partners were twice as likely to contract the virus from them.

The Depo-Provera shot, used by over 90 million women worldwide, is made convenient by the fact that it only needs to be administered once every three months to be effective. The active ingredient in the shot is the hormone progesterone, which is normally at its highest levels during the second half of a woman’s menstrual cycle. As a contraceptive, progesterone acts by thinning the uterine wall so that a fertilized egg cannot attach. However, this hormone also thins the vaginal wall, which may make it easier for the HIV virus to infect uninfected women and to be passed on to their male partners thereafter.

So why are some scientists basically saying “I told you so”? Well, fifteen years ago in 1996, a study was published in Nature Medicine (a well-read journal) that showed female rhesus monkeys with progesterone implants had 7.7 times the risk of contracting simian immunodeficiency virus (essentially monkey HIV) compared to monkeys implanted with placebo.

“How many years has it been that the non-human primate model, and other researchers, have been warning about this and being ignored? What, 15 years now? Shocking.” - John Moore, HIV scientist at Weill Cornell Medical College of Cornell University, in an email to colleagues and journalists on October 5.

The WHO will meet early next year to decide whether to revise the recommendation for injectable contraceptive use in HIV-positive women and women partners of HIV-positive men. But why weren’t these issues considered 15 years ago, when the study in monkeys came out? The first author of that study, Preston Marx, says it’s because nobody wanted to deal with a threat to a cheap and accessible contraceptive method with numerous benefits in developing countries. He says,

“I was in one meeting accused of massaging the data. It was real heat.”

On the other side of the debate, professionals in public health and epidemiology point out that hormonal contraceptive use was low among the cohort studied (anywhere between 15-33% of women depending on the time point in the study). Also, birth control is of especially great benefit in developing countries where unwanted pregnancies can bring serious harm or even death to the pregnant woman.

That said, this is clearly a very controversial finding with incredibly far-reaching implications, depending on what follow-up studies conclude. At the very least, women everywhere who are on birth control or considering it, as well as the partners of those women, should be aware of this ongoing debate.

In the interest of being balanced, check out this story about what people consider the confounding factors in this study: “The Faulty Birth-Control-HIV Link” in The Daily Beast.

Stay nerdy and stay safe.

Wadman, M. (2011). Contraceptive risk of HIV long suspected Nature DOI: 10.1038/news.2011.582

Heffron R, Donnell D, Rees H, Celum C, Mugo N, Were E, de Bruyn G, Nakku-Joloba E, Ngure K, Kiarie J, Coombs RW, Baeten JM, & for the Partners in Prevention HSV/HIV Transmission Study Team (2011). Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study. The Lancet infectious diseases PMID: 21975269

Marx PA, Spira AI, Gettie A, Dailey PJ, Veazey RS, Lackner AA, Mahoney CJ, Miller CJ, Claypool LE, Ho DD, & Alexander NJ (1996). Progesterone implants enhance SIV vaginal transmission and early virus load. Nature medicine, 2 (10), 1084-9 PMID: 8837605

That guy's simle says, "They're so impressed - thanks, Try Nerdy!"

Let’s be honest: Sometimes, you just want to know enough to sound reasonably informed during your coffee break. Here at Try Nerdy we totally respect that, so we’re putting together a list of the coolest nerdiest things that have had people talking in the last few days and weeks. And if you haven’t yet found yourself pulled into a conversation about one of these topics, then get people talking and get nerd credibility by asking “Hey, did you hear about…?”

1. “…That planet made of diamond?” Yes, Kim Kardashian’s 20.5-carat diamond engagement ring has been officially upstaged, and in a major way.  In late August, the journal Science published an article by researchers at the Swinburne University of Technology in Australia that, rather humbly, describes using a telescope to find a planet that is 4,000 light years away and most likely made of diamond. I say “humbly” because, despite the epicness of the find, the word “diamond” appears only once in the article, at the very end, and in parentheses:

The chemical composition, pressure and
dimensions of the [planet] make it certain to be
crystallized (i.e., diamond).

It’s the mark of a responsible, down-to-earth scientist to go on for pages with formulae and talk of pulsars before wrapping up with, “So, yes, in conclusion, we’re pretty darn certain we’ve found an entire planet made of diamond out there.” Kudos.

"O hai, I iz glowin."

2. “…Those cats that glow in the dark?” Truthfully, the coolest nerdiest thing about these cats isn’t the fact that they glow. Scientists at the Mayo Clinic have designed these cats to produce the monkey version of an enzyme that protects their cells from being infected with FIV, the cat version of HIV (which commonly leads to AIDS in humans). The green color is just a tool that’s been added to track with the monkey gene and make it easier to see whether the kittens of these cats inherit the gene (they do).

Well, I know what would be on the Christmas lists of 8-year-old girls everywhere…if 8-year-old girls stayed on top of disease research.

3. “…Those gamers who outsmarted scientists?” See, you don’t always need some fancy-pants degree to make a newsworthy breakthrough (although, 99.99999% of the time you do, so stay in school, kids). Briefly, the back-story here is that in order for the AIDS virus to do its dirty work and propagate itself inside someone, it needs to use an enzyme called a protease. Scientists would love to inhibit this enzyme, but to inhibit it they need the structure, and (until now) they just couldn’t figure the structure out. Enter the team of nerds gamers who play FoldIt, an online game for people to help science by predicting how proteins will fold (a really, really hard thing to do in most cases). The models created by the gamers were sufficiently accurate that researchers could determine the structure of the protease enzyme and even guess at where to target it with drugs.

More useful than Angry Birds...

Seriously, we need more games like that one.

4. “…That autistic ape?” First off, I’m never happy about disease in a human or an animal, but Teco the autistic bonobo is something of an awesome find for scientists who have been eluded by the mechanism of autism for years. Oh, and Teco is adorable:

For some reason, maybe because of his difficult birth or maybe because of his genetics, Teco shows many of the symptoms of autism that we see in human children: aversion to physical contact, avoidance of eye contact, fixation on shiny things, trouble with limb coordination, and more interest in objects than in his family. As mentioned, Teco is a bonobo, and bonobos are essentially a type of chimpanzee, which could make Teco a very near-human case study of autism. His genetics, studies of which are going on right now, have the potential to enlighten us about the extremely complex genetics of autism in humans.

So, hopefully this is enough to at least fill that awkward silence when you run into your boss at the water cooler, if not to make you the nerdy envy of everyone within earshot. Thank us by looking way over there on the right-hand side of your screen and liking us on Facebook (or following us on Twitter, or subscribing to our RSS feed… ).

What nerdy stuff has had you talking lately? I’d love to hear from you in the comments. Stay nerdy.

Bailes M, Bates SD, Bhalerao V, Bhat ND, Burgay M, Burke-Spolaor S, D’Amico N, Johnston S, Keith MJ, Kramer M, Kulkarni SR, Levin L, Lyne AG, Milia S, Possenti A, Spitler L, Stappers B, & van Straten W (2011). Transformation of a Star into a Planet in a Millisecond Pulsar Binary. Science (New York, N.Y.) PMID: 21868629

Wongsrikeao P, Saenz D, Rinkoski T, Otoi T, & Poeschla E (2011). Antiviral restriction factor transgenesis in the domestic cat. Nature methods PMID: 21909101

Cooper S, Khatib F, Treuille A, Barbero J, Lee J, Beenen M, Leaver-Fay A, Baker D, Popović Z, & Players F (2010). Predicting protein structures with a multiplayer online game. Nature, 466 (7307), 756-60 PMID: 20686574

However, despite the benefits of anti-retroviral therapies against AIDS progression, the authors of this paper suggest that these same therapies are associated with the accumulation of mutations in the energy-producing mitochondria of cells — the same kinds of mutations that would naturally occur later in life as part of the aging process.

Title: Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations

Authors: Brendan A. I. Payne, Ian J. Wilson, Charlotte A. Hateley, Rita Horvath, Mauro Santibanez-Koref, David C. Samuels, D. Ashley Price & Patrick F. Chinnery

Date of publication: June 26, 2011

Direct Link: http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.863.html

PMID: 21706004

Abstract: In the past few years it has been reported that people who are successfully treated with anti-retroviral therapies against HIV infection show signs of premature aging and ultimately experience progressive multi-organ disease. By performing extensive DNA sequencing and analysis on the single-cell level, these researchers found that patients who had used anti-retroviral drugs had increased mutations in their mitochondria (a cellular subcompartment for generating energy). Because the patients also exhibited premature aging, these results suggest that mitochondrial DNA mutations may play a role in the normal aging process that we all experience.

Methods: The authors obtained frozen muscle biopsy samples from HIV-positive patients treated with or without retroviral drugs and looked for abnormalities in mitochondrial proteins. Also, extremely sensitive sequencing of mitochondrial DNA was used to characterize the mutations in that DNA.

Results: Thirty-three HIV-positive adults under the age of 50 provided muscle biopsies for this work. The authors were looking at a mitochondrial protein that is used by the mitochondria to make energy - the more abnormal the protein, the less healthy the mitochondria. In the patients who had not received anti-retroviral drugs, the amount of this protein, cytochrome c oxidase (COX), was the same as in an HIV-negative control population. However, HIV-positive patients who had received anti-retroviral drugs showed a significant reduction in the amount of COX protein – the protein levels were comparable to or even more reduced than what would be found in the elderly. DNA was analyzed in single cells from these patients and the cells deficient in COX protein showed significantly more deletions in the mitochondrial DNA, including deletions commonly seen in healthy elderly adults (recall, though, that the patients in this research are less than 50-years-old). Also, the total amount of mitochondrial DNA in COX-deficient cells was significantly increased, and the authors propose a theory of “clonal expansion” in these patients: some of the mutated DNA underwent rapid replication, propagating the mutation until a high proportion of the total DNA was mutated.

Bottom line: This research makes two points that I think are highly relevant for disease and health: 1) The knowledge that some anti-retroviral therapies induce a premature aging effect is something that every HIV-positive individual has a right to know before beginning those treatments. Also, now that a potential mechanism has been described for how these drugs may be having an aging effect, researchers have the option to develop combination therapies to stop HIV virus replication while also preventing mitochondrial DNA mutations from accumulating. 2) This work supports the idea that mitochondrial DNA mutations may be part of what causes aging in healthy people, rather than a consequence of the aging process itself.

Payne BA, Wilson IJ, Hateley CA, Horvath R, Santibanez-Koref M, Samuels DC, Price DA, & Chinnery PF (2011). Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations. Nature genetics PMID: 21706004