Systems Theory, Sea Squirts, and Pot

I wrote a piece in 2013 about loose relationships among the cannabinoid system, evolution, sea squirts and more. The article appeared at Salon.com. It was speculative, a way to bring together interesting information. Some interdisciplinary fun! It reflected my reading materials and interests over and/or persisting through the past 20+ years. Systems theory. The use of politics. Evolution. The science of the cannabinoid system. The politics of marijuana. Kuhn’s structure of paradigm shift. (Yeah, I’m a blast at parties.)

Since, I’ve spent a year learning about and writing about cells and cancer. The article at Salon had been written as speculative fun. But what I’ve learned about cells over the past year does not dissuade me from those speculations.

The title is totally weird. I have no idea why they did that.

You can read it here.

 

Writing "Polar Bears: A Marijuana Story"

In spring of 2009, I had just finished writing my novel and just finished a legislative session. I’d worked as lobbyist for twenty years and had been claiming each legislative session was my last since 2001. At the same time, at the coffee counter at which I’d been a regular going on for at least 12 years, a new conversation was cropping up among the usual commentaries on politics and the news.

Medical marijuana. Montana had passed a citizens’ initiative in 2004 allowing for the use of marijuana for medicinal purposes. Though I don’t remember it, I do vote, and I assume I voted for it because it’s something I would have voted for. It hadn’t made any impression on me, however. Even as someone who worked in politics, it wasn’t on my radar. But in the spring of 2009, I found my middle age coffee counter compadres often talking about getting their “cards” and going to marijuana stores – dispensaries - and legally buying and using marijuana.

Because of my background, I was interested in what the state statute said. What was the law supporting this phenomenon? The profile of medical marijuana was on the rise in Montana, in part, because of an entrepreneurial sociopath who had started a traveling clinic that made the availability of doctor referrals more visible.

These clinics, though, were card mills, which isn’t to say they didn’t also help people who could benefit from medical marijuana.

 Having just finished writing my novel (Shaking Out the Dead), my mind was on scan for the next. The phenomenon of medical marijuana struck me as something that would make for a good background for a story.

So, the research began. I went to a clinic. Not the circus ones being run by the sociopath, but something more dignified. I called the doctor I had met with two weeks later and asked him to lunch. Turned out, he had had a marijuana testing lab being run by a Ph.D. chemist that tested the “caregivers’” (medical marijuana growers) marijuana samples and provided information about the balance of the different cannabinoids in the plant, some psychoactive, some not. CBD (cannabidial, non-psychoactive) and THC (tetrohydrocannabinol, psychoactive) were of primary interest at the time when it came to medical applications. The doctor was also just the next week bringing in a cannabis (marijuana) plant expert from Holland, also a Ph.D., Dr. Arno Hazekamp.

I was able to meet with the two Ph.D.s one afternoon as well as attending Hazekamp’s public presentation as well as informal social events surrounding his visit. I formed a friendship with the doctor whose clinic I had gone to and started learning about the human cannabinoid system, which is the body’s system that takes in and responds to the cannabinoids in marijuana, in addition to the cannabinoids the body makes itself and the synthetics ones used in studies and in drugs such as Marinol.

As I like to put it, I was a political professional, but I came to marijuana politics through the science door.

Then, I started to meet the growers, some through the lab, some through the growing political conversation. I went to national conferences. I started quietly investigating the quiet work going on planning the next legislative move. I started quietly uncovering who was quietly involved, the lawyers, the lobbyists, in this quasi-legitimate world where people, more often than not, were paid in cash.

The law, as it was, was not written for a burgeoning industry. It was written for a model of a Good Samaritan growing marijuana for a few sick people. But between the travelling clinics and Obama’s Attorney General’s, Eric Holder, announcement that they would not prosecute medical marijuana providers in states that allowed for medical use and were following state laws, the number of users and businesses exploded, some reputable, some not.

 As to whether certain business practices and protocols were “legal,” the answer, frequently, was that “the law doesn’t say you can’t.” Thus, simple statutes were used, some claimed “abused,” to support a complex production and delivery system.

 A girl needs to eat. So, I ended up lobbying in the 2011 legislative session for the Alliance for Cannabis Science representing doctors, testing labs, and some businesses doing innovative things, such as energy efficient growing. The group was formed to have a “science voice” at the legislature, with the hope it would help foster legitimacy. But I wasn’t the only lobbyist. Early in the session, it appeared the political battle would be about how new regulations would favor some business models over others, the internal battle moving from who had the best weed to who can pass the law that supports their business model at the expense of others’.

But the movement, it turns out, was naive. That wasn’t the political battle. As the Montana Senate Judiciary committee voted on legislation to repeal medical marijuana in Montana altogether, simultaneously, federal raids broke out all over the state. Coincidence? Nobody thought so.

Repeal did pass but was vetoed by the Governor. However, the legislature passed an additional law that dismantled the medical marijuana program in Montana and the number of patients dropped from near 30,000 to 8000. There would be no program at all if several of the law’s provisions hadn’t been enjoined temporarily by the courts, which is where it still sits today, waiting on a Montana Supreme Court decision.

The science was amazing. The competition was cut throat at all levels. There was a lot of money at stake and in the process of wading into this world my eyes were opened to the insidiousness of the prison-industrial complex and the financially-driven component of the criminal justice system and the War on Drugs.  

I used to joke that marijuana was addictive, as a subject. The science, the history, the politics, the economics. It's not a joke when I say that wading into the issue changed the way I see many things. The unforeseen risks of being involved, even at a political level, have marked me. 

Polar Bears: A Marijuana Story is short fiction on the aftermath of the 2011 federal raids that leveled the medical marijuana market in Montana. In the story, following the raids, only one man, Dan Hoey, took on the Feds in court. Following the verdict, a blogger, a misguided activist, a greenhouse worker, and a juror must contend with the reality of the imperfection of their movement and how law, justice, and right and wrong work in an America on the inbetween. 

Based on true events, the characters in Polar Bears: A Marijuana Story express the complex motivations that drove thousands into the marijuana movement in the first decade of the 21st century. 

Available at Amazon here


Skin Cancer Awareness Month: What We Know About Cannabinoids and Skin Cancer

It’s Skin Cancer Awareness Month. Here’s some more information from a project I’m collaborating on on the role of cannabinoids in the treatment of cancer.

According to skincancer.org, nearly 5 million people are treated for skin cancer in the U.S. each year, a number which constitutes more cases of skin cancer than the incidence of breast, prostate, lung and colon cancer combined.

There is considerable research on the role cannabinoids can play in the treatment of skin cancer. Consistent findings include that both healthy skin tissue and skin tumors express cannabinoid receptors. Activation of these receptors induce the regression of skin tumors whether through direct apoptosis of cancer cells (self-destruction) or the inhibition of tumor angiogenesis, which is the process by which new blood vessels grow from existing ones, a fundamental step for benign tumors becoming malignant ones. Just as cannabinoid receptors have been found to exist in melanoma cells, melanoma cells also have been found to produce cannabinoids (as well as other bioactive lipids), via the arachidonic acid metabolizing enzymes they express. These cannabinoids, in turn, act on our cells’ CB1 and CB2 receptors. (1)

Given that the growth and development of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) tumors seem to rely on an early burst of neovascularization (2) and that melanoma cells demonstrate a resistance to apoptosis, which makes chemotherapies often ineffective (3), findings demonstrating cannabinoids apoptotic and anti-angiogenetic  properties hold promise for the treating of skin cancer. 

Though CB2 receptors have been found to exist in normal human skin and in malignant melanoma, the expression of CB2 receptors is significantly higher in malignant melanoma than healthy skin tissues. (4) Researchers have also looked at the expression of CB2 in sarcoidosis and granuloma annulare, other diseases of the skin. They found that the expression of CB2 was lower in normal tissue than in those diseases, just as they found when comparing normal tissue to malignant melanoma. They concluded that it "may be interred that intensive expression of CB2 in these diseases was related to higher cellular proliferation tendency and aggregation in tissues"and that "CB2 receptor agonists can play an inhibitive role in the origin and development of non-infectious granulomatous disease and tumors by immune regulation." (5)  

In other words, disease and high expression of CB2 receptor was correlated and stimulating activity at the CB2 receptor could generate anti-cancer activity.

Researchers have also experimented with the CB1 receptor, which is the cannabinoid receptor that when stimulated can generate psychoactive results.  A group of researchers from the National Institute of Oncology in Budapest, Hungary reported that two synthetic cannabinoids, one that stimulated the CB1 receptor and one that inhibited it, (Met-F-AEA and AM251, respectably) both  inhibited proliferation of human melanoma cells in lab studies. In fact, CB1 antagonist, AM251, induced massive apoptosis (up to 50%) of human melanoma cell lines. (6)

Another study indicated the role of cannabinoids and the CB1 receptor in inhibiting the migration of melanoma cells to other organs, in addition to the anti-cancer properties mentioned above (promoting apoptosis and inhibiting angiogenesis). In this 2012 mouse study, researchers found that the systemic administration of the synthetic cannabinoid and CB1 agonist, ACEA, “specifically inhibited liver colonization of human melanoma cells.” (7)

Thus, the three hallmarks of the anti-cancer properties of cannabinoids - decreased proliferation and vascularization, increased apoptosis of tumor cells, and inhibition of tumor cell metastatic spreading - have all been demonstrated in skin cancer whether in lab studies, mouse studies, or both. Studies also indicate that cannabinoids create these effects on cancer cells without negatively impacting healthy ones. 

 

More on the anti-cancer properties of cannabinoids here

  

1.http://www.aacrmeetingabstracts.org/cgi/content/meeting_abstract/2008/1_Annual_Meeting/2678

2. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC151833/

3. http://www.fasebj.org/content/20/14/2633.full?ijkey=958a31584b617C

4. http://www.res-medical.com/dermatosis-and-std/64093 

5. http://www.res-medical.com/dermatosis-and-std/64093

6.http://www.aacrmeetingabstracts.org/cgi/content/meeting_abstract/2008/1_Annual_Meeting/2678

7. http://www.ncbi.nlm.nih.gov/pubmed/22447182

 

 

 

 

 

 

 

World Cancer Day 2015, Marijuana, and the Cannabinoid System

It’s World Cancer Day so I’d like to tell you a few things I’ve learned from a writing project I’m working on.

The reason why marijuana (cannabis) has an effect on human bodies is because the plant-based cannabinoids in marijuana fit into the receptors of the human cannabinoid system.  The human cannabinoid system is involved in many of the body’s activities including modulation of the cell cycle which of course would have something to do with cancer.

 Human cannabinoid receptors can be activated by

  • Human cannabinoids made by the body, endocannabinoids (we know of two)
  • The plant-based cannabinoids in marijuana (we know of many, but it is primarily CBD and THC that are studied for their therapeutic applications)
  • Synthetic cannabinoids such as those that may be manufactured by pharmecudical companies.

The cannabinoids would be considered “ligands” that bind  to the cannabinoid receptors of which we know of two, CB1 and CB2. Activation of the CB1 receptor is necessary for the psychotropic effects. Activation of the CB2 receptor does not result in psychotropic effects.

Cannabinoid receptors are of a class of cell membrane receptors that fall under the G protein-coupled receptor superfamily. “G protein-coupled receptors (GPCRs) play important roles in a variety of biological and pathological processes. They are considered among the most desirable targets for drug development.” Studies have demonstrated that many GPCRs have been implicated in tumor formation and the metastasis of many human cancers. This class of receptors have been found to be involved with many diseases. They are “the target of approximately 40% of all modern medicinal drugs.1    

Because the G-protein-coupled receptor known as the cannabinoid receptor is involved in the cell cycle, it has been explored by scientists as a target in the treatment of cancer.

Below are three processes undertaken by cells, healthy or cancerous, and the action of the cannabinoid receptor  in that process when cancer is present.

Apoptosis

Cell proliferation and cell death both have a role in a correctly functioning body and the cannabinoid system is involved in keeping this cellular process functioning properly.2  In study after study of different kinds of cancer, cannabinoid therapy has been found to induce apoptosis in cancer cells – meaning it leads them to self-destruct. Yet, unlike chemotherapy, cannabinoid therapy leaves healthy cells unaffected.

These studies have been conducted in vitro (lab studies) and in vivo (primarily mouse studies). They have entailed the use of both plant-based and synthetic cannabinoids.

Angiogenesis  

Angiogenesis involves the process through which new blood vessels are formed from existing ones. This process, however, can be utilized by disease.  

Angiogenesis is a fundamental step in the transition of tumors from a benign state to a malignant one. Just as healthy tissue requires oxygen and nutrients for hits growth, so do tumors. “To this purpose a tumor induces the formation of new blood vessels from vessels present in the surrounding healthy tissues. Once formed, these vessels not only facilitate the growth of the primary tumor, but also favor the spreading of cancer cells to distant organs (metastasis).” 3

Because tumor angiogenesis is critical to the growth of a tumor, blocking angiogenesis results in dramatically reduced tumor growth. This has led to the use of angiogenesis inhibitors in the treatment of cancer.4  Studies have demonstrated that exogenous cannabinoids, such as those found in cannabis or synthetic cannabinoids, can inhibit tumor angiogenesis. 5

Cell Migration

 The orchestrated movement of cells to specific locations is critical to tissue formation, such as that which occurs during embryonic development and wound healing. However, cell migration is also the basis for metastasis, which is the spread of a cancer from one organ or part of the body to another not directly connected with it.

Two teams led by molecular biologists Dr. Pierre Desprez and Dr. Sean McAllister at California Pacific Medical Center in San Francisco found that the vast majority of metastatic cancer cells tended to express high levels of ID-1, a natural protein that is highly involved in the embryonic development of humans, a process which involves cell migration.6   

After embryonic development, the ID-1 protein essentially turns off and stays off. But when “Desprez manipulated cells in the lab to artificially maintain a high level of ID—1 to see if he could stop the secretion of milk, he discovered that these cells began to look and act like cancer cells.” 7 8 

The researchers found that though the ID-1 gene regulates the normal development and death cycle of epithelial cells in healthy people, in people with cancer “something goes haywire with the molecular mechanisms that regulate this complex system and cells encoded with the ID-1 gene begin to proliferate uncontrolled.” 9

CBD, a cannabinoid in cannabis, has been found to have a corrective impact on these ID-1 genes. The researchers found that when aggressive breast cancer cells were combined with CBD in a petri dish, “the metastasizing ID-1 cells simply turn off and return to a normal, regulated state.” 10 The authors of the study believe that CBD will have similar impacts, that is restoring cells to a regulated state, in other cancer types where high levels of ID-1 are present.

This cannabinoid found in cannabis, CBD, also has been found to be able to inhibit the migration of tumor cells, particularly of glioma cells (brain cancer cells).

Other interesting tidbits:  

  • WIN-55,212-2 is a synthetic cannabinoid activating both CB1 andCB2 receptors. Sami Sarfaraz of the University of Wisconsin in 2005 conducted a study which demonstrated for the first time that expression levels of both cannabinoid receptors, CB1 and CB2, are higher in human prostate cancer cells than in normal cells. Her study determined that WIN-55,212-2 treatment with androgen-responsive cells resulted in an inhibition of cell growth. The treatment also induced apoptosis (cell death) of the cancer cells. 11
  • Many cancer cells tend to “overexpress” cannabinoid receptors. For example, a common skin cell expresses CB1 receptors. A skin cancer cell expresses not only more cannabinoid receptors, but also CB2 receptors in addition to the CB1 receptors in healthy skin cells.
  •  Liver cancer cells also exhibit an overexpression of CB1and CB2 receptors. Further, the expression of CB1 and CB2 receptors has been found to increase from cells of a normal liver to one with chronic hepatitis to one with cirrhosis. 12 In other words, as the liver deteriorates, the number of cannabinoid receptors on those cells increase. Not only that, univariate analysis, that is, an analysis considering a single variable as the unit of analysis, has indicated that disease-free survival of liver cancer is significantly better in those patients with high CB1 and CB2 expression versus those with low CB1 and CB2 expression. 13

 

We think of cancer cells as being mindless and destructive to the very organism that allows for them to exist, and this is true. Yet, it also seems that some cancer cells are generating the very mechanisms that will induce the biochemical cascade that leads to their destruction and that mechanism lies in the cannabinoid system.

In study after study it is also demonstrated that while cannabinoid therapies impact cancer cells, they do not impact healthy ones, which is very different than chemotherapy that takes down the good cells with the bad.

 And just one more thing because it’s interesting:

 In 2008, the University of Minnesota released a study in the May edition of Cancer Research indicating that they may have found the earliest event in sun-induced skin cancer. When the researchers went looking for the gene that played a role in the absorption of UV radiation, they started with the assumption that because plants interacted with UV light for the purposes of photosynthesis, the human gene that interacts with UV light may be similar in structure. “When they compared plant genes for UV receptors to human genetic material, they found that the human genes for cannabinoid receptors matched.” When researchers genetically modified mice and removed their cannabinoid receptors, the mice were resistant to the “development of UV-induced inflammation and skin tumors.” In addition, researchers found that when cannabinoid receptors were exposed to UV light, they “changed from an inactive to an active state, indicating they had absorbed and responded to the light.”

Researchers didn’t know why cannabinoid receptors respond to both UV light and cannabinoids

That's the news in recognition of World Cancer Day 2015. More from this project as it progresses. For more information, contact me here. 

Read about cannabinoids and skin cancer here.