Cannabis Biomedicine: NOT the Magic Bullet Pharmaceutical Model
In the early 1990’s, I had a set of revelations as a biosciences professor that provoked me to publish a paper in an academic journal entitled “Magic Bullets and Biological Information Networks.” It argued that the war metaphor of magic bullet drugs ran counter to the essence of biological systems as information-processing networks — hierarchies of them at every organizational level of biology. Inner-nets. From gene networks to metabolic-enzyme networks to cells to organs, organ systems, whole organisms, food webs, and ecosystems. Networks that process biological information in real time.
In this post, I’ll discuss whole-plant Cannabis therapy in light of this aspect of biology, contrasting it with the idea of drugs as “magic bullets.” In this context, important notions are those of the “entourage effect” and also what I’ll call an “octopus of tweaks.”
The essence of this argument is that at all these levels of living systems, the fundamental notion is that of feedback information processing and response. Put simply, provoking a change in any physiological process naturally leads to second, third, and possibly further feedback changes that are normal consequences of a networked system’s ability to process and adapt to that first change. As Deepak Chopra once observed about this idea, “touch one strand and the entire web trembles.” (The brain is the ultimate, but hardly the only example.) This turns to folly the idea of a magic-bullet drug, one with a singular and stringently limited effect on our bodies. And by implication, one without side-effects.
Unfortunately, it is this magic-bullet idea that has driven pharmaceutical company drug development for decades. And although there has evolved a better understanding about expected side-effect profiles, Big Pharma continues to search for so-called narrow-acting drugs: those chemical compounds that affect single molecular processes such as receptor binding with little or no impact on other processes. And despite an improved realization that side-effects will occur through network feedback, commonly listed side-effects such as constipation or sleepiness may well ignore more-subtle impacts to our bodies based partly on our individual genetics. A poignant example is found in the instance of hair-loss drugs like Propecia, whose singular (magic-bullet) effect is to inhibit the enzyme 5-alpha reductase, but whose side-effects can be numerous and horrific (see, for example, https://medium.com/s/story/my-life-has-been-ruined-by-an-anti-baldness-propecia-finasteride-side-effects-ed8b2fcd1e90 )
WHY CANNABIS BIOLOGY SUGGESTS A UNIVERSAL MODULATORY SYSTEM
From the available research, I conclude that Cannabis therapeutics encompasses a more botanical-medicine approach, one in which whole plants contain an entourage of physiologically active compounds, many with more-subtle activity. This is a therapeutic approach that modulates — tweaks, if you like — a number of areas of cell and organism biology without a heavy-handed war-metaphor impact on any one process. Not a bullet, but rather a bunch of gentle shoves, perhaps even including some tickles. I think of it as collective encouragement to the patient’s physiology to modulate into a better, a more sustainable, configuration.
ENTOURAGE
I perceive two major reasons for this view. First is the fairly well-known entourage effect. This acknowledges that beyond actual phyto-cannabinoids like THC and CBD, Cannabis sativa (and indeed many other plants) contains a diversity of molecules with biological activity in humans and other animals. Examples abound, but for simplicity, consider the sesquiterpene Beta caryophyllene (BC), present in many strains of Cannabis (but at higher levels in certain strains). Research has shown that BC is active at stimulating signaling through the CB2R (cannabinoid-2 receptor), a receptor that binds the body’s own endo-cannabinoids anadamide and 2-AG. It was once assumed that CBD activated the CB2 receptor, but it’s now thought that CBD is actually a weak blocker (antagonist) of the CB2 receptor’s activation. More important, the terpene BC’s stimulatory (agonist) activity at the CB2 receptor could mean that your own endo-cannabinoids might have improved activity at stimulating that CB2 receptor. In other words, this terpene (also found in black pepper, cloves, and hops) appears to up-regulate a portion of your body’s internal cannabinoid system. This activity has been demonstrated to account for effects in laboratory animals. These include protection against brain damage in oxygen deprivation, as well as possible mitigation of certain of the metabolic disruptions of Type 2 Diabetes. Other studies have suggested anti-inflammatory, anti-anxiety, even anti-cancer effects. Another example, the terpene humulene, has been shown to have potent anti-inflammatory effects in mouse respiratory allergic inflammation. Decreases are observed in several measures of this inflammation, including, for example, white blood cell numbers and mucus production.
Bottom line: In the right strains of Cannabis, all this activity comes along with the cannabinoids. They complement each other. It’s one example of Entourage. This potentially gives such strains more therapeutic value for patients with particular ailments. Of course, more research is needed.
OCTOPUS of TWEAKS — WIDE-ACTING CANNABINOIDS
But entourage is only one aspect of this anti-magic-bullet mindset. The other aspect involves the fact that, for several reasons, cannabinoids are rather wide-acting in our bodies. First the two definitive cannabinoid receptors, CB1R and CB2R (there are quite possibly others) are widespread in the body in functionally diverse contexts. In one respect, this resembles an informational molecule-receptor combination like thyroid hormone, whose receptors occur in just about every cell type in the body. Thyroid hormone is thus said to be “wide acting” in its signaling of metabolic adjustments. Apparently, so is the cannabinoid system, its receptors present in the brain, immune system, reproductive organs, GI Tract, adrenal glands, heart, lungs, fat (adipose tissue), bone, and possibly elsewhere. An additional twist, as I’ve written in a prior Medium post, is that cannabinoids have been implicated as sending retrograde (backward) information in the brain, which I have speculated might represent metadata. In this context, metadata would be information about the quality of the other data in a biological network. [ https://medium.com/@vinlopresti/marijuana-as-metadata-19c28adb3364 ].
This wide cannabinoid receptor distribution merely scratches the surface. For in addition to their activity at their own CB1 and CB2 receptors, phyto- (and presumably endo-cannabinoids) have a sort of supportive (partial or “tweaking”) effect at receptors for other informational molecules. It’s known for example that CBD and CBDV positively tweak the activity of an important brain receptor called GABA-A. This is likely to underpin part of the effect of CBD in quelling the seizure activity in many patients who derive little benefit (but rather unpleasant side-effects) from the several other anti-seizure drugs. Or consider that THC negatively tweaks a brain receptor known as 5HT-3A, a receptor for the well-known informational molecule, serotonin (5HT). This may underpin some of the effect of THC in decreasing the vomiting (emesis) reflex in certain cancer patients. THC and the endocannabinoid system also influence the brain’s potent dopamine system in ways not entirely clear and that are likely to show individual variation. There is even some evidence that cannabinoids may be tweakers of receptors inside a cell’s nucleus, where they might help turn gene expression up or down.
WHOLE PLANT: NO MAGIC BULLETS
Join together entourage and this octopus of tweaks, and it’s fairly easy to appreciate why this is no magic bullet in the war-metaphor sense. There’s just so much going on pharmacologically. It also suggests that the pharmaceutical companies putting out drugs like Epidiolex — CBD without the other components of the Cannabis plant — probably shouldn’t lead us to assume equivalence to whole-plant CBD from an appropriate strain.
AGREEMENT WITH THE FUNDAMENTAL NETWORKED-INFORMATION PROCESSING CHARACTERISTICS OF LIFE
Perhaps the most important point of this discussion is a bit philosophical. I’ll pose it as a question. If we focus on the nature of cells, their nano-machines and their aggregate organs, systems, and entire bodies as networks of information processing — isn’t it more sensible to change the dynamics of those networks by several more subtle interventions rather than by one magic-bullet hammer blow?
FEWER AND MORE-MANAGEABLE SIDE-EFFECTS?
Which is likely to have more severe kickback side-effects, an extended-release opiate that bangs its way into continually activating the mu-opioid receptor or whole plant Cannabis, with an octopus of actions that together might tweak a system or systems closer to a more desirable homeostatic balance?
Because I spent almost 20 years addicted to extended-release opiates for severe chronic headache and spinal pain that I now manage with Medical Cannabis, that side-effect answer is abundantly clear to me from a personal perspective. I suggest that the biology of our bodies and of the Cannabis plant both strongly point in the same direction: away from magic bullets and toward less-damaging side-effects. Perhaps in a harmonious symbiosis.
I will try to post revisions of this article as more research information becomes available. Abundant thanks to Professor of Pot for his/her work. http://www.profofpot.com
