Cannabis Synergy: Beyond THC

Cannabis is a plant as ubiquitous as it is therapeutic. For centuries Cannabis has held an integral role in many societies as a medicine and as a relaxant. A century ago, Cannabis extracts were used in the United States as a normalizer for disruptions in appetite and for cases of nausea, amongst their plethora of other alleviative properties. Since the early twentieth century, reports of Cannabis use turned to an anecdotal form due to the social controversy over the psychoactivity of Cannabis and the scheduling of Cannabis on the controlled substance list. Since then, illicit use continued, with anecdotes of profound therapeutic potential. The diversity of therapeutic effects attributed to Cannabis is staggering. Reports encompass relief from gastrointestinal disruption and illness, decrease in ocular pressure, analgesia, and normalizing depression to list just a few. This wide range of purported medical benefit is unlikely to be attributed to merely one psychoactive compound, the notorious delta-9 THC. THC may be accredited to a large variety of therapeutic benefit, but the variance in psychoactivity seen between strains invites the theory that these variances are caused by different relative ratios of THC to the other cannabinoids, and perhaps even more importantly, the terpenoids.

Contrary to the omnipresent terpenoids, phytocannabinoids are produced exclusively in Cannabis. Their involvement with the endocannabinoid receptor system in humans has been an intriguing mystery, with theories such as the surreptitious mimic and others that are beyond the scope of this review (for more information, refer to the National Insitute of Medicine’s publication in 2003: “Marijuana and Medicine: Assessing the Science Base). Its evolutionary role as a functional component of the plant is much clearer. Many phytocannabinoids carry antifungal activity, and the sticky nature of the glandules that carry them allows for insect defense. However, most interesting are the biochemical interactions with the human endocannabinoid system as well as other possible receptors, and the combined interaction of multiple cannabinoids. In terms of cannabinoids production, increases are seen with light exposure as well as with soil fertility. (p. 1345)Terpenoids are small organic molecules that are derived from 5-carbon isoprene units. These units assemble in a diverse manner and utilize different functional groups to create a vast array of terpenoids. Their relative small size (THC, for example, has 21 carbon atoms) adds to a volatile characteristic, meaning that these molecules can more easily dissipate into the air. This contributes to their aroma, and arguably the slight loss in medical efficacy with samples that have not been stored properly, and thus lost much of their volatile terpenoid content. Terpenoids, like cannabinoids, increase in production with light exposure, but interestingly decrease in production with soil fertility.

In 2010, Ethan Russo set out to consolidate the mass of research that has been conducted on phytocannabinoids and terpenoids, and in particular their synergistic effect when combined with THC. He defined synergy into four characteristics:

  1. Multi-target effects
  2. Pharmacokinetic effects such as improved solubility or bioavailability
  3. Agent interactions affecting bacterial resistance
  4. Modulation of adverse events

Russo theorized that “phytocannabinoids [could] function analogously to the endocannabinoid system (ECS) with its combination of active and ‘inactive’ synergists…This type of synergism may play a role in the widely held (but not experimentally based) view that in some cases plants are better drugs than the natural products isolated from them” (p. 1345). This is a solid explanation for anecdotal evidence that patients do not respond as well to marinol or drobadil (synthetic analogues of THC) as they do to whole-plant extracts. The presence of other phytocannabinoids and terpenoids is lost, and any therapeutic benefit arising from synergy is gone.

Bodily Effects of Cannabis
Bodily Effects of Cannabis

The Phytocannabinoids
The most psychoactive phytocannabinoid, THC, “is produced in the plant via an allele co-dominant with CBD. THC is a partial agonist at CB1 and cannabinoid receptor 2 (CB2), analogous to AEA [anandamide], and underlying many of its activities as a psychoactive agent, analgesic, muscle relaxant and antispasmodic. Additionally it is a bronchodilator, neuroprotective antioxidant, antipruritic agent in cholestatic jaundice and has 20 times the anti-inflammatory power of aspirin and twice that of hydrocortisone” (p. 1348).

CBD is an extremely versatile cannabinoid that is best known for its analgesic properties, and its ability to mediate the psychoactivity and other adverse side effects caused by THC. It has little affinity towards the cannabinoid receptors that THC binds to; however, it does act as an antagonist in the presence of THC (in other words, modulating the uptake of THC). Through the regulation of nitric oxide, CBD is also a neuroprotective antioxidant that is more potent than tocopherol or ascorbate. In fact, there are many more therapeutic benefits to which CBD has been attributed. For years, Cannabis breeding efforts have focused on increasing THC levels, which inevitably has led to a decreased amount of CBD in samples. However, recent study and burgeoning interest into the medical efficacy of CBD has led to an increased effort to create libraries of high-CBD strains. Russo cites research that studied perceived pain response in the presence of CBD, THC, and THC/CBD. The cancer patients (who were unresponsive to opioid treatment) who were treated with THC failed to distinguish from a placebo. Those treated with CBD received moderate analgesia, and the combination of THC/CBD resulted in successful reduction of 30% or more in pain. This synergy is an important revelation, as it directly supports the anecdotal evidence that the natural plant has more analgesic efficacy than synthetic THC mimics currently licensed for prescribed use.

There are many other phytocannabinoids present in the Cannabis plant. Although THC and CBD are the most prevalent and carry the most therapeutic efficacy, there are a few other worth noting, particularly THCV (tetrahydrocannabivarin), a propyl analogue of THC. Generally found in native West African strains of Cannabis, it carries 25% of the psychoactive potency of THC. The most interesting of its properties is its ability to produce weight loss and decreased body fat; in other words, contradicting the increase in appetite associated with THC.

The Terpenoids
Terpenoids are in such high use that the Food and Drug Administration deem them to be safe. They are also extremely potent – concentrations of above 0.05% are considered to be of pharmacological interest, and animal studies have supported that the levels found in Cannabis are certainly of high enough concentration to carry a pharmacological effect.

Lemons and citrus fruits may attribute much of their ‘sour’ nature to D-limonene, the second most prevalent terpenoid in nature. It also is a precursor to many other terpenoids. It has been linked to powerful anxiolytic and antidepressant activity. It also helps to induce apoptosis in breast cancer cells. Limonene is rapidly metabolized; however, there are “indications of accumulation and retention in adipose tissues (e.g. brain)” (1350).

Another common terpenoid found in Cannabis is B-myrcene, a potent sedative amongst its many other properties. It acts as an anti-inflammatory as well as carries a small analgesic property. It has a strongly herbal aroma and is a major component of bay, thyme, and hops.

Alpha-Pinene, known for creating the strong aroma from pine needles, is the “most widely encountered terpenoid in nature” (1350). It acts as an anti-inflammatory, as well as a bronchodilator (perceived expansion in the lungs). It also has a very interesting attribute of inhibiting acetylcholinesterase; in other words, aiding memory retention. Russo argues that “this feature could counteract short-term memory deficits induced by THC intoxication” (1352).

There are many other terpenoids present in Cannabis; all of which have an impressive Rolodex of therapeutic attributes. D-linalool, most commonly found in the lavender plant, has a local anesthetic property that is equal to those of procaine and menthol. It also contains anxiolytic and anticonvulsant attributes. B-Caryophyllene, common to black pepper, is another potent anti-inflammatory. Nerolidol, present in orange and citrus peels, is a sedative. This diverse array of terpenoids and the multitude of therapeutic pathways they provide are quite astounding, yet minute in magnitude when taken into consideration co-administration with a whole complex of phytocannabinoids and the potential synergy that may arise.

Specific Examples of Synergy
Acne sufferers are one group that may benefit from Cannabis synergy. CBD had previously been shown to induce sebocyte apoptosis. This attenuation at the pathological root of acne is a promising revelation. Russo argues that a few Cannabis terpenoids may also offer complementary activity. Limonene had been shown to inhibit Propionibacterium acnes (at a potency higher than that of triclosan). Pinene also inhibits P. acne. Linalool functions to suppress inflammation in response to acne. Russo argues that an isolation of CBD prepared with terpenoids is “a novel and promising therapeutic approach that poses minimal risks in comparison to isotertinoin”(p. 1353).

MSRA, or Methicillin-resistant Staphylococcus aureus, is a particularly nasty bacterium that is responsible for a number of extremely difficult-to-treat infections. In fact, it caused more deaths last year in the USA than those attributed to human immunodeficiency virus. CBD, as well as the phytocannabinoid cannabigerol (CBG), have been proved to powerfully inhibit MSRA. Additionally, pinene was shown to be as effective against MSRA as vancomycin and other agents. Pinene also has the ability to increase skin permeability, a large barrier against uptake of phytocannabinoids. CBD/CBG-based extracts with pinene may prove to be a fruitful investigation into battling MSRA.

Pre-1937 Cannabis Drug Bottle
Pre-1937 Cannabis Drug Bottle

Psychopharmacological Synergy
Terpenoid and cannabinoid application in psychiatry has been largely ignored in past years, due to governmental restrictions and methodological concerns. However, a few synergies have come to light that may prove useful in future study. Those terpenoids associated with citrus (ie limonene) have particularly effective anti-depressant capabilities; a combination of this with CBD and small amounts of THC could offer a therapeutic benefit. In fact, Russo ties in the theory of neural plasticity (burgeoning research is occurring in this field) with hypothetical connections to this phytocannabinoid synergy. He presents a hypothesis of deep, neurological treatment of depression, and not simply momentary alleviation of symptoms. Additionally, CBD has been consistently linked to providing relief from anxiety; the anxiolytic limonene or linalool may prove to be a synergistic combination with CBD. Cannabis extracts have also been linked to many other psychiatric benefits such as that of assisting sleep, and certainly this field of study will bear abundant discoveries.

There is one more psychopharmacological synergy that is worth noting with phytocannabinoids and a non-native Cannabis extract. Russo cites ancient “Ayurvedic tradition of India (Lad, 1990, p. 131):

Calamus root is the best antidote for the ill effects of marijuana … if one smokes a pinch of calamus root powder with the marijuana, this herb will completely neutralize the toxic side effects of the drug.” (p. 1355)

Specifically, the toxic side effects mentioned generally have to do with a “clearer thinking and improved memory” (p. 1355), to which Russo attributes the compound beta-asarone. An acetylcholinesterase inhibitor, beta-asarone does carry biochemical significance to improving memory. Pinene was also described to act as a memory enhancer on a biochemical level; this may add synergy.

So Cannabis has synergy – what does this all mean?
Cannabis has been described to have a rich variety of phytocannabinoids and terpenoids that have a diverse set of therapeutic and biological significance. However, there is a discontinuity when taking into regard the fact that for the past twenty years, Cannabis breeding efforts have focused almost solely on increasing THC production. Russo argues that the general breeding evolution to simply maximize THC results in an improperly balanced set of phytocannabinoids and terpenoids in the flower, and indeed a deficit of these cannabinoids and terpenoids. Therefore “selective breeding of Cannabis chemotypes rich in ameliorative phytocannabinoid and terpenoid content offer complementary pharmacological activities that may strengthen and broaden clinical applications and improve the therapeutic index of Cannabis extracts containing THC, or other base cannabinoids” (p. 1355). In essence, high-THC extracts do not prove to be of a particularly large medical significance when compared to the synergy that is displayed with the combination of natural phytocannabinoids and terpenoids. And, by selecting extracts or flowers that carry the specific terpenoids and phytocannabinoids that prove therapeutic to a patient’s particular ailment, one could dramatically increase the medical efficacy and alleviation that is provided.

Author’s Note
All information herein was provided by Ethan Russo’s article, cited below. Please refer to the article in order to gain original citations of facts and experiments. Additionally, ideas not explicitly stated to be that of Russo’s are those of the author’s and not necessarily stated by Russo.

Russo, Ethan B. “Taming THC: Potential Cannabis Synergy and Phytocannabinoid-terpenoid Entourage Effects.” British Journal of Pharmacology Part I Cannabinoids in Biology and Medicine (2011): 1344-364.