Beyond Delta-9-THC and CBD: Current Evidence for Medical Benefit of Terpenes and Less Studied Cannabinoids

June 14, 2019
Volume: 
2
Issue: 
3
Figure 1
(Click to enlarge): Figure 1: Structures and biosynthetic pathway of cannabinoids. (Adapted and reprinted with permission from J. Nat. Prod. 2016.)
Figure 2
(Click to enlarge): Figure 2: CBC-type compounds show variable antibacterial activity. (a) CBC molecule skeleton. “R” denotes where chemical analogs differ (90). (b)–(f). Diameter of bacterial inhibition zones 48 h after application of CBC compounds to Bacillus subtilis (b), Escherichia coli (c), Mycobacterium smegmatis (d), Pseudomonas aeruginosa (e), and Staphylococcus aureus (f) cultures (19).

Abstract / Synopsis:

Cannabis sativa has been used medicinally for more than 4000 years. With resurgent interest in medical cannabis, 31 states have approved its use by patients with various conditions. Unlike conventional pharmaceuticals, cannabis varies widely in the abundance of medically beneficial compounds. Due to federal prohibition, little information is available to medical professionals, patients, or dispensary staff concerning specific components of cannabis and their known medicinal properties. This can result in patients choosing cannabis products with molecular profiles that are not well-suited to their precise medical needs. Besides the two main active compounds in C. sativa, 9-delta-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), other cannabinoids and aromatic molecules called terpenes have demonstrated therapeutic effects. Here we explore evidence that lesser-known cannabinoids and terpenes may be useful to patients with specific conditions. This information should facilitate better recommendations to patients and empower them to choose effective medical cannabis products.
 

 

Article:

Although Cannabis sativa contains more than 483 different phytochemicals (1), most medicinal properties of the plant are thought to result from specific cannabinoids and terpenes, acting both discretely and synergistically. The most well-known cannabinoids are 9-delta-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). Preparations of these compounds have been studied in randomized, placebo-controlled clinical trial with favorable outcomes. Δ9-THC has been approved by the U. S. Food and Drug Administration (FDA) for treating both anorexia associated with HIV and AIDS and nausea and vomiting because of chemotherapy (2), while CBD has been approved by the FDA as an antiseizure medication (3,4). These two major cannabinoids have also shown clinical benefits in eight human trials for the reduction of chronic pain (neuropathic pain and cancer pain), in five human trials for the reduction of spasticity because of multiple sclerosis or paraplegia, and also in human trials for anxiety disorder, sleep disorder, psychosis, and Tourette’s syndrome (5). However, there is also evidence that other, comparatively lesser studied cannabinoids may have therapeutic potential.

All phytocannabinoids are aromatic, oxygen-containing hydrocarbons. They are derived from a cannabigerol (CBG)-like skeleton, consisting of a benzene ring bound to two oxygen atoms and a 3- or 5-carbon propyl- or pentyl-chain (Figure 1). The various cannabinoids display unique properties mainly because they differ in how the CBG-skeleton is cyclized. In addition to CBD and Δ9-THC, dozens of other naturally occurring cannabinoids have been identified in C. sativa (1). The cannabinoids are thought to have differing physiological effects based on their varied interactions with the known cannabinoid receptors CB1 and CB2, although phylogenetic evidence suggests that additional cell membrane-bound receptors may also respond to cannabinoids (6). Consistent with this theory, several receptor knockout experiments have shown cannabinoids can exert their effects even when treated cells are missing the CB1 or CB2 receptor (7–9).

Cannabis terpenes are organic molecules made up of one or more 5-carbon isoprene units. C. sativa produces mainly monoterpenes (two isoprene units) and sesquiterpenes (three isoprene units), which make up 48–92% and 5–49% of the plant’s terpene content, respectively (1). Terpenes, which are extremely volatile, are responsible for the odor and flavor of cannabis. C. sativa is only one of many plants that produce terpenes; in fact, terpenes are the primary active constituent in most essential oils (EOs). Because many terpenes are synthesized by plants other than C. sativa, comparatively more data on terpenes is available than on alternative cannabinoids. However, much of the available data is derived from studies on EOs and not pure terpenes (9). Although in some cases, a particular terpene makes up as much as 95% of the EO tested (10), we cannot exclude the possibility that another chemical constituent of the EO acting in synergy with that terpene is responsible for the pharmacological effects observed.

Both cannabinoid and terpene production depend on strain, sex, age, plant part, and growth conditions. Harvest methods and post-harvest conditions also affect terpene and cannabinol (CBN) content (1). Terpenes and cannabinoids are both mainly stored in glandular trichomes (11,12). Terpenes constitute up to 4% of cannabis flower dry weight, while cannabinoids constitute up to 30% (13).

The following paragraphs will discuss health benefits of specific cannabinoids and terpenes. It is important to keep in mind cannabis science is an emerging field and most available data is extremely preliminary. Double-blind, randomized, placebo-controlled clinical trials have not been conducted, limiting our ability to draw conclusions at present. Almost all evidence collected to date on cannabinoids is either from animal models, cell culture (in vitro), or purely biochemical or molecular. It is therefore impossible to extrapolate even approximate human dosage equivalents from the most rigorous of these studies. This is especially true given animal studies most often administer drugs of interest intravenously, subcutaneously, or parenterally, whereas patients often administer medical cannabis products through inhalation. Data from in vitro studies is equally limited in its utility for human patient applications, often drawing conclusions from only one cell type that is incubated in a container for a specific length of time with specific concentrations of the compound of interest. Molecular and biochemical data (for example, receptor binding, gene, and protein expression) will not be considered in this review because of  the even greater difficulty of providing context for their interpretation.

Compounding the challenges of interpreting in vitro and animal studies is the variability in cannabinoid and terpene content in different cannabis strains and preparations. Clinical trials involving multiple commercial strains, alternative medical cannabis products, and single and polycompound extracts are urgently needed. Crucially, the lack of human studies signifies an absence of data on adverse effects or events. Therefore, it is imperative that patients should only attempt to medicate with cannabis products while under the supervision of an experienced and knowledgeable physician.

 

Cannabichromene

Cannabichromene (CBC) showed anti-inflammatory properties in both a rat paw edema (swelling) test (14) and a murine colitis assay (15,16), which is consistent with anti-inflammatory effects observed in murine cell culture (15,16). CBC also inhibits cancer growth in several different cell lines as well as reducing lung metasteses from cancer cell injections, but has a markedly weaker effect than CBD (17). CBC was shown to have a weak analgesic effect in a mouse model, but not as strongly as Δ9-THC (18). Most promisingly, microbial culture assays show CBC has strong antibacterial properties, even stronger than antibiotics in some cases, and rivaling that of Δ9-THC and CBD (19). This study also showed that CBC has mild antifungal activity. CBC strongly inhibited drug-resistant Staphylococcus aureus (MRSA). However, this effect was not unique to CBC (20). These antimicrobial studies used several different versions of synthesized CBC, and found that antimicrobial effects varied depending on the exact arrangement of the molecule (Figure 2). Therefore, extracted CBC preparations will likely have varying efficacies depending on the relative abundance of the different chemical analogues.

 

Cannabigerol

Cannabigerol (CBG) compounds were also found to exert strong antibacterial and mild antifungal properties in cell culture (19). CBG also strongly inhibited MRSA growth, although CBD had slightly higher efficacy (20). Similar to CBC, CBG inhibited cancer cell growth in several cell lines (17,21), but not to the extent that CBD did. Similarly, CBG inhibited keratinocyte proliferation, implying a possible use against psoriasis and acne (7). Although some reviews cite CBG studies that showed antidepressant or antihypertensive effects, these works were not peer-reviewed.

 

Cannabinol

Cannabinol (CBN) showed weak anticonvulsant activity compared to Δ9-THC and CBD in a murine model (22), although vehicle-treated animals were not included in the data shown (it is assumed here that electroshocks reliably induced convulsions in 100% of vehicle-treated animals). CBN inhibited pentobarbital metabolism in vitro, although not to the extent of CBD (23), however another study found little effect on pentobarbital metabolism (24). Curiously, a more recent study showed that CBN-treated mice slept about twice as long as controls after pentobarbital administration (25), indicating that CBN may actually enhance the sedative effects of other drugs.

CBN also had an analgesic effect in a mouse model, but it was weaker than that of low dose aspirin (26). CBN showed pronounced antibacterial activity against several MRSA strains (20). CBN also inhibits keratinocyte proliferation at dosages similar to CBG, Δ9-THC, and CBD (7), indicating potential therapeutic use in acne and psoriasis. CBN also showed substantial (almost three-fold) appetite-stimulating effects in a rat model (8). There is also evidence that CBN can act as a vasorelaxant in isolated rat hepatic arteries (27). Claims that CBN stimulates bone formation are not based on peer reviewed research; in fact, a peer-reviewed study found that the effects of CBN on bone marrow in live mice were “not clearly interpretable” (28).

 

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Victoria Allen, PhD, is with Pinnacle CT Labs in Westminster, Maryland. Direct correspondence to [email protected].

 

How to Cite This Article:
Allen V., Cannabis Science and Technology 2(3), 46-55 (2019)