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

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.

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.

Figure 1 (click to enlarge)

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

Figure 2 (click to enlarge)

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).

Cannabidivarin

Cannabidivarin (CBDV) has some of the strongest evidence favoring a therapeutic effect. First studied in rodent models, it reduced seizure frequency by about 40% in rat hippocampal slices (in vitro), and had an even greater effect of reducing seizures in live mice (29). Notably, CBDV also reduced mortality in two models of seizure induction in both mice and rats; in one rat model, mortality in CBDV-treated animals was reduced to less than 20% compared to controls (29). Although CBD and CBDV show comparable anticonvulsant activity in different animal studies (30), they have not been compared in a single study. It remains to be determined whether individual patients may experience greater efficacy or improved tolerance from CBDV than from CBD, but a pharmaceutical company is already patenting the use of CBDV for treatment of seizures (31). The same company has initiated Phase II clinical trials of a CBDV preparation (32) after Phase I trials revealed a “reassuring safety profile” with a lack of adverse events. CBDV has also shown an antinausea effect in a rat model, reducing the nausea-index behavior by about a third (33).

Tetrahydrocannabivarin

Rock and colleagues (33) also demonstrated that Δ⁹-tetrahydrocannabivarin (Δ⁹-THCV) completely blocked the behavioral effects of nausea and reduced saccharin palatability, indicating a possible antiappetite effect. This anorectic or hypophagic effect was substantiated by a second trial in mice, which also showed that Δ⁹-THCV reduced body weight (34). As a caveat, a Δ⁹-THCV-rich cannabis extract did not produce the same effect. The authors speculate that this was because of residual Δ⁹-THC, and were able to restore the effect by supplementing the extract with CBD. This demonstrates that patients seeking these therapeutic effects may need to try a variety of cannabis preparations. Although Riedel and colleagues (34) demonstrated these effects in lean mice, research has also indicated that Δ⁹-THCV can improve glucose tolerance in two murine obesity models and increase insulin sensitivity in the diet-induced model (35).

Δ⁹-THCV has also dramatically reduced pain sensitivity in two murine in vivo models (36). Notably, the animals’ average nociceptive response was decreased from 2 min to almost 0 in one model, and the withdrawal latency (time from stimulus to pain response) was increased about two-fold in both models. Δ⁹-THCV also reduced edema (swelling) by about 25% in both models. Δ⁹-THCV has also been tested for antiepileptic activity; in that study it reduced epileptiform activity in vitro by about half, and increased the number of animals with a complete absence of induced seizures (37). Taken together, these results indicate potential utility for Δ⁹-THCV in many human conditions.

Cannabinoid Acids

Certificates of analysis usually contain data about cannabinoid acid content as well as the cannabinoid they are derived from. Cannabinoid acids are believed to have largely the same effect as their activated forms, that is, Δ⁹-THCA has the same effects as Δ⁹-THC, because cannabinolic acids are decarboxylated upon heating and lose their carboxylic acid moiety, as the creation of CO₂ is extremely favorable thermodynamically. This means that cannabinoid acids will be converted to their activated form when cannabis is smoked, vaporized, or heated, as in most processing for edibles, extracts, and distillates. These decarboxylated molecules are better able to cross membranes and barriers because of their reduced polarity. Anecdotally, some patients have reported a slower onset and more balanced effects from using “live” or “raw” cannabis preparations made without heating (38), possibly because of the relatively higher concentration of cannabinoid acids in these preparations. Consistent with the naming conventions for “activated” cannabinoids, one study found that Δ⁹-THCA did not show the neuroprotective effect that Δ⁹-THC did. Neither Δ⁹-THC nor Δ⁹-THCA demonstrated a clear advantage when inhibition of cancer cell growth was measured in vitro (17).

Terpenes

Table I (click to enlarge)

Although 140 terpenes have been identified in cannabis, this review will focus on the 17 most abundant (Table I) (39). Except for Δ³-carene, all of these are designated as “Generally Recognized As Safe” (GRAS) by the FDA, or are approved as food additives by the Flavor and Extract Manufacturers’ Association (9). Therefore, medical cannabis patients can be relatively confident that selecting for desired terpene effects will not affect the safety of their medications. Although terpenes are not a major constituent of cannabis (less than 4% by weight), they are highly bioavailable through inhalation (reviewed in [9]). Most cannabis terpenes have been widely studied in animal models and in vitro to earn their safety designation.

Three terpenes with an overwhelming variety of documented effects are β-myrcene, D-limonene, and β-caryophyllene. There is evidence that β-myrcene can exert sedative, anti-inflammatory, analgesic, muscle-relaxant, and neuroprotective effects. It may also have potential applications in arthritis and peptic ulcers (9). Similarly, D-limonene has been reported to have sedative, antidepressant, antimicrobial, anticancer, analgesic, and anti-inflammatory effects, with therapeutic prospects for patients suffering from gastro-esophageal reflux, colitis, or obesity (9). β-caryophyllene, the most common terpenoid in cannabis extracts, has demonstrated evidence for anti-inflammatory, analgesic, antianxiety, antidepressant, cardioprotective, hepatoprotective, gastroprotective, neuroprotective, nephroprotective, antioxidant, antimicrobial, and immunomodulatory effects (9). As these three examples show, given the sheer number of animal and cell culture studies on terpenes, along with the challenges in using them to shape recommendations for medical cannabis patients, this review will address only those terpene studies involving humans, as well as some of the more general claims about cannabis terpenes (Table I).

Proposed Antioxidant Effects

Most cannabis terpene molecules contain one or more double bonds between carbon atoms (9). These double bonds can often act as electron-accepting centers, giving them antioxidant properties in vitro. Antioxidants are beneficial to organisms partly because they can scavenge these highly-reactive, damaging free radicals by directly accepting unpaired electrons (40). Thus, antioxidants have been associated with a reduction in the cellular damage that can lead to cancer (41,42). We can therefore expect that some cannabis terpenes might act as antioxidants and chemoprotective agents against cellular damage and cancer, and many of the terpenes have already been tested for these purposes (43–57); reviewed in (9).

Notably, antioxidant studies do not consistently support or refute the idea of antioxidant administration having clinical value (58–60). A more recent study suggested that administration of exogenous antioxidants could actually increase the likelihood of metastatic events in cancerous mice (61). Another unknown is how antioxidant properties of terpenes may affect medical cannabis patients differently depending on the route of administration, since part of the harm to cannabis smokers’ lungs is thought to be caused by oxidative stress (62). Because of the complications inherent in interpreting antioxidant properties, the following discussion will focus on observed physiological effects, rather than potential antioxidant effects of the most prevalent cannabis terpenes.

Proposed Antimicrobial Effects

It is widely understood that plants produce terpenes for protection against pests (63). Therefore, it is unsurprising that many terpenes have well-documented activity against bacterial (45,48,64–74), fungal (48,65,75–78), and protozoan pests (74,79). However, since these were all in vitro studies, it remains unclear how these antimicrobial effects might help prevent infections in medical cannabis smokers.

Proposed Neurobiological Effects

Proposed neurobiological effects for many cannabis terpenes include analgesic, sedative, anticonvulsant, anti-anxiety, and antidepressant properties (9). However, with few exceptions, these studies have mostly been undertaken in rodent models, making it impossible to extrapolate how different dosages or routes of administration might affect human patients. Additionally, since cannabis terpenes are typically consumed in combination with Δ⁹-THC, CBD, and other cannabinoids, it is difficult to predict how specific neurobiological effects of terpenes might interact with neurobiological effects from cannabinoids.

Human Studies

α-Pinene

α-Pinene has been studied in humans as an irritant and bronchodilator (80). Although it had mildly irritating effects, measures of bronchodilation were not significantly changed. In this study, irritation resulted from an atmospheric concentration of 450 mg/m³, a level unlikely to be found in cannabis smoke.

Δ³-Carene

Sweden has established the occupational exposure limit for Δ³-carene at 150 mg/m³ (81), given its documented effects as an eye and nose irritant (81,82). Similarly, this concentration of Δ³-carene is higher than in cannabis smoke.

D-Limone

As the main component in citrus fragrance, limonene has been studied in humans for treatment of depression (83). In this study, citrus fragrance reduced Hamilton Depression Scores (HADS) to a similar extent as tricyclic antidepressants, reduced urinary cortisol and dopamine levels, and reduced perceived need for antidepressants. Limonene has also been studied in Phase II clinical trials on advanced human breast cancer patients, but the treatment was ineffective (84). More promisingly, daily supplementation with a 95% limonene preparation reduced a peripheral inflammatory marker in elderly humans (85).

Linalool

A recent study retrospectively analyzed the anticonvulsant effects of cannabis in patients with epilepsy (86), and noted that strains higher in linalool may be more effective. However, retrospective observations such as these must be interpreted critically, as they lack rigor when compared with randomized, controlled trials.

Patient Summary

Every effort has been made to address the limitations of the animal and in vitro studies presented here. From the available data, no conclusions can be drawn on how any cannabinoid or terpene preparation, dosage, or route of administration will affect humans. The FDA has not approved even a single drug containing lesser-known cannabinoids for the treatment of any condition. Exaggerated claims about the cannabinoids and terpenes discussed above are rampant on the internet; leading sites feature blog articles that make claims about these phytochemicals apparently unsubstantiated by in vivo or in vitro evidence. This underscores the need for better patient and caregiver education on the phytochemical components of medical cannabis products.

Furthermore, cannabis flower probably lacks sufficient concentrations of any of the minor cannabinoids to deliver their medicinal effects. For example, a recent online search found that the strains with the highest CBC content measured at only ~0.5% of dry weight. Similarly, CBC, CBG, and CBN are minor cannabinoids and most strains contain 1% or less, although CBN content can be increased with storage (87). Selective breeding or genetic modification might create CBC and CBG strains in the future, but patients seeking relief today may wish to try extracts or other processed products.

CBC, CBG, and CBN

Preparations of these cannabinoids show strong antibiotic activity. They may aid patients who are immunocompromised or otherwise at risk for infections. However, commercially available extraction products will have varying levels of activity based on the specific composition of different CBC and CBG analogues. CBG and CBN have the potential to ameliorate acne and psoriasis as they inhibit keratinocyte proliferation. The evidence is comparatively weak for their anti-inflammatory, anticancer, and analgesic effects. CBN may act to increase sedative effects of other drugs, but this result has not been replicated.

CBDV

Cannabidivarin has strong anticonvulsant properties in mice and rats, and a CBDV preparation has passed Phase I clinical trials. Epileptic patients who suffer side effects from CBD or incomplete reduction in seizures might consider trying CBDV.

Δ⁹-THCV

Single studies show that Δ⁹-THCV may aid in weight loss, ameliorate insulin resistance, reduce nausea, pain, and epileptic seizures, although CBD also has these therapeutic properties (88,89). Appetite reduction is the only physiological application of Δ⁹-THCV which has been reproducible.

Terpenes

Although terpenes are found in low concentrations in cannabinoids, they are highly bioavailable (9). Amongst the 17 most common cannabis terpenes, there is substantial overlap in predicted effects. For example, multiple terpenes have shown evidence of antioxidant, antimicrobial, analgesic, sedative, anticonvulsant, antianxiety, and antidepressant effects, however no human data is available for most of these effects. Add to this the low concentrations and variable terpene profiles in different cannabis strains, and it becomes extremely complicated to recommend specific terpene profiles for any specific purpose. Single human studies do support antidepressant and anti-inflammatory effects from limonene (83) and another suggests an anticonvulsant effect (86) from linalool. Therefore, patients seeking antidepressant and anti-inflammatory effects might experiment with high-limonene strains, and patients seeking anticonvulsant effects might experiment with high linalool strains under the supervision of their physicians.

Conclusion

Few recommendations can be drawn from existing research on terpenes and minor cannabinoids. As cannabis moves toward legality in the U.S., this should facilitate more rigorous human studies to help prescribers, budtenders, and medical cannabis patients obtain suitable medicines for their individual needs.

Acknowledgements

The author wishes to thank Niles Gunsalus for assistance with chemistry topics, Christopher Williams and Brett Peterson for their helpful review of the manuscript, Karrissa Miller and Christina Resuello for Pinnacle CT Labs’ cannabis statistics, and Gregory Gottheimer for support and encouragement of this work.

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Victoria Allen, PhD, is with Pinnacle CT Labs in Westminster, Maryland. Direct correspondence to vallen@pinnaclelabs.com.

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

Disclosures:
This article was originally published by Cannabis Science and Technology in June 2019. The original story can be found here: https://www.cannabissciencetech.com/view/beyond-delta-9-thc-and-cbd-current-evidence-medical-benefit-terpenes-and-less-studied-cannabinoids