Research Studies Relating to the Synergy/Entourage Effect of Full Spectrum Extracts

Research Summaries by Dr. Karen Hufnagl


Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads.  https://www.ncbi.nlm.nih.gov/pubmed/28826544  

This 2017 paper published in Advances in Pharmacology detailed the beneficial entourage effect of whole plant extracts of cannabis.  While the synergy of CBD with THC has garnered significant investigation over the past 15 years, the authors state that more recent research has provided additional focus “on the pharmacological contributions of mono- and sesquiterpenoids to the effects of cannabis flower preparations.”  Of particular note is the ability of “these aromatic compounds to contribute modulatory and therapeutic roles in the cannabis entourage far beyond expectations considering their modest concentrations in the plant.”

In a detailed review of the pharmacological mechanisms of cannabis compounds, the authors point out the following: “compounds that may affect the pharmacology of cannabinoids are abundant in nature, and so we may dangerously and mistakenly consider their presence to be trivial. If so, this could cause us to lose sight of the subtlety and efficiency of their design when applied in combination.”  In fact, this paper documents that “Sativex®, a standardized oromucosal whole cannabis extract that is now approved as a prescription in 29 countries, was purposely designed to incorporate terpenoids, which comprise 6%–7% of total cannabinoid.”  

These conclusions are strong support for the use of full spectrum cannabis extract as a superior choice over single compounds such as CBD isolate.


Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165946/ 

A review paper published in the British Journal of Pharmacology highlights that “the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated” and discusses the phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus).

Terpenoids (terpenes) are aromatic components of plants, and over 200 have been reported in cannabis.  “Terpenoids are quite potent, and affect animal and even human behavior when inhaled from ambient air…they display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts.”

As discussed in this review paper, several terpenoids have been shown to exhibit synergistic effects with cannabinoids in inflammation, antibacterial/anti-septic outcomes, depression, pain, anxiety, sedation/sleep, and addiction treatment. 

CBD and CBN are also referenced as phytocannabinoids having synergistic effects and the author concludes that the “body of information supports the concept that 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 phytocannabinoids.”


The current status of artisanal cannabis for the treatment of epilepsy in the United States   https://www.ncbi.nlm.nih.gov/pubmed/28254350 

Published in 2017, this is a retrospective study of 272 patients in Washington and California, combined with 4 case reports of epileptic patients in a private cannabinoid medicine practice in Maine.  All patients were using artisanal cannabis preparations for treatment of medically intractable epilepsy.

The artisanal cannabis preparations included cannabis from local growers (most of the 47 patients in Washington) and CBD-rich whole plant cannabis extract in either olive oil or coconut/MCT oil taken sublingually or orally (225 patients in California).  All patients used products laboratory-tested for cannabinoid potency and serum levels of CBD, THC, and THCA were monitored using a CLIA-certified laboratory. 

A reduction in seizures was seen in 86% of cases and 10% of patients experienced a complete clinical response.

The authors state that the case reports included in the study illustrate “the synergy of cannabinoids and terpenoids in artisanal preparations.”  


Overcoming the Bell‐Shaped Dose‐Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol   http://dx.doi.org/10.4236/pp.2015.62010

In 2015, researchers published a study directly evaluating the anti-inflammatory and pain-relieving effects of a specific standardized whole plant cannabis extract (clone 202) containing high amounts of CBD with the anti-inflammatory and pain-relieving effects of CBD isolate. 

The results of this animal study clearly revealed that the whole plant extract was significantly more efficient for relieving pain than the CBD isolate.  The whole plant extract also demonstrated a correlative dose-response on inflammation, with higher doses resulting in a greater anti-inflammatory effect.  In contrast, higher doses of CBD isolate had less effect on inflammation (the so-called “biphasic dose response curve” widely documented in studies using CBD isolate).

As compared to CBD isolate, the authors report that “the higher efficiency of plant extract might be explained by additive or synergistic interactions between CBD and minor phytocannabinoids or non-cannabinoids presented in the extracts.” 

This paper also documents three other studies showing that “CBD in a standardized Cannabis sativa extract is more potent or efficacious than pure CBD.”  For reference, these include:

http://dx.doi.org/10.1016/j.phymed.2013.11.006  (Romano  et al., 2014)

http://dx.doi.org/10.1016/j.urology.2010.12.006  (Capasso  et al., 2011)

http://dx.doi.org/10.1111/j.1476-5381.2012.02027.x (De Petrocellis  et al., 2013)


The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219532/

CBD has been shown to have beneficial effects in epilepsy, and researchers have shown that “another interesting compound of the plant, d-9-tetrahydrocannabivarin (d-9-THCV), a novel CB1 [receptor] antagonist, also exerts potentially useful actions in the treatment of epilepsy.”

A full spectrum standardized extract allows for the simultaneous benefit of multiple cannabinoids known to affect particular health conditions in a complementary way.  Given that there are multiple cannabinoids that can provide benefit for a given condition, use of an isolated cannabinoid may not provide the full benefit available from the plant.


Cannabis, a complex plant: different compounds and different effects on individuals  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736954/

Cannabis is a complex plant containing at least 85 different cannabinoid compounds, some of which have been shown to impact the effects of others.  A 2012 paper published in Therapeutic Advances in Psychopharmacology reviewed the effects of the two main cannabinoids, d-9-THC and CBD, and the endocannabinoid system. 

It was noted that “CBD potentiates the pharmacologic effects of d-9-THC…by enhancing the level of CB1 [receptor] expression in the hippocampus and hypothalamus” and “CBD also decreased the anxiety component of d-9-THC effects in such a way that the subjects reported more pleasurable effects.”

As such, it can be stated that without the synergistic effect of CBD, d-9-THC could have lower efficacy and a greater degree of negative side effects.