Cannabinoids and medicinal specificity.

Could terpenes truly

set the rules?
Short Communication by E.Kalo, Ph.D, eSense-Lab, CTO

Introduction for Cannabis and Entourage effect

Cannabis is well described for its pharmacological distinction. When looking back Ten years ago the
credit for such pharmacological versatility was mostly attributed to the different cannabinoid profiles
and ratios of the various strains. Yet, in recent years it is more accepted that such pharmacological
distinction is not only driven by the cannabinoid variation of the plants but rather that other players are
involved as well. To be more specific and as published by Ethan Russo at 2011 "There are biochemical ,
pharmacological and phenomenological distinctions between available cannabis ‘strains’, such
phenomena are most likely related to relative terpenoid contents and ratios” (4)

Terpenes, and entourage.

Terpenes are naturally occurring poly Carbone compounds, accounting for flavor and fragrance
synthesized by plants. Terpenes can play a key protecting role defending plants from pathogens or insect
predator attacks. In parallel, they can serve as pheromonic attractant tempting insects for fertilization
purposes.
Up to date, Cannabis was characterized with over 200 different terpenoid molecules, but only a few
studies have concentrated on their pharmacology. Terpenes and cannabinoids are co-produced in the
trichomes of the plant sharing similar chemical structure. They were also found to share similar
pharmacological effects. Various indications in the literature show that terpenes, in similar to
cannabinoids, have the ability to induce sedative, anxiolytic, anti-convulsant, anti-inflammatory, cancer,
pain relief, anti-spasm, gastro protection, neuro protection, anti-bacterial and anti-parasite properties.
This pharmaco-similarity, is in fact the fundamentals of the entourage assumption related to both
medicinal and recreational properties of the Cannabis plant (3,4).
Entourage, known also as synergism is defined by a superior outcome of two or more parts which is
greater than their sum. Herbal drugs are well known for their pharmacological and therapeutic
superiority in compare to isolated single constituents. For example, when a Cannabis plant extract
enriched with CBD and other phytochemicals was tested for its anti-inflammatory activity in a mice
model, it was shown to be much more effective in compare to a tested purified CBD alone (5).
Two basic mechanisms have been proposed for synergistic effect, 1) multi-target effect and 2)
pharmacokinetic effect. Multi target effect means that the active molecules of the plant extract can turn
on the activation of multiple signaling pathways (could be either stimulating or repressive) which are
than cooperated to bring a maximal biological response. Pharmacokinetic effect is characterized by the
ability of certain molecules within the plant extract to enhance the signaling of other active ingredients
via making them more available to the targeted tissue (7).

3 Pinchas Sapir st. (@Daren Labs)

Ness Ziona 7403626, Israel
www.esense-lab.com
Can terpenes truly define the medicinal properties of Cannabinoids?
Evidence from Cannabis consumers clearly show that a specific Cannabis strain with a certain
cannabinoid profile may be highly effective against pain relief while another strain, which has similar
cannabinoid profile, may be more efficient to treat anxiety. This discrepancy of two plants sharing
similar cannabinoid level may be partially explained by their different terpenoid proportion and profile
(4).
Unfortunately, not much of an exploratory attention was given to terpenes as pure molecules. Few of
the terpenes have been studied as purified compounds in an effort to understand their mode of action in
regarding to specific medical indications. Moreover, the cross activity of purified terpenes and
cannabinoids is still seeking for true scientific answers and resolutions to the questions of how and if
terpenes can modulate cannabinoids-derived medicinal specificity.
Accordingly, one of eSense-Lab R&D goals is to characterize different Cannabis strains for their
terpenoid profiles along with their medicinal specificity. Our vision as a terpene expert company is to
be able to provide distinct terpenes mixes with a commercial value that would deliver specific medicinal
effect in a cooperative way with cannabinoids. To that end, eSense has engaged in to a serial of
experimental procedures in an effort to provide some supportive evidence to the assumption that terpenes
might truly affect the medicinal specificity of cannabinoids.
Esense-Lab has developed several terpene blends reconstructed based on nine most popular Cannabis
strains in the USA. Each of our blends consists of a different terpenoid profile and proportions. Our first
step in this exploration journey was to choose a medical indication of which both terpenes and
cannabinoids are well characterized to have beneficial effect on. Obviously, inflammation is the most
studied indication for both terpenes and cannabinoids where each showes a potent anti-inflammatory
activity via its own unique mechanism of action (2,6). Hence, a macrophage cell type of the immune
system was chosen to be our primarily inflammatory tested model. The selected macrophage cells were
stimulated for the occurrence of inflammation and the anti-inflammatory effect of the terpene blends
was assessed upon them via tracking the secretion of two major inflammatory mediators, Nitric Oxide
and TNF-Alpha. These inflammatory mediators, termed also as cytokines, play a critical role in the cause
of inflammation and pain.
Interestingly, we discovered that each one of our terpene mixes behaved differentially showing a range
of an anti-inflammatory potency. While Some blends demonstrated a selective anti-inflammatory effect
inhibiting the secretion of either one of the measured cytokines, other blends were almost completely
inactive. However, there was one terpene mix that showed a clear and potent anti-inflammatory effect
observed by its ability to significantly inhibit the secretion of both of the measured cytokines. The blend
is a copy of the terpene profile of OG-Kush Cannabis strain which is also well characterized for its
beneficial pain relief effect. Accordingly, we suggest that terpenes comprising OG-Kush blend are
arranged in a profile and ratio that allows them to efficiently activate signaling cascades that lead to a
better anti-inflammatory response in compare to the other tested blends. Hence, the choice for a terpene
mix to be infused with CBD for inflammation and pain management would obviously be OG-Kush, as
the odds for such a blend to achieve a multi targeted synergistic effect with CBD for that manner would
be with the highest probability among all blends. While CBD will activate CB2 receptors to reduce
inflammation, OG-Kush terpene blend will contribute its part by efficiently activating alternative anti-
inflammatory (complementary or parallel) signals to produce the aforementioned synergistic effect.
On the other hand, Super Lemon Haze, one of our terpene blends that was mixed based on the Super
Lemon Haze Cannabis strain, was found to be with the poorest anti-inflammatory effect. This blend
3 Pinchas Sapir st. (@Daren Labs)
Ness Ziona 7403626, Israel
www.esense-lab.com
showed a weak inhibitory effect for both of the measured inflammatory cytokines. Yet, we have a
grounded reason to believe that this particular blend has a great potential to treat epilepsy or Parkinson
when combined with CBD extract.
Based on that and mentioned above, it is tempting to speculate that each of these two terpene profiles
can specify CBD activity. While CBD mixed with OG-Kush terpenes may achieve a strong anti-
inflammatory response, the same CBD infused with Super Lemon Haze terpenes may be directed to
work more efficiently for epilepsy or Parkinson. Though great research activity is still need to be done,
we have some budding results implying that eSense's various terpene compositions may work in a
different efficacy to alleviate specific medical indications in the presence of cannabinoids. eSense R&D
team puts its efforts to keep exploring the Cannabinoids-terpene relationship around medical specificity
in an effort to bring the market mixes of terpenes with Cannabinoids related proven medicinal effect.

Reference:

1) Jun Chen, Qiu-Dong Jiang, Ya-Ping Chai2, Hui Zhang, Pei Peng and Xi-Xiong Yang (2016).
Natural Terpenes as Penetration Enhancers for Transdermal Drug Delivery Molecules 21:
1709-1731
2) Rita de Cássia da Silveira e Sá, Luciana Nalone Andrade and Damião Pergentino de Sousa
(2013). A Review on Anti-Inflammatory Activity of Monoterpenes. Molecules 18: 1227-1254.
3) Roman Paduch, Martyna Kandefer−Szerszeń, Mariusz Trytek and Jan Fiedurek. Terpenes:
substances useful in human healthcare. Arch. Immunol. Ther. Exp 55: 315–327
4) Russo E.B (2011). Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid
entourage effects. British Journal of Pharmacology 163: 1344–1364
5) Ruth Gallily, Zhannah Yekhtin, Lumír Ondřej Hanuš (2015). Overcoming the Bell‐Shaped
Dose‐Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol-
Pharmacology & Pharmacy 6: 75‐85
6) Sumner Burstein (2015). Cannabidiol (CBD) and its analogs: a review of their effects on
inflammation. Bioorganic and Medicinal Chemistry 23: 1377-1385.
7) Wagner H (2011). Synergy research: approaching a new generation of phytopharmaceuticals-
Fitoterapia 82(1):34-7

3 Pinchas Sapir st. (@Daren Labs)

Ness Ziona 7403626, Israel
www.esense-lab.com