LETTER/REPLY
The Entourage Effect of the Phytocannabinoids
Juan Sanchez-Ramos, PhD, MD
A recent editorial dismisses medical marijuana as a smokescreen for
recreational use of the plant.1 Why push for medical marijuana when
we already have the option to prescribe D9-tetrahydrocannabinol
(D9THC; Marinol)? Most physicians are not aware that D9THC
monotherapy is not effective for many conditions for which cannabis
preparations containing combinations of D9THC and cannabidiol
(CBD) have been shown to be beneficial. These therapeutic effects
were documented in class I studies (randomized double-blind,
placebo-controlled studies) in multiple sclerosis patients with spastic-
ity, and patients with chronic neuropathic pain, cancer pain, bladder
hyperactivity, and urge incontinence.2,3 The cannabis preparations
were taken orally as whole cannabis extracts, smoked or vaporized, or
by oralmucosal spray (Sativex) of an extract of the plant containing
D9
THC and CBD in a 1:1 ratio.
Why is it that D9THC alone does not seem to be effective for
these neurologic conditions? Orally administered D9THC has very
long latency of onset and cannot be easily titrated to a therapeutic
dose without eliciting adverse effects in some patients. A more
important explanation relates to the synergistic effects achieved
when D9THC is administered along with an entourage of phyto-
cannabinoids found in the plant, especially CBD and terpenes.
The entourage effect was first brought up in relation to
the endocannabinoid system, with its combination of active and
inactive synergists.4 The concept was refined and qualified by
Mechoulam: this type of synergism may play a role in the
widely held view that in some cases, plants are better drugs
than the natural products isolated from them.5 A recent review
of the phytocannabinoids supports the entourage concept that
combinations of cannabinoids can in certain circumstances be
more effective than D9THC or CBD alone.6
The entourage effect is not unique to the phytocannabinoids.
Pharmaceutical monotherapies against human malaria are effective,
but ephemeral, because of the inevitable evolution of resistant para-
sites. Dried whole-plant Artemisia annua has been reported to be
more effective in slowing the evolution of malaria drug resistance
than artemisinin, the pure drug isolated from the plant.7
Rather than cast off medical marijuana as a ploy for rec-
reational use, the medical profession would do well to seriously
study the endocannabinoid system in health and disease. The
federal government should reschedule cannabis and allow scien-
tists to develop a rational approach to cannabinoid therapeutics
that takes into account the entourage effect.
Potential Conflicts of Interest
Nothing to report.
Department of Neurology, University of South Florida, Tampa, FL
References
1. Saper CB. Up in smoke: a neurologists approach to "medical mari-
juana". Ann Neurol 2015;77:1314.
2. Koppel BS, Brust JC, Fife T, et al. Systematic review: efficacy and
safety of medical marijuana in selected neurologic disorders: report
of the Guideline Development Subcommittee of the American
Academy of Neurology. Neurology 2014;82:15561563.
3. Benbadis SR, Sanchez-Ramos J, Bozorg A, et al. Medical marijuana
in neurology. Expert Rev Neurother 2014;14:14531465.
4. Ben-Shabat S, Fride E, Sheskin T, et al. An entourage effect: inac-
tive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-
glycerol cannabinoid activity. Eur J Pharmacol 1998;353:2331.
5. Mechoulam R, Ben-Shabat S. From gan-zi-gun-nu to anandamide
and 2-arachidonoylglycerol: the ongoing story of cannabis. Nat
Prod Rep 1999;16:131143.
6. Russo EB. Taming THC: potential cannabis synergy and
phytocannabinoid-terpenoid entourage effects. Br J Pharmacol
2011;163:13441364.
7. Elfawal MA, Towler MJ, Reich NG, et al. Dried whole-plant Artemi-
sia annua slows evolution of malaria drug resistance and overcomes
resistance to artemisinin. Proc Natl Acad Sci U S A 2015;112:821
826.
DOI: 10.1002/ana.24402
Reply to Letter
Clifford B. Saper, MD, PhD
In my editorial,1 I pointed out that modern medicine uses very few
medicinal plants or their extracts, but instead relies on purified
drugs. With respect to marijuana, tetrahydrocannabinol (THC) is
already available as an US Food and Drug Administration (FDA)-
approved drug in the United States. Nabilone, a semisynthetic can-
nabinoid, is also FDA-approved and commercially available.
Dr Sanchez-Ramos raises the important question of
whether the effects of cannabis may be due to a suite of bioac-
tive compounds, especially cannabidiol (CBD), rather than just
THC. To support this point, he cites the American Academy of
Neurology systematic review of medical marijuana in multiple
sclerosis (MS)2 and another review on the use of cannabinoids
in neurology.3 He characterizes these reviews as demonstrating
with class I studies that there are many conditions for which
combinations of THC and CBD are effective, whereas THC
alone is not. That is not what the studies that are cited in these
reviews show. Very few class I studies have been done with
head-to-head comparisons of THC vs CBD1THC, and several
of these have found that both treatments failed in reaching their
primary endpoints (eg, relief of spasticity in MS by the
Ashworth scale4 or neuropathic pain relief5).
I have also received several letters privately from pediatric
neurologists concerning the use of CBD to treat refractory seiz-
ures, although they concede that class I evidence is not yet
available for efficacy.
C 2015 American Neurological Association
V 1083