Posted on

entourage effect cbd

Entourage effect cbd

There is a growing body of research exploring the idea that health benefits may be stronger​ when multiple compounds from the cannabis plant are present, which is known as the ‘entourage effect​’.The desire to understand this effect further was very prominent in the researchers’ study. “Testing the notion of the entourage effect has been at the forefront of our minds over the last five years,” ​shares Jonathon Arnold, Associate Professor, Faculty of Medicine and Health at the University of Sydney.

Cannabis is a complex mixture of bioactive molecules including cannabinoids and terpenoids, so it made sense to the researchers that they might interact to produce different effects to individual constituents.

A team of researchers at the Lambert Initiative for Cannabinoid Therapeutics explored the role cannabinoids play in treating anxiety and seizures. Their research shows that hemp extracts provide high concentrations of cannabinoid acids in mice due to the pharmacokinetic entourage mechanism.

Related tags: Cbd, Research

Getty | Tinnakorn Jorruang

“The real challenge has been in demonstrating this entourage effect scientifically and also providing biological mechanisms through which this occurs,”​ notes Arnold. “The entourage effect is likely very complex and could work through a multitude of different mechanisms in the body,” ​Arnold adds.

The entourage effect

Entourage effect cbd

Hence, in cases of treatment resistance, novel treatment approaches, as discussed in this review, may address the risk of neuroprogression.

May cannabis consumption affect the microbiota-gut-brain axis? Only few evidences up to date support such a connection. In mice, THC altered the microbiota, including an increase in the presence of Akkermansia muciniphilia bacterial strain that is associated with reducing insulin resistance, weight loss, and improving intestinal barrier function [102]. However, whether THC or other cannabis-derived compounds may directly affect the microbiota-gut-brain axis remains to be determined.

Although both THC and CBD have therapeutic potential, it is CBD that was suggested to exhibit relatively high potency in relieving mood disorders: depression, anxiety and bipolar disorder [8, 9]. THC, a direct agonist of CB1 and CB2 receptors [24], has been shown in rats to have antidepressant-like effects on males more than on females [25]. In humans, it has been shown that THC has potential efficacy in the reduction of depression in joint administration with CBD [26]. CBD is a non-psychoactive component and demonstrated positive effects on several psychiatric disorders [27, 28], neurologic disorders like multiple-sclerosis [29] and epilepsy [29] and it is considered to possess neuroprotective characteristics [30]. The multiple pathways in which CBD exerts its effects are only partially understood [31]. CBD has repeatedly exerted antidepressant-like and anxiolytic-like effects in animal models [32-34]. These studies utilize standardized behavioral tests (such as elevated plus maze (EPM) for anxiety-like behavior and forced swim test (FST) for testing depressive-like behavior) to assess changes in symptom severity and activity of drugs. Indeed, fluorinated CBD derivatives showed high potency for behavioral effects in the EPM and FST [24-26, 35, 36].

Mood disorders are the most prevalent mental conditions encountered in psychiatric practice. Numerous patients suffering from mood disorders present with treatment-resistant forms of depression, co-morbid anxiety, other psychiatric disorders and bipolar disorders. Standardized essential oils (such as that of Lavender officinalis) have been shown to exert clinical efficacy in treating anxiety disorders. As endocannabinoids are suggested to play an important role in major depression, generalized anxiety and bipolar disorders, Cannabis sativa was suggested for their treatment. The endocannabinoid system is widely distributed throughout the body including the brain, modulating many functions. It is involved in mood and related disorders, and its activity may be modified by exogenous cannabinoids. CB1 and CB2 receptors primarily serve as the binding sites for endocannabinoids as well as for phytocannabinoids, produced by cannabis inflorescences. However, ‘cannabis’ is not a single compound product but is known for its complicated molecular profile, producing a plethora of phytocannabinoids alongside a vast array of terpenes. Thus, the “entourage effect” is the suggested positive contribution derived from the addition of terpenes to cannabinoids. Here, we review the literature on the effects of cannabinoids and discuss the possibility of enhancing cannabinoid activity on psychiatric symptoms by the addition of terpenes and terpenoids. Possible underlying mechanisms for the anti-depressant and anxiolytic effects are reviewed. These natural products may be an important potential source for new medications for the treatment of mood and anxiety disorders.


Some of the phytocannabinoids mimic the activity of endocannabinoids via binding to the endocannabinoid receptors. For example, THC which is the major psychoactive compound in the cannabis plant, and its metabolite 11-OH-THC is even more potent [20, 21]. These cannabinoids are agonists of endogenous cannabinoid CB1 receptors that are spread in large amounts in the spinal cord and peripheral nerves and in the brain, mainly in the cerebral cortex, including the cingulate cortex, hippocampus, basal amygdala, corpus striatum and other areas involved in mood disorders [22]. Unlike THC, CBD has relatively low affinity for the endocannabinoid receptors, however, there is evidence that it can interact with CB1 and CB2 receptors at reasonably low concentrations. In line with its low affinity for these receptors, most research with CBD has been directed at understanding CB1– and CB2-independent modes of action [23].

Further research is warranted to investigate the potential therapeutic value of adding terpenes to treatment with CBD, with or without additional THC for the benefit of patients suffering from depression, anxiety or BD. The understanding that terpenes hold important biological and behavioral abilities is a novel concept, which brings forth many difficulties when testing it in natural situations [73]. However, the value of such entourage effects, enhancing the beneficial influence of cannabis, is very high as the side effects and additional risks of other conventional treatments for psychiatric disorders are considerable. The effects of combining this original treatment with the conventional pharmacological approach also require further investigation.

Cannabinoids have been shown to modulate a variety of immune cell functions in humans and animals [87-91]. It seems that cannabinoids and their agonists can exert both immunomodulatory and neuroprotective effects [92]. For example, CBD can inhibit immune cell migration and thus induce anti-inflammatory effects [91]. In addition, JWH-015, a synthetic CB2-selective agonist triggered apoptosis in thymocytes in vitro and inhibited the proliferative response of T and B cells to mitogens through the induction of apoptosis [93].


In addition to cannabinoids, other secondary metabolites of cannabis have shown anxiolytic effects. A comprehensive preclinical study showed that plant-derived chemicals like alkaloids, terpenes, flavonoids, phenolic acids, lignans, cinnamates, and saponins possess anxiolytic properties using various animal models of anxiety-like behavior [66]. Terpenes are an important class of compounds produced by C. sativa, contributing its characteristic aroma [22]. Each cannabis strain bears a typical terpenoid profile, differing from other strains both qualitatively and quantitatively according to their relative amounts and the assemblage of the given terpenes present [67]. Terpenes and terpenoids are not unique to cannabis as many other flower-producing plants also produce them.

In a randomized, double-blind, double-dummy trial, 539 adults with Generalized Anxiety Disorder according to DSM-5 criteria and a Hamilton Anxiety Scale (HAMA) total score of 518 points, participated and received 160 or 80 mg Silexan (a lavender essential oil), 20 mg paroxetine (an antidepressant of the selective serotonin reuptake inhibitor, SSRI), or placebo once a day for 10 weeks. Silexan produced more anxiolytic effects than paroxetine [78], supporting its potential as a non-addictive alternative to benzodiazepines. However, in an animal model study, Linalool (a major component of lavender) did not show anxiolytic efficacy and its activity was not through the GABAA receptor [79].