The Entourage Effect Explained – How Cannabinoids Create Blissful Synergy
For thousands of years, plants have been used to activate the natural cannabinoid responses of the body and nervous system by native and indigenous healers. In all cases, these so-called “master plants” have been taken in a full or whole plant form. The more recent Western approach with master plants like cannabis Sativa has focused on isolating and consuming pure extracts of single components – for example, CBD (cannabidiol) isolate (1). So the question begs, is there any benefit to taking a full-spectrum array from a cannabinoid regulator, or is it best to use a standardised single component isolates? New research has pointed in the direction of full-plant forms of cannabinoid regulators as these have demonstrated an “entourage effect” (2) in which a variety of “inactive” metabolites and closely related molecules markedly increased the activity of the primary endogenous cannabinoids in our bodies – anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Below we discuss what we now know about the endocannabinoid system and important information in using it therapeutically. We also evidence the entourage effect and discuss the pros and cons of different cannabinoid activators.
The endocannabinoid system (ECS) is a security and defence system that seeks to maintain internal harmony and balance within the body. It is linked with and can regulate the nervous, immune, hormonal or the endocrine systems (3) and the enteric nervous system (ENS) (4) of the gut sometimes called the “second brain”. The ECS acts like a master switch to control all other systems.
The role of the ECS is to relay important and timely information between these systems, but also prepare the body to adapt to external or internal stressors (3). Acting as an inbuilt thermostat the ECS seeks out and maintains the homeostatic balance point for each of the body’s systems and responses to the external environment. Think of it like a thermostat on a heater set to maintaining the room at a desired temperature that is comfortable for all.
The ECS responds to various stimuli, like injury, chronic inflammation, different forms of pain and infections (3). It protects cells and cell components, like the mitochondria and nerve cells, which are highly sensitive and prone to damage. In addition, the ECS attempts to re-balance and remove other toxic insults, like carcinogens, solvents, UV light, pesticides, and more (3).
The ECS can be activated to help treat and manage the following health conditions.
- Low back pain
- Neuropathic pain
- Muscle spasms
- Multiple Sclerosis
- Chronic Pain
- Chronic Fatigue
- Brain trauma
Anandamide and the ECS – How it Works
The ECS is all throughout the body and consists of signalling molecules called endocannabinoids (ECBs – keys) and receptors (locks). The main cannabinoid receptors are called CB1 and CB2, while the signalling molecules that unlock them are called anandamide (AEA), and 2-acyl glycerol (2-AG), collectively known as ECBs (6). Research has also discovered other receptors linked to the ECS including GPR55, GPR119, the ion channel receptor TRPV1 through which pain is mediated, and PPAR-alpha receptors, located in the nucleus of cells, that take part in regulating genes associated with pain and inflammation (7).
When harmful triggers like inflammation and injury act on the body, the ECS activates the production of ECBs like AEA or 2-AG from the membranes of cells in the vicinity of the injury. ECBs are produced on demand whenever the body requires their services. AEA for example can respond to external stimuli by activating the CB1 receptor in the brain and influence the production of serotonin and regulation of the HPA response of the body – our body’s main stress response system (8). Through this approach, the nervous system can rapidly adapt the body’s physiological response to the original stimuli and return balance and harmony.
Figure 1. Anandamide regulates the nervous system by feeding back messages to the CB1 receptor allowing adaption to external or internal stimuli.
How to activate the ECS
By using exogenous molecules not produced by the body that directly bind the CB1 or CB2 receptors known as endocannabinoids or cannabinomimetics (9). The most well-known of these is the plant cannabinoid Tetrahydrocannabinol (THC) present in some strains of cannabis (10). Beyond this, there are many other plants and cannabimimetic that have been discovered to directly bind the cannabinoid receptors, for example, Salvinorin A from the plant Salvia Divinorum (11), Yangonin from Kava Kava (12), and Perrottetinene (13) from New Zealand Liverwort (Figure 2). All four of these examples are molecules extracted from traditional medicines used by different cultures to treat and manage pain or for enhancing spiritual practices.
The benefits of using a direct cannabinomimetic are that it acts rapidly with high potency. It can offer relief for severe or chronic conditions associated with pain and can assist in the treatment of chronic inflammation. The drawbacks are that it can be difficult to dose adjust to ensure that desensitisation of CB receptors does not occur. Using cannabinomimetics like THC regularly or excessively increases the risk for developing a dependency on it and can result in an inability to manufacture sufficient natural ECBs like anandamide (14). People who develop a dependency on cannabinomimetics may find they suffer from withdrawal effects like brain fog, lethargy, and anxiety when the mimetic is withdrawn (14). In addition, some CB1 agonists like THC can be psychoactive, a property that is not ideal for everyone and often not wanted when consuming it for medicinal benefits.
Figure 2. Examples of some plants and their components that act directly on the endocannabinoid receptors.
2. Indirectly – the entourage effect
By using molecules not produced by the body that increase production or sensitivity of our natural endocannabinoids like Anandamide, but do not themselves bind the CB1 or CB2 receptors. This is known as the cannabinoid entourage effect (15). Studies in cannabis have shown that using pure THC or CBD (isolate) is not as effective as the whole plant extract as different components in the full plant work in synergy to promote enhanced healing over any one single compound (16). The entourage effect may occur through different mechanisms, e.g., preventing the breakdown of the ECB’s by enzymes that are responsible for their destruction in which case the ECB’s last longer in the body giving a prolonged and enhanced action, or improving the binding of ECB’s on various receptors, or by activating other receptors, e.g., opening up ion channels that cause a synergistic effect of the major molecule. The most commonly targeted ways to improve cannabinoid entourage are via inhibition of FAAH – the key enzyme that breaks down our ECB’s or through slowing re-uptake of ECB’s (17). Plants like Peruvian maca act as entourage enhancers through a series of FAAH inhibitors known as macamides that are produced during the traditional drying and preparation processes. In addition, quality ceremonial cacao paste can contain N-acetyl-ethanolamines (18) that also can act as FAAH inhibitors to enhance the natural production and function of ECBs. Both maca and cacao have been traditionally used for their abilities to indirectly regulate the ECS and improve resilience to stress (Figure 3). A further class of entourage enhancers called terpenes is discussed in more detail below.
Endocannabinoids have significant advantages over endocannabinoids or cannabinomimetics. They are locally produced, so act at the site of production and are more specific. The amount the body produces is in proportion to the demand, and the dose is well known. Once they have performed their service they are quickly broken down by the body and recycled back to the components of cellular membranes from which they originated. As a result, there are little to no issues with side-effects or dependency and different entourage plants or extracts can be combined for more enhanced synergy. They can be used long-term and are well tolerated.
Figure 3. Examples of some plants and their components that act indirectly on the endocannabinoid system.
How to create entourage using maca and cacao
Maca is a traditional medicine used in Peru to improve health and well-being and to bring balance and build resilience towards stress. When correctly prepared maca produces molecules called macamides that act as FAAH inhibitors (17). Inhibition of FAAH can increase the production and lifespan of our natural cannabinoids like anandamide as well as improving the sensitivity of cannabinoid receptors. Not all maca is equal however and it is important to ensure that you are using a traditionally prepared quality maca powder that has been tested and standardised by macamide levels. The right type of maca to use depends on the condition being treated.
Certain cacao beans and ceremonial cacao paste can contain molecules called N-acetyl-ethanolamines (18) that also can act as FAAH inhibitors. As these molecules are fat-soluble it is important to find a quality cacao paste or full cacao beans/nibs as these are the highest sources of N-acetyl-ethanolamines. Cacao powder does not contain the same levels as its full bean equivalents.
Daily consumption of maca and cacao provides FAAH inhibitors that increase and protect natural anandamide from rapid breakdown, allowing better regulation of the ECS. This entourage enhancement of activity can improve health outcomes for those struggling with issues like hormonal imbalances, chronic inflammation, mental health, adrenal or endocrine imbalances, cancer, and more. It can also combine with and alleviate some of the negative side effects of using direct cannabinomimetics.
Figure 4. The ECS response with FAAH inhibitors – protecting our natural anandamide (left). FAAH inhibitors enhance natural anandamide function and build resilience fluctuations during stress. This can improve our total body health and well-being, especially when dealing with chronic health conditions (right).
Mood elevation and entourage with terpenes
Terpenes are a large and diverse class of organic compounds produced by a variety of plants. Terpenes are what give each flower, herb, and fruit its unique scent and flavour. Every day, everywhere you go, you encounter terpenes. When you zest a lemon, you smell terpenes. Open a jar full of herbs; what you sense is the terpenes. Stop and smell the roses? More like stop and smell the terpenes. Terpenes are aromatic compounds that, when inhaled, applied to the skin or consumed, enhance our sensory experience and greatly influence flavours and aromas.
The cannabis plant is known to contain more than 100 terpenes (15), and most plants contain only a handful of terpenes, the different terpenes in cannabis are dependent upon a variety of factors such as the strain of cannabis, growing methods i.e., indoor/outdoor or environmental factors (19). Terpenes have been shown to work in synergy with both exogenous and endogenous cannabinoids to promote the entourage effect’ (20).
Research (21) indicates that combining specific terpenes (Limonene, Pinene, Myrcene, Linalool, etc.) with cannabinoids can improve efficacy in treating mood disorders, depression, and anxiety. When it comes to cannabis all the constituents combine to create the experience. Thinking of this example like flying in an airplane as an analogy the cannabinoids such as THC, CBD control the altitude and velocity, but the terpenes provide the direction like the rudder. This direction, controlled by the terpenes, is the feeling of being couch-locked, in a chill or calm state, or a focused and alert state.
Figure 5. Examples of some common terpenes and their properties
- The endocannabinoid system (ECS) is a vital part of our natural defence against illness and can promote better health and wellbeing. It can be used to treat a range of different health conditions.
- It can be activated either directly or indirectly using cannabinoid plants, extracts or molecules via a range of different methods each with their own pros and cons.
- Direct cannabinomimetics act fast, with high potency but require careful dose adjustment and monitoring to prevent system de-sensitisation.
- Indirect cannabinoid regulators work to enhance the activity of our natural cannabinoids through different approaches including protection of endocannabinoid uptake, breakdown or increased receptor sensitising. This is known as the “entourage effect”.
- Some common entourage molecules include macamides (from maca), N-acetylethanolamines (from cacao) and terpenes (from cannabis and other plants).
- Entourage plants can be used to enhance a cannabis experience and to negate some of the negative side-effects associated with using direct cannabinomimetics.
- It is important to select a quality form of an entourage plant as not all are created equal.
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Video Key Timestamps:
0:59 What is the ECS?
3:09 How does the ECS work?
7:41 How do we activate our ECS?
8:28 Directly – cannabimimetics
13:08 Indirectly – “entourage effect”
21.59 Cannabinoids in cannabis sativa
24:58 Cannabidiol – CBD
26:38 THC and cannabis addiction
31:48 Cacao and entourage
34:57 Maca and entourage
39:04 How to use maca for entourage
42:21 Meet Good Herb Soda
43:09 Therapeutic composition of cannabis
44:59 Cannabis vs Hemp
47:07 What are terpenes
48:34 The entourage effect with terpenes
50:59 Cannabis regulations in New Zealand 2020
53:24 The 6 main terpenes found in cannabis
54:14 1. Myrcene
59:36 2. Limonene
105:40 3. Pinene
109:47 4. Beta-Caryophyllene
112:58 5. Linalool
116:20 6. Terpinolene
119:36 What is Good Herb Soda?
120:53 How do you use Good Herb Soda?
125:18 Where can you buy Good Herb Soda?
- Bonn-Miller M. O., ElSohly M. A., Loflin M. J. E., Chandra S., Vandrey R. (2018). Cannabis and cannabinoid drug development: evaluating botanical versus single molecule approaches. Int. Rev. Psychiatry 30 277–284.
- (a) McPartland J. M., Russo E. B. (2001). Cannabis and cannabis extracts: greater than the sum of their parts? J. Cannabis Ther. 1 103–132. (b) McPartland J. M., Russo E. B. (2014). “Non-phytocannabinoid constituents of cannabis and herbal synergy,” in Handbook of Cannabis ed. Pertwee R. G. (Oxford: Oxford University Press; ) 280–295. (c) Russo E. B. (2011). Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br. J. Pharmacol. 163 1344–1364.
- Cristino, L., Bisogno, T. & Di Marzo, V. Cannabinoids and the expanded endocannabinoid system in neurological disorders. Nat Rev Neurol 16, 9–29 (2020).
- DiPatrizio NV. Endocannabinoids in the Gut. Cannabis Cannabinoid Res. 2016;1(1):67‐77.
- (a) The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington (DC): National Academies Press (US); 2017 Jan 12. 4, Therapeutic Effects of Cannabis and Cannabinoids. Available from: https://www.ncbi.nlm.nih.gov/books/NBK425767 (b) Kogan NM, Mechoulam R. Cannabinoids in health and disease. Dialogues Clin Neurosci. 2007;9(4):413‐430. (c) Croxford, J.L. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):179-202. (d) Davies, M.P. Cannabinoids in pain management: CB1, CB2 and non-classic receptor ligands. Expert Opin Investig Drugs. 2014 Aug;23(8):1123-40.
- Fernando rodríguez de fonseca, ignacio del arco, francisco javier bermudez-silva, ainhoa bilbao, andrea cippitelli, miguel navarro, the endocannabinoid system: physiology and pharmacology, alcohol and alcoholism, volume 40, issue 1, january/february 2005, pages 2–14, https://doi.org/10.1093/alcalc/agh110
- Marzo, V., Bifulco, M. & Petrocellis, L. The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 3, 771–784 (2004). https://doi.org/10.1038/nrd1495
- Hill, M. et al. J Neurosci. Functional Interactions between Stress and the Endocannabinoid System: From Synaptic Signaling to Behavioral Output. 2010 Nov 10; 30(45): 14980–14986.
- VincenzoDi Marzo. ‘Endocannabinoids’ and other fatty acid derivatives with cannabimimetic properties: biochemistry and possible physiopathological relevance. Biochimica et Biophysica Acta (BBA) – Lipids and Lipid Metabolism, Volume 1392, Issues 2–3, 15 June 1998, Pages 153-175
- Jahan P. Marcu, Chapter 62 – An Overview of Major and Minor Phytocannabinoids, Editor(s): Victor R. Preedy, Neuropathology of Drug Addictions and Substance Misuse, Academic Press, 2016, Pages 672-678, ISBN 9780128002131, https://doi.org/10.1016/B978-0-12-800213-1.00062-6.
- Orton E, Liu R. Salvinorin A: A Mini Review of Physical and Chemical Properties Affecting Its Translation from Research to Clinical Applications in Humans. Transl Perioper Pain Med. 2014;1(1):9‐11.
- Ligresti A, Villano R, Allarà M, Ujváry I, Di Marzo V. Kavalactones and the endocannabinoid system: the plant-derived yangonin is a novel CB₁ receptor ligand. Pharmacol Res. 2012;66(2):163‐169. doi:10.1016/j.phrs.2012.04.003
- Toyota M, Shimamura T, Ishii H, Renner M, Braggins J, Asakawa Y. New bibenzyl cannabinoid from the New Zealand liverwort Radula marginata. Chem Pharm Bull (Tokyo). 2002;50(10):1390‐1392. doi:10.1248/cpb.50.1390
- E.A Carlini, The good and the bad effects of (−) trans-delta-9-tetrahydrocannabinol (Δ9-THC) on humans, Toxicon, Volume 44, Issue 4, 2004, Pages 461-467, ISSN 0041-0101,https://doi.org/10.1016/j.toxicon.2004.05.009.
- Ethan Russo – Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165946/
- Pamplona FA, da Silva LR, Coan AC. Potential Clinical Benefits of CBD-Rich Cannabis Extracts Over Purified CBD in Treatment-Resistant Epilepsy: Observational Data Meta-analysis [published correction appears in Front Neurol. 2019 Jan 10;9:1050]. Front Neurol. 2018;9:759. Published 2018 Sep 12. doi:10.3389/fneur.2018.00759
- Alasmari M, Bӧhlke M, Kelley C, Maher T, Pino-Figueroa A. Inhibition of Fatty Acid Amide Hydrolase (FAAH) by Macamides. Mol Neurobiol. 2019;56(3):1770‐1781. doi:10.1007/s12035-018-1115-8
- di Tomaso E, Beltramo M, Piomelli D. Brain cannabinoids in chocolate. Nature. 1996;382(6593):677‐678. doi:10.1038/382677a0
- Variations in Terpene Profiles of Different Strains of Cannabis sativa L https://www.researchgate.net/publication/235348187_Variations_in_Terpene_Profiles_of_Different_Strains_of_Cannabis_sativa_L
- (a) John M McPartland and Ethan B Russo – Cannabis and cannabis extracts: Greater than the sum of their parts? Journal of Cannabis Therapeutics https://www.researchgate.net/publication/228897917_Cannabis_and_cannabis_extracts_Greater_than_the_sum_of_their_parts (b)Ethan B Russo – The case for the entourage effect and conventional breeding of clinical cannabis No strain no gain Frontiers in Plant Science https://www.researchgate.net/publication/330260128_Russo_The_case_for_the_entourage_effect_and_conventional_breeding_of_clinical_cannabis_No_strain_no_gain_Front_Plant_Sci_2019
- (a) The “Entourage Effect”: Terpenes Coupled with Cannabinoids for the Treatment of Mood Disorders and Anxiety Disorders https://pubmed.ncbi.nlm.nih.gov/31481004/ (b) Ethan B Russo & Jahan Marcu – Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads – Advances in Pharamcology