Understanding Cannabis’s Entourage Effect

Benefits of Whole Plant Medicine

Whole plant medicine is based on the idea that many different elements of a medicinal plant work together in our bodies to create beneficial outcomes. That is, the interactions of different compounds create an entourage effect or synergy, where joint outcomes generated by the plant as a whole are better than outcomes achieved using isolated ingredients from the plant. Modern medicine recognizes the benefits of combining different pharmaceuticals into drug cocktails or combination therapies to improve outcomes for patients being treated for HIV, hepatitis C, autoimmune diseases, and mood disorders, among other others.[1]

Advocates of whole plant medicine describe several interconnected benefits:

1. Improved Efficacy: By combining multiple components of a plant, patients often end up achieving better therapeutic effects. [2]
2. Improved Tolerability: By combining multiple components of a plant, patients often end up suffering from fewer or less severe unwanted side effects. [3]
3. Reduced Tolerance/Resistance: By combining multiple components of a plant, patients are often more resistant to building up a tolerance or having their disease become resistant to the medication.[4]

Generally speaking, when a drug is more effective, we often use less of it, which then saves money, reduces the severity of side effects and prevents us from building up a tolerance. Whole plant medicine thus has the potential to provide fantastic benefits over single-ingredient medications.

Advocates of medical cannabis tout the ability of whole plant cannabis to provide better outcomes than isolated cannabis extracts because whole plant cannabis benefits from the entourage effect. But how, exactly, does cannabis’s entourage effect work? What are the mechanisms involved in creating synergies between different components of the cannabis plant? That is the question this investigation seeks to answer.

Brief Overview of Cell Signaling

Before we proceed to understanding exactly how the various compounds in cannabis interact with one another to create the entourage effect, we need to understand some basics about how the cells in our bodies communicate with each other.

Much of the cannabis activity in our bodies takes place in neurons, which are the cells in the Nervous System. The Nervous System detects environmental changes within and outside of our bodies, then it works with our other body systems to respond to those changes.[5]

Figure 1 provides an illustration of two neurons. Neurons communicate with each other through interactions between the axons of one neuron and the dendrites of another neuron.

Figure 1

To provide some perspective, the human brain has about 86 billion neurons,[6] each of which is connected to 5,000 to 200,000 other neurons,[7] and each of which sends signals between 5 and 50 times per second.[8]

Figure 2 illustrates how neurons communicate with each other by sending signals (neurotransmitters) from the axon terminal of the sending cell, across the gap between the two cells (the synapse), and to the dendrites of the receiving cell. Actions are generated when neurotransmitters from sending cells activate receptors of receiving cells.

Figure 2

Notably, receptors have primary binding sites that serve as the main locus of activity. Yet, receptors also have secondary binding sites where additional molecules can bind and affect the reactions caused by the primary binding (see Figure 3). This issue will be important for understanding allosteric modulation discussed below.[9]

Figure 3

Returning to Figure 2, cell-to-cell communications work as follows.

1. Neurotransmitters are produced (synthesized) in sending cells
2. When ready to be released, neurotransmitters are transported by synaptic vesicles to the border of the axon and synapse.
3. There, neurotransmitters in the vesicle are released into the synapse,

After neurotransmitters are released into the synapse, one of three events take place:[10]

4. Neurotransmitters travel across the synapse and activate receptors on the receiving cell. Once neurotransmitters have activated receptors, they are released back into the synapse to be broken down; or
5. Neurotransmitters are broken down by enzymes in the synapse; or
6. Neurotransmitters are taken back into the sending cell (reuptake) for retransmission or breakdown.

The cannabinoids (THC, CBD, CBG, etc.) in cannabis are plant-created neurotransmitters that mimic the neurotransmitters created in our bodies (AEA, 2-AG, etc.).