How do cannabis terpenes contribute to the entourage effect?

The ‘entourage effect’ is attracting more and more interest in both the cannabis community and the scientific world. Terpenes (i.e. aromatic compounds) are believed to help modulate the effects of marijuana in conjunction with other components present in the plant. It has even been theorised that they produce similar effects to those of cannabinoids. Here we explain the role of these fragrant compounds and how their therapeutic potential has placed them in the spotlight.

Terpenes are aromatic organic compounds that can be found in many plants and fruits, providing them with their aroma and flavour. They are the basic components of essential oils and are added to soaps, perfumes, creams, or even food. Terpenes have been used for thousands of years for their therapeutic properties with countless applications.

Cannabis is known for its great variety of aromas and flavours, which are characteristic of each strain. This plant is very rich in terpenes, with the main ones being the following:

• ß- Myrcene.
• α-Pinene.
• ß-Pinene.
• Limonene.
• Linalool.
• ß- Caryophyllene.

These are the terpenes that appear in greater proportions in the composition of cannabis. However, the list is much longer, and includes about 400 different types. The different combinations and proportions of these terpenes lead to a wide range of aromas and flavours: citrus, pine, wood, coffee, herbal, or Diesel, for instance.

These different terpene profiles not only influence the smell and flavour of cannabis but also its effects.

How do terpenes interact in the human body?

Terpenes can interact with a wide spectrum of receptors and neurotransmitters in our body. This means that they can activate cellular mechanisms involved, for instance, in the release of dopamine, the reduction of anxiety, or the interruption of inflammatory processes, amongst many others. Here are some examples:

• ß-Myrcene: This is one of the most common terpenes in cannabis and has been attributed with various pharmacological effects, including boosting the antibiotic activity of some essential oils or acting as a sedative and analgesic.
• Limonene: This is a common terpene in citrus plants and is also found in cannabis. It can activate the serotonin levels in the brain, reduce anxiety, and stimulate the immune system. It also has antibiotic properties.
• α-Pinene: This terpene can act as an anti-inflammatory, bronchodilator, and antibiotic.
• Linalool: It is mainly extracted from lavender, rose, and basil, in addition to cannabis. Linalool has sedative, antidepressant, and anxiolytic effects, and can also help boost the immune system.

The list of terpenes with therapeutic properties is incredibly long, with a wide range of cellular pathways coming into play. But terpenes not only produce effects by themselves: they can also affect the activity of other cannabis components. This influence is what gives rise to the ‘entourage effect’.

What is the entourage effect?

For years, there has been an open debate about how different marijuana components interact to create the unique and characteristic effect of each strain, what causes this, and which specific components play a part.

The entourage effect in cannabis was first postulated in 1998 by Israeli chemists Raphael Mechoulam and Shimon Ben-Shabat. This theory argues that several components of the plant (cannabinoids, terpenes, flavonoids, etc.) act synergistically to enhance their properties, making their effects greater than those of a single isolated component.

The interaction between CBD and THC is relatively well known, but these two cannabinoids alone cannot explain the wide variety of therapeutic and psychoactive effects of all cannabis strains (sedative, relaxing, stimulating, etc.). Those suspected of interfering with these effects are terpenes.

Indica and sativa effects and the involvement of terpenes

It is believed that the role of terpenes in the entourage effect means that, even when two different varieties have the same proportion of cannabinoids, their psychoactive effects will be different. This could be the reason for the differences between the effects of indica and sativa strains.

Although terpenes don’t produce any psychoactivity, their ability to modulate cannabinoid activity would explain how two plants that contain the same CBD and THC concentration, for instance, can deliver opposite effects. One may produce typically indica sensations (e.g. narcotic and relaxing), whereas the other may deliver sativa-like effects (e.g. energising and cerebral).

How do terpenes contribute to the entourage effect?

Following this lead, a study published in 2021 in the journal Scientific Reports, conducted by the University of Arizona (USA), tested the entourage effect on a selection of terpenes. The tests were performed on mice and in vitro cell lines, aiming to see if these terpenes could trigger the endocannabinoid receptors, such as CB1 and CB2, and how this would affect cannabinoid activity.

Although much has been theorised on this subject for a number of years, and other lines of research have tried to prove this without much success, this study was actually the first to show that terpenes modulate the effects of cannabinoids, which therefore confirms their role in the entourage effect.

The study also concluded that terpenes achieve this by binding with several cell receptors inside and outside the endocannabinoid system. Among them is CB1 (specific to THC and A2a) linked to inflammatory processes.

The results suggest that terpenes can stimulate the receptors of the endocannabinoid system and produce some effects similar to those of endocannabinoids. This has been described as ‘cannabimimetic’ action.

The way terpenes activate receptors, as well as their ability to influence the activity of different cannabinoids, is still under investigation. The results of this study, however, support the interest that the entourage effect has aroused in recent years regarding the medical use of cannabis.

Terpenes and the entourage effect in the medical sector

The entourage effect of terpenes is a great tool to improve medical cannabis therapies due to its potential to modulate their side effects.

THC and CBD have been shown to have therapeutic value for the treatment of various complaints, such as chronic pain relief. However, the use of THC for medicinal use can also lead to some unwanted side effects (dry mouth, tachycardia, paranoia, etc.). Finding a way to maximise its therapeutic action whilst at the same time reducing those annoying effects would be possible thanks to the modulation of its activity with terpenes.

In the field of mental health, for example, researchers such as Dr. Sari Goldstein, lead author of the study “The ‘Entourage Effect’: Terpenes Coupled with Cannabinoids for the Treatment of Mood Disorders and Anxiety Disorders”, have highlighted the benefits that would be obtained with the application of terpenes in cannabinoid therapies for the treatment of anxiety, depression, and bipolar disorder.

Given the strong side effects of anxiolytic and antidepressant drugs, and the reported benefits of CBD and THC therapies for these diseases, the research of new treatments with cannabinoids and terpenes could bring great benefits to patients

The use of terpenes in combination with opioids could also help reduce certain types of pain. The long-term goal is to use terpenes (generally recognised as safe by the drug agencies) in combination with cannabinoids or opioids to develop dose reduction strategies that achieve the same level of effectiveness.

This way, pain relief would be achieved with lower medication doses and fewer secondary effects. This could certainly be a panacea to reduce the hundreds of thousands of deaths that occur each year from overdoses of synthetic opioids (such as fentanyl) in countries like the US, whose number has increased significantly during the recent Covid-19 crisis.