Overview

The endocannabinoid system (ECS) modulates several body responses like stress, anxiety, alertness, sleep, appetite, pain, memory, body temperature, inflammatory reactions and more. The ECS is composed of cannabinoid receptors and chemicals that stimulate them, the endocannabinoids. 

Cannabis compounds, like THC and CBD, are structurally similar to the endocannabinoids that are naturally present in the nervous system and our  immune systems. This compatibility enables the plant's chemicals to interfere with the ECS-dependent body regulations.¹

Cannabis has been investigated for a number of reasons. Their compounds are versatile and of interest for many health conditions like epilepsy, multiple sclerosis, insomnia, and more. Studies on their effects and benefits for cancer treatment has shown that cannabinoids can be useful for both antitumor drugs and improving quality of life by managing symptoms. There is relevant evidence on the use of cannabis compounds inhibiting tumor cell proliferation, metastasis and chemoresistance.²

Components of the Endocannabinoid System

Cannabinoid Receptors

The main receptors involved with the endocannabinoid system are named CB1 and CB2. CB1 is widely spread in the brain. For outnumbering other types of receptors, it highly influences regulation of most neurotransmitters. Significantly modulates systems related to hunger, body temperature, and alertness.¹

CB2 is mainly found in the immune system, modulating a diversity of inflammation responses. Interesting drug target, as it does not cause the psychoactive effects related to the stimulation of CB1.¹

Endocannabinoids

Endocannabinoids are chemicals naturally produced by the body. They are structurally similar to the phytocannabinoids (cannabis compounds, like THC and CBD). These chemicals are capable of interfering in body responses by binding to receptors present either in the nervous or the immune systems.³

Arachidonoylglycerol (2-AG) and arachidonylethanolamide (Anandamide) are the most known and well described endocannabinoids. They often have inhibitory functions, which means that, when binded to a receptor, they interrupt a signal from one neuron to the other. an important response for neuroprotection. But endocannabinoids, in general, can trigger different effects depending on the cells they act on and the receptors they bind.⁴

Enzymes

The ECS is also dependent on several enzymes for its balanced management. These enzymes are proteins mainly responsible for synthesizing, breaking or carrying endocannabinoids.⁴

The ECS’s Role in Cancer and Tumor Biology

The complex network of the ECS is connected to both the nervous and the immune systems. Depending on the cannabinoid involved and the cell type, the ECS is capable of either triggering or blocking several tumor mechanisms, like:⁵

• Angiogenesis and Metastasis: interfering on angiogenesis (new blood vessel formation) and metastasis (spread of cancer cells)
• Cancer Cell Growth: impact on cell proliferation, apoptosis (cell death), and metastasis
• Immune Response: modulating immune system and its potential to influence tumor growth or suppression

Cannabinoids in Cancer Treatment

Types of Cannabinoids

• Phytocannabinoids: derived from the cannabis plant. The main phytocannabinoids, being most abundant, are the THC and the CBD⁶
• Endocannabinoids: signaling molecules naturally produced by the human body to support the ECS. The best described yet are the 2-AG and Anandamide⁷
• Synthetic cannabinoids: psychoactive substances that are artificially produced to be similar in structure to the naturally-occurring cannabinoids. Approved drugs based on cannabinoids can be composed of a synthetic form, like Epidiolex, used for epilepsy treatment⁸

Mechanism of Action in Cancer Cells

Many elements within the ECS can be affected by cannabinoids. Some consequences are noticeable, like the psychoactive side effects of cannabis, but others occur on the cell level. The impact depends, mainly, on the receptor binded to and the type of cell that is receiving the signal. The effects of cannabinoids are numerous. Among them, there are antitumor, but also tumor promoting effects. Several mechanisms are still unclear, but some have been described in recent decades.

Inhibit cancer cell growth

There are different mechanisms through which cannabinoids can reduce tumor growth and proliferation. One of the most widely observed is the inhibition of a specific protein, called kinase B (Akt), and its adjacent mechanisms. Different types of tumor cells have been tested for this type of blockage, responding with reduced proliferation and, therefore, slowed cancer progression.²

Reduce inflammation

The immune cells' attack against tumors affects healthy tissue as well. Cannabinoids have means to act on reducing such responses. They are able to induce anti-inflammatory elements, while suppressing the existing proinflammatory factors. This immune modulation is crucial to sustain the combat against cancer development.⁹

Induce apoptosis

Investigations on THC and CBD, the main phytocannabinoid, and their benefits for cancer treatment, have shown that the chemicals induce cell death (apoptosis). Many results have been positive when testing them for their potential to induce death of different tumor cells.² 

Therapeutic Uses and Benefits of the ECS in Cancer Treatment

• Pain and symptom management: improve overall quality of life by alleviating pain, nausea, and other cancer-related symptoms
• Potential anticancer effects: cannabinoids’ potential to slow tumor growth, block proliferation and metastasis, trigger cancer cell death and reabsorption

Challenges and Future Directions

Legal and Regulatory Issues

Cannabinoids used for medical means depend on legal and regulatory issues. Their medicinal use depends on the region. Renowned regulatory organs, like the FDA, have approved cannabinoid-based drugs for the treatment of health conditions, including cancer.

Need for Clinical Research Support

The stigma around both the recreational and medical use of cannabis and similar compounds makes it a complex research subject. In comparison to other medical topics of study, this has more gaps in clinical evidence, because of its slowest progression. The research is important and can be crucial for a number of critical patients, but many social and legal barriers are dealt with in order to publish valuable and reliable information that can back up treatment advancements. 

Personalized Treatment Approaches

The versatility of cannabinoids for cancer treatment and the heterogeneity of tumors, makes this type of treatment one that requires a specific approach for each case. It depends, primarily, on patient characteristics and cancer types. The numerous variables involved in balancing this type of treatment requires solid support from research and legal aspects.

Summary

The endocannabinoid system is involved with many important body functions, from mood, sleep, hungriness, alertness, to a cell level of different functions. Through chemicals called endocannabinoids, it sends signals to different tissues and cells, modulating them. For their similar structures, phytocannabinoids and synthetic cannabinoids can induce the same activities as the ones produced by the body. That is how substances from the cannabis plant can induce several effects in the human system, because they can act directly on the ECS and influence all of its functions. 

When any of the cannabinoid structures bind to a receptor, either activating or blocking it, a signal is sent, commanding an action. In the usage of cannabinoids for cancer treatment, such command is usually connected to inflammation, cell growth and proliferation, or even apoptosis (cell death). These potential modulations can impact on tumoral mechanisms and have been studied for a while, more deeply and extensively in recent decades. The effects of cannabinoids for cancer patients depends on the type of tumor they have and which cells are being affected.

The modulating impact of the ECS for these cases can be either positive or negative, as it can favor or damage tumor tissue. That's why it is important to exhaustively investigate these approaches. The positive outcomes provided by the versatility of the modulation of the ECS can make it a valuable and crucial strategy for patients who are resistant or non responsive to other methods. Knowing this, continuously exploring the mechanisms of action of cannabinoids and the ECS for cancer treatments, is supporting medical advances that can improve quality of life and even save patients that were hopeless. This area of ​​study is highly dependent on legal and regulatory issues, but the stigma surrounding cannabis is probably the main cause of the slow progress in this type of study compared to others in the medical field.