The Endocannabinoid System Explained: Why Cannabis Affects Everyone Differently

If you ask 10 individuals to relate a time when they experienced cannabis, you will likely receive 10 meaningful descriptions that differ from each other. For example, one individual felt extremely relaxed while using cannabis; however, the same individual used the exact same product at an identical dosage and instead felt very anxious.

One person’s use of cannabis increased their ability to concentrate; whereas, their companion found they were unable to concentrate at all. The first time many users do not feel anything as they continue to experiment; yet others become overwhelming affected. While some of these differences may be due to various personalities, or what has been referred to as “placebo,” there can be no doubt that there are real biological variations in the way in which this substance affects the user.

The primary reason for the diverse responses produced by cannabis is because of the workings of the endocannabinoid system. Therefore, understanding how this biological system functions is the single most valuable and relevant biological information for anyone that uses cannabis, is interested in learning more about its use or would like to know why the effect of cannabis is so variable and specific to each user.

What the Endocannabinoid System Actually Is

The endocannabinoid system was first identified by scientists as recently as the 1990s. This is still very recent from the perspective of the study of the human body. The reason for this discovery was largely due to an attempt on the part of THC researchers to determine why THC caused reactions within the body. In doing so, researchers identified that THC does not cause a new foreign response in the body. Instead, THC uses an existing biological regulatory system in the body.

The ECS consists of three core components:

Endocannabinoids — molecules produced naturally by the body that are chemically similar to the cannabinoids in cannabis. The two most studied are anandamide (named after the Sanskrit word for bliss) and 2-AG (2-arachidonoylglycerol)
Receptors — protein structures embedded in cell membranes throughout the body that endocannabinoids and cannabinoids bind to. The primary receptors are CB1 and CB2, though others including GPR55 and TRPV1 are increasingly recognised as part of the broader system
Enzymes — proteins that synthesise endocannabinoids on demand and break them down after use. FAAH breaks down anandamide; MAGL breaks down 2-AG

What makes the ECS unusual compared to most neurotransmitter systems is that it works retrograde — signalling backwards across synapses, from the receiving neuron back to the sending neuron, acting as a feedback mechanism that modulates how much of other neurotransmitters are released. It is, in effect, a master regulator of other systems.

Where the ECS Is Found and What It Does

The reason for the broad spectrum of action exhibited by Cannabis can be explained as follows. There are two main receptor systems in which the ECS operates; these being CB1 and CB2.

CB1 Receptors predominantly located within the Central Nervous System (CNS):

Hippocampi — formation of memories and spatial orientation.
Pre-frontal cortex — decision making, attention, executive functions.
Amygdale — emotional processing, fear reaction and anxiolytic activity.
Basal Ganglia — motor control and rewarding aspects of behaviour.
Cerebellum — co-ordination and timing.
Brain Stem — analgesia, anti-nausea.
Peripheral Nervous System — transmission of pain signals.

CB2 Receptors mainly located in the Immune System and Periphery^

Immune Cells — T-cells, B-cells, Macrophages and Mast Cells etc.
Splenus & Tonsills.
Gastrointestinal Tract — regulatory functions of digestion and gut/immune interface.
Skin — inflammatory responses, sebaceous gland secretion and wound healing.
Bone — regulation of Bone Density.

The various physiological mechanisms that regulate through the ECS include:

Pain Perception / Modulation
Inflammation Response
Appetite / Metabolism
Emotional Regulation / Mood
Consolidation of Memory / Forgetting
Architecture of Sleep / Circadian Rhythm
Function of Immunity / Inflammatory Signalling
Response to Stress / Cortisol Regulation
Reproduction Function
Regulatory Functions of Cardiovascular

How Cannabis Interacts with the ECS

When cannabis is consumed, its cannabinoids enter the bloodstream and interact with the ECS in ways that mimic, amplify, or modify endocannabinoid signalling:

THC binds directly and strongly to CB1 receptors — more strongly than anandamide, the body’s own equivalent. This produces the psychoactive effects associated with cannabis: altered perception, heightened sensory experience, impaired short-term memory, changes in time perception, and the euphoria or anxiety that different users experience differently. THC also partially activates CB2 receptors, contributing to its anti-inflammatory properties.

CBD does not bind significantly to CB1 or CB2 receptors directly. Its mechanisms are more complex and multiple:

It inhibits FAAH, the enzyme that breaks down anandamide — effectively raising the body’s own endocannabinoid levels
It acts as a negative allosteric modulator at CB1 receptors, reducing THC’s binding efficiency and softening its psychoactive effects
It activates TRPV1 receptors involved in pain and heat sensation
It interacts with serotonin receptors (5-HT1A), contributing to its anxiolytic properties
It activates PPARγ receptors involved in inflammation and metabolism

CBN, CBG, and minor cannabinoids interact with the ECS through various receptor pathways and are the subject of increasing research, though the evidence base is less developed than for THC and CBD.

Why Everyone's ECS Is Different

This is the main reason why Cannabis has such different effects on people. Every individual’s Endocannabinoid System (ECS), while basically the same, can be quite different and variable among people and thus can create varying experiences when taking Cannabinoids.

The ECS isn’t the same in each individual – genetic variations in each individual can create variability in the way Cannabinoids interact within their ECS.

Genetic Variability:

CNR1 Gene = Codes for the CB1 Receptor.

Polymorphisms in the CNR1 Gene can influence CB1 Receptor Density, Binding Affinity and Distribution within the Brain. Individuals who carry specific CNR1 Variants will likely have Fewer or Less Sensitive CB1 Receptors, resulting in THC producing Weaker Effects – or as stated above – an individual’s ECS being less capable of Regulating Anxiety and Mood Baselines.

FAAH Gene = Codes for the Enzyme that Breaks Down Anandamide.

One common variant of the FAAH gene is C385A, reducing FAAH activity and resulting in higher circulating levels of anandamide. Individuals who carried this variant tend to have lower baseline anxiety, faster fear extinction and may respond differently to both THC and CBD.

CYP2C9 & CYP3A4 = Liver Enzymes Responsible for Metabolizing THC.

Genetic variations that slow THC metabolism produce longer and more intense effects from the same dosage. Fast metabolizers will clear THC quicker and thus may find standardized dosages underwhelming

Sex and Hormonal Variation:

Estrogen has direct interaction with the ECS, by increasing CB1 receptor expression as well as FAAH activity. Therefore, we can say the ECS is dynamic throughout the menstrual cycle. The individual’s cannabinoid sensitivity will vary due to hormonal fluctuations. Research has shown that, for similar amounts of marijuana, women are more responsive to its effects than men, have quicker tolerance development and experience stronger acute effects.

Basal Endocannabinoid Tone:

Individuals’ basal endocannabinoid tone varies depending on their genetic predisposition, their life style (e.g., smoking), their level of stress, dietary patterns, the quality of their sleep and the amount of exercise they participate in. Individuals who have low basal endocannabinoid tone (individuals associated with conditions such as depression, PTSD, fibromyalgia and migraine – conditions some researchers refer to as “Clinical Endocannabinoid Deficiency”) tend to exhibit greater sensitivity to cannabis. Conversely, individuals exhibiting high basal endocannabinoid tone may experience little effect from cannabis.

Tolerance and Receptor Down-Regulation:

Continued use of cannabis leads to CB1 receptor down-regulation; this is the brains response to prolonged exposure to activated receptors. In other words, the brain decreases the number of available receptors and the sensitivity of those receptors. This is the reason why chronic users require more marijuana to elicit the same effect. Periodic abstinence from marijuana allows the brain to begin up regulating the number of receptors available and increase the receptors’ sensitivity which takes anywhere from one to four weeks.

Psychological & Contextual Factors:

The ECS is intricately linked with both the brain’s stress and emotion regulatory mechanisms. An individual’s pre-existing state of anxiety, his/her relationship with marijuana, his/her environmental surroundings and his/her expectations regarding marijuana will affect how he/she experiences CB1 receptor activation. Marijuana’s effect on the amygdala (the brain’s threat detection center) indicates that when an individual is consuming marijuana in a familiar/relaxed environment they will perceive a much smaller effect then if they were experiencing those same stimuli in an unfamiliar/stressful environment.

The Entourage Effect: Why the Whole Plant Is Different from Isolated THC

The Entourage Effect – or Hypothesis – of cannabis research is one of the most important and disputed. The idea of cannabis has been hypothesized as a synergistic (the whole being greater than the sum of its parts) interaction among cannabinoids and terpenes; that the effects produced by these compounds would be distinctly different when they were used separately versus in combination.

The Evidence Base:

Terpenes such as Linalool, Myrcene, Beta-Caryophyllene, etc., interact with Neurotransmitter Systems and the Endocannabinoid System (ECS), modifying the effects of THC and CBD through a variety of mechanisms.
CBD negatively allosterically modifies CB1 Receptors, therefore a full spectrum product containing both THC and CBD will have a distinct “high” from a product containing only THC.
Other minor cannabinoids such as CBG and CBN may also contribute to the total effect profile, but it appears there is less evidence available regarding the role of each.

Thusly, the implication for users, manufacturers and retailers is that two products with identical THC percentages may cause significantly disparate effects based upon their total cannabinoid and terpene profile. This is just one reason why percentage based thinking regarding cannabis potency is an over simplification.

What This Means in Practice

Understanding ECS variation suggests several practical principles for anyone using cannabis:

Your response is genuinely individual — comparing your experience to someone else’s is useful only as a rough guide, not a benchmark
Start low, go slow is not just cautious advice — it’s the rational response to not knowing where your CB1 receptor density, FAAH activity, and THC metabolism sit relative to the average
THC:CBD ratio matters more than THC percentage alone — the modulating effect of CBD on CB1 receptors changes the experience qualitatively
Tolerance is a biological process, not a personal failing — receptor downregulation is a predictable consequence of regular use, and tolerance breaks restore sensitivity because they allow receptor upregulation
Set and setting are biochemically real — the ECS’s integration with stress and emotional regulation systems means environment and mindset genuinely alter the pharmacological experience, not just the perception of it

The Bigger Picture

The discovery of the endocannabinoid system has been one of the major biological breakthroughs over the last fifty years. In comparison to the magnitude of this system, as well as how important it is to both our physical and mental health, there is still much research needed to be done on this topic. The reason we know so much about how cannabis works (as opposed to many other substances) is because of an evolutionary relationship between humans and the cannabis plant. This relationship is only just being mapped by scientists today.
Cannabis’ effects on different people can’t be explained by either chance or hearsay. What happens when cannabis is ingested is exactly what the endocannabinoid system is supposed to happen — each individual responds based on their own unique configuration of the system which receives the same signal from cannabis.

This article is for informational purposes only. Cannabis Assembly blog always encourages informed, responsible cannabis use. If you have specific health concerns related to cannabis use, consult a healthcare professional.