Neurotransmitters & Cannabis

How the endocannabinoid system, CB1, and CB2 are related to dopamine, GABA, glutamate, and serotonin—and why THC and CBD act in neurobiologically far more complex ways than simple “raise or lower neurotransmitter” explanations.

Cannabis does not act simply via a single “cannabis receptor.” Its effects arise in a complex network of cannabinoid receptors, the body's own endocannabinoids, and classic neurotransmitter systems.

At the center is the endocannabinoid system, or ECS for short. It regulates how strongly certain nerve cells pass signals to other nerve cells. As a result, it is involved in processes including memory, stress response, reward, pain processing, sleep, appetite, and emotional processing.

THC intervenes directly in this regulatory system. CBD behaves pharmacologically quite differently and acts via a multitude of potential molecular targets.

This is precisely why the statement:

Cannabis increases dopamine or lowers GABA.

is far too simple.

The more interesting question is:

At which synapse, via which receptor, at what time, and under what conditions does a cannabinoid alter signal transmission?

What are neurotransmitters?

Neurotransmitters are chemical signaling substances used by nerve cells to transmit information.

A nerve cell releases a messenger substance at a synapse. This substance crosses the synaptic cleft and binds to receptors on the next cell.

Known neurotransmitters include, for example:

• Dopamine
• Serotonin
• GABA
• Glutamate
• Acetylcholine
• Norepinephrine

In addition, there are neuropeptides like endorphins as well as neuromodulatory lipid signals like endocannabinoids.

These substances do not have simple functions based on the pattern:

Dopamine = happiness
Serotonin = good mood
GABA = relaxation

Such translations are popular, but neurologically far too crude.

A neurotransmitter can produce completely different effects depending on the:

• Receptor type
• Brain region
• Cell type
• Signaling pathway

that it activates.

The brain does not have a simple “neurotransmitter balance”

It is often said that mental health issues arise because neurotransmitters get “out of balance.”

This notion is also too simple.

The brain simultaneously regulates:

• Synthesis
• Release
• Reuptake
• Enzymatic degradation
• Receptor density
• Receptor sensitivity
• Neural circuitry
• Synaptic plasticity

The concentration of a single messenger substance alone therefore explains neither mood nor behavior.

Cannabis also does not simply change a single neurotransmitter concentration; it modulates neural networks.

This is exactly where the endocannabinoid system becomes important.

What is the endocannabinoid system?

The ECS consists, in simple terms, of three components:

Cannabinoid receptors

above all:

• CB1
• CB2

Endocannabinoids

in particular:

• Anandamide – AEA
• 2-Arachidonoylglycerol – 2-AG

Enzymes

for the synthesis and degradation of these signaling substances.

These include, among others:

• FAAH
• MAGL
• DAGL

The ECS is thus the body's own signaling system, which existed long before humans used cannabis.

THC did not get its name because the body had evolved cannabis receptors.

Conversely, the body's own ligands were discovered because cannabis compounds helped to identify this system in the first place.

CB1 – the most important cannabinoid receptor in the brain

The CB1 receptor is widespread in the central nervous system.

It is particularly relevant that CB1 is often located presynaptically.

This means:

The receptor is located on the nerve cell that is about to release a neurotransmitter.

When CB1 is activated, the release of this neurotransmitter can be reduced.

As a result, the ECS can influence, among other things:

• GABA
• Glutamate
• Acetylcholine
• Norepinephrine
• indirectly also dopamine

THC acts as a partial agonist at the CB1 receptor and can thus influence this endogenous regulatory system from the outside.

CB2 is not just an immune receptor

In the past, CB2 was overly simplified and described as a peripheral or immune cannabinoid receptor.

The modern picture is more nuanced.

CB2 is particularly abundant in immunologically relevant cells. However, the receptor has also been detected in the central nervous system – including on microglia and specific neuronal populations. Its expression can increase, especially under neuroinflammatory conditions.

CB2 is significantly less dominant in the brain than CB1.

The formula:

CB1 = brain, CB2 = body

is nevertheless too simple.

Anandamide and 2-AG

The two best-known endocannabinoids are:

Anandamide – AEA
and
2-Arachidonoylglycerol – 2-AG

Both are lipid signals, which distinguishes them from many classical neurotransmitters that are stored in vesicles and released as needed.

2-AG, in particular, is frequently synthesized de novo on demand.

It can subsequently act backward across the synapse.

This unusual principle is known as:

retrograde signaling.

What does retrograde signaling mean?

In a classical synapse, the information flow is, simply put:

presynaptic cell → postsynaptic cell

With endocannabinoid feedback, it can then go in the other direction.

The postsynaptic nerve cell, for example, produces 2-AG.

This travels back to the presynaptic terminal.

There, it activates CB1.

CB1 subsequently reduces further neurotransmitter release.

Simplified:

Neuron A → Neurotransmitter → Neuron B

then:

Neuron B → 2-AG → CB1 on Neuron A → less further release

This mechanism has meanwhile been demonstrated directly in vivo for inhibitory synapses as well.

The ECS thus functions partly as a local feedback regulator of a synapse.

GABA and Glutamate – two central systems

The relationship of the ECS to GABA and Glutamate is particularly important.

Glutamate

is the most important excitatory neurotransmitter in the human brain.

GABA

is the most important inhibitory neurotransmitter.

These terms also do not mean:

Glutamate = bad and overactive
GABA = good and calm.

Both systems are indispensable.

What is decisive is their precise temporal and spatial regulation.

CB1 receptors are located on both glutamatergic and GABAergic nerve terminals.

Endocannabinoids can therefore reduce the release of both systems.

Why cannabis does not simply “slow down the brain”

This leads to an apparent contradiction.

If CB1 inhibits an inhibitory neurotransmitter like GABA, the result can be a disinhibition of the next nerve cell.

That means:

less inhibition → more activity

At another synapse, by contrast, CB1 can reduce glutamate:

less excitation → less activity

Therefore, the same cannabinoid can produce seemingly opposite effects depending on the circuit.

That is precisely why THC cannot simply be neurobiologically classified as:

• sedative
• stimulating
• inhibitory

It modulates networks.

THC – what happens at the CB1 receptor?

THC, or Δ9-tetrahydrocannabinol, is the most important intoxicating cannabis compound.

THC is a partial agonist at CB1 and CB2.

The psychoactive effects are particularly strongly associated with CB1.

Following the activation of CB1, various intracellular signaling pathways can be altered. In simple terms, this frequently leads to a lower probability of neurotransmitter release presynaptically.

As a result, THC can influence neuronal processes involved in:

• perception
• memory
• reaction time
• reward processing
• attention
• motor coordination
• emotional processing

The effects depend, among other things, on dose, consumption experience, genetics, and context.

THC and dopamine

Dopamine is one of the best-known neurotransmitters and is particularly associated with:

• motivation
• reinforcement learning
• reward processing
• movement
• salience

The popular phrasing:

THC releases dopamine

is, however, too direct.

THC is not a classical dopamine agonist.

The effect occurs indirectly via neuronal circuits involving, among others, GABA, glutamate, and CB1.

How strongly does THC increase dopamine in humans?

Interestingly, this effect is significantly smaller and more inconsistent than with many classical drugs.

An early PET study involving seven people found increased dopamine release in the ventral striatum after THC. Another study with 13 participants, however, found no significant increase in striatal dopamine release despite clear THC effects.

A joint reanalysis of this data finally found a small but significant effect in the limbic striatum.

The authors explicitly described the THC-induced increase in dopamine as modest compared to other drugs.

More recent PET data after smoked cannabis also support the possibility of transient dopamine responses in the ventral striatum, but still originate from relatively small samples.

The more precise statement is therefore:

Acute THC can increase dopaminergic activity in parts of the human striatum, but the effect is relatively small and not completely consistent across studies.

Dopamine is not simply the “happiness hormone”

This cannabis myth is also worth correcting.

Dopamine does not simply create happiness.

The system is central to:

• motivation
• learning
• expectation
• action selection
• reward prediction
• the significance or salience of stimuli

This better explains why dopaminergic systems also become relevant in addiction and reinforcement learning.

A behavior repeatedly experienced as rewarding can be learned and prioritized more strongly.

However, this applies not only to cannabis but fundamentally to numerous rewarding behaviors and substances.

Cannabis, dopamine, and habituation

Acute and long-term effects should also be separated.

An acute THC effect does not mean that chronic consumption permanently alters the dopaminergic system in the same direction.

With repeated exposure, the following can occur, among other things:

• receptor adaptations
• tolerance
• changes in network response
• learning processes

Therefore, the phrasing:

Cannabis increases dopamine.

is only a snapshot of a much more complex system.

THC, memory, and the hippocampus

CB1 receptors are also strongly represented in brain regions involved in learning and memory.

This includes, in particular, the hippocampus.

Acute THC can impair memory performance. A randomized, double-blind study with 120 cannabis users published in 2026 found impairments in numerous areas after THC – including verbal and visual-spatial memory, source and prospective memory, as well as temporal sequencing.

This fits well with the role of the ECS:

Synaptic plasticity requires very finely tuned neurotransmission.

Strong external CB1 activation by THC can alter this endogenous timing.

CBD works completely differently than THC

CBD, or cannabidiol, is often described as “non-psychoactive THC.”

This is also imprecise.

CBD is not intoxicating like THC, but it definitely possesses pharmacological effects in the central nervous system.

It binds only weakly directly to CB1 and possesses a much broader pharmacological target profile. Interactivity has been described with, among others:

• 5-HT1A
• TRPV1
• GPR55
• adenosine signaling pathways
• PPARγ
• endocannabinoid metabolism

However, the exact significance of many of these mechanisms in humans has not yet been fully clarified.

CBD and serotonin

CBD is particularly frequently associated with the serotonin system.

At the center is the 5-HT1A receptor.

Earlier cell studies described CBD as an agonist at this receptor. Numerous preclinical studies also found that certain CBD effects can be attenuated by blocking 5-HT1A.

This led to the widespread statement:

CBD acts via serotonin.

Modern research is more cautious.

A comprehensive pharmacological review from 2025 concludes that CBD and 5-HT1A clearly interact with each other, but the exact pharmacodynamic relationship remains debated and may be dose-dependent.

This is significantly more precise than simply calling CBD a “serotonin booster.”

Does CBD increase serotonin?

Not in the simple sense of a classical serotonin reuptake inhibitor.

CBD can influence serotonergic signaling pathways, but it does not automatically follow that:

more CBD → more serotonin in the brain.

Furthermore, 5-HT1A receptors are located both:

• presynaptically as autoreceptors
• as well as postsynaptically

and can produce different effects depending on the localization.

Therefore, the following also applies here:

Receptor effect is more important than a single neurotransmitter count.

CBD and anxiety – what do human studies say?

CBD is studied particularly frequently in connection with anxiety.

A 2024 meta-analysis included eight studies with a total of 316 participants and found a statistical signal in favor of CBD. However, the authors explicitly emphasized the small clinical data basis and the uncertainty of the results.

A 2026 systematic review on functional imaging in stress and anxiety is even more cautious: the twelve included studies with 146 participants provided heterogeneous results, and the certainty of the evidence was rated as low to very low.

CBD is therefore scientifically interesting.

The statement:

CBD treats anxiety disorders reliably.

would nevertheless not be justified based on current evidence.

Serotonin is also not a "happiness hormone"

Serotonin is also frequently oversimplified.

The serotonergic system possesses numerous receptor families and influences, among other things:

• Sleep-wake regulation
• Appetite
• Anxiety processing
• Impulse control
• Perception
• Digestion
• Pain processing

A 5-HT1A receptor behaves completely differently than, for example, a 5-HT2A or 5-HT3 receptor.

Therefore, the statement:

CBD influences a serotonin receptor

does not by any means mean:

CBD generally improves mood.

Cannabis and GABA

The GABA system is closely linked to CB1.

CB1 receptors are located on numerous GABAergic nerve endings.

If these are activated, less GABA can be released.

As a result, a downstream nerve cell can be disinhibited.

This principle plays a role in dopaminergic reward networks, among others.

Endocannabinoids can thus indirectly increase the activity of a nerve cell, even though CB1 itself inhibits neurotransmitter release.

This sounds paradoxical at first, but is typical for neuronal networks.

Cannabis and glutamate

Glutamatergic nerve endings also possess CB1.

Here, activation can lead to a lower release of glutamate.

Endocannabinoids thus regulate both:

excitatory glutamate signals
as well as
inhibitory GABA signals.

Exactly this interplay makes the ECS an important component of synaptic fine regulation.

Acute and chronic are not the same

Another common error is to transfer results of acute THC experiments directly to long-term consumption.

Acute cannabinoid exposure can in the short term:

• alter neurotransmitter release
• alter perception
• impair memory
• alter reaction time

Repeated exposure, on the other hand, can trigger adaptation processes.

These include, among others, changes in:

• CB1 availability
• signal transduction
• tolerance
• synaptic plasticity

Therefore, a distinction should always be made between:

acute pharmacology
and
long-term neuroadaptation.

Dose plays an enormous role

Cannabinoid effects are often non-linear.

More THC does not simply mean the same effect, only stronger.

With increasing dose, the following can change:

• intensity
• perception
• anxiety reaction
• cognitive impairment
• psychotomimetic effects

change.

Especially with very THC-rich products, there are increasing indications of less favorable psychological outcomes.

A 2025 systematic review with 99 studies and more than 221,000 participants found particularly consistent unfavorable correlations between high-concentration THC products and psychosis or schizophrenia, as well as cannabis use disorder. However, the quality of many included studies was only moderate or low.

Thus:

higher THC concentration

is not a neutral difference in a data sheet.

THC and anxiety

THC can subjectively evoke very different reactions.

In some people or conditions, it can be experienced as pleasant or relaxing.

Under other conditions, it can reinforce:

• anxiety
• restlessness
• paranoia
• dysphoria

This apparent paradox fits the network biology of the ECS.

The reaction is influenced by, among other things:

• dose
• consumption experience
• individual sensitivity
• environment
• expectation
• THC concentration
• other product components

Therefore, a strain or cannabinoid should not be sweepingly described as "against anxiety."

Cannabis and mental health

It is precisely here that the separation between neurobiological mechanism and clinical therapy is particularly important.

Just because the ECS is involved in anxiety, stress, reward, or sleep, it does not automatically follow that:

Cannabinoids treat disorders of these systems.

A 2026 meta-analysis published in The Lancet Psychiatry examined 54 randomized studies with 2477 participants on cannabinoids for mental health and substance use disorders.

For some areas, there were signals of potential efficacy – among others, certain sleep, tic, and cannabis withdrawal symptoms.

For:

• anxiety disorders
• PTSD
• psychotic disorders
• opioid use disorder

however, no significant benefits were found.

For depression, there was no suitable RCT evidence at all as a primary treatment. The quality of the evidence was low for most outcomes, and cannabinoids were overall associated with more adverse events.

The authors consequently concluded that routine use of cannabinoids for the treatment of mental illnesses is currently only rarely justified.

CBD and THC must be separated in this context

"Cannabis" is pharmacologically not a single substance.

THC and CBD differ significantly.

A 2025 systematic review, for example, came to the result that in controlled studies, higher CBD doses sometimes showed short-term anxiety improvements, while THC was more frequently associated with dose-dependent adverse effects and could even cause worsening in psychosis.

Therefore, a statement such as:

Cannabinoids work well against anxiety

is too non-specific.

One must at least ask:

Which cannabinoid? Which dose? Which disorder? Which study design?

Why people react differently

The effect of cannabis is not solely a property of the strain.

It arises from multiple levels.

These include:

Product

• THC
• CBD
• other cannabinoids
• form of application
• actual dose

Person

• metabolism
• age
• prior experience
• tolerance
• genetic differences
• psychological baseline

Situation

• environment
• expectation
• stress
• social situation

This also makes it understandable why two people can react completely differently to the same product.

Terpenes and neurotransmitters

Terpenes are frequently pulled into the same discussion.

For example, it is said that:

• myrcene is sedating
• limonene improves mood
• linalool calms
• pinene improves memory

Interesting preclinical data exists for many such statements.

The clinical question, however, is:

Do the concentrations occurring in cannabis actually reach a sufficiently high systemic exposure in humans to trigger such effects in a reproducible manner?

This question has not yet been convincingly answered for many terpenes.

A terpene profile is therefore excellently suited for describing aroma and chemical identity.

It should not automatically be interpreted as a neurotransmitter interpretant.

Endorphins and Cannabis

Endorphins are among the body's own opioid peptides.

They are not part of the endocannabinoid system, but both systems can functionally interact with each other.

The endocannabinoid and opioid systems overlap in networks that are involved in, among other things:

• Reward
• Stress
• Pain
• Motivation

However, this does not mean that cannabis simply “releases endorphins”.

Here, too, indirect network interactions are the more accurate description.

Cannabis does not alter a single messenger substance

After considering all these mechanisms, one central point can be established.

THC does not only influence:

Dopamine.

CBD does not only influence:

Serotonin.

And cannabis does not only influence:

GABA or glutamate.

Cannabinoids alter the activity of an already existing neuromodulatory system, which in turn controls several neurotransmitter circuits.

This is exactly what leads to:

• diverse effects
• dose-dependent differences
• individual reactions
• sometimes opposing effects

The endocannabinoid system functions more like a network regulator than a single on/off switch.

Typical myths about cannabis and neurotransmitters

THC simply releases dopamine

Too simplistic. Human PET studies find a possible, but rather small, striatal dopamine effect that is not detectable in every study.

Dopamine means happiness

No. Dopamine is much more strongly linked to motivation, learning, salience, and reward prediction.

CBD simply increases serotonin

Not proven. CBD can influence 5-HT1A signaling pathways; the exact pharmacological mechanism remains a subject of debate.

CBD is completely non-psychoactive

CBD does not produce the typical THC high. However, it can influence the central nervous system and behavior, making it pharmacologically quite neuroactive.

THC inhibits the brain

Not generally. CB1 can reduce both GABA and glutamate release. Depending on the circuit, this can lead to inhibition or disinhibition.

CB2 only exists in the immune system

No. CB2 has also been described in the central nervous system on microglia and certain neuronal populations.

The endocannabinoid system consists only of CB1 and CB2

No. AEA, 2-AG, and their synthesis and degradation pathways are also part of the ECS; furthermore, cannabinoids interact with other targets.

Cannabis brings neurotransmitters back "into balance"

There is no such simple biological model for this.

Because the ECS regulates stress, cannabis treats anxiety

Not automatically. The current RCT meta-analysis found no sufficient evidence for cannabinoids as a general treatment for anxiety disorders.

FAQ – Frequently asked questions about neurotransmitters and cannabis

What are neurotransmitters?

Neurotransmitters are chemical signal substances that nerve cells use to communicate with each other. Examples include dopamine, serotonin, GABA, and glutamate.

Is the endocannabinoid system a neurotransmitter system?

It is more of a neuromodulatory lipid signaling system. 2-AG, in particular, can be produced on demand and retrogradely regulate presynaptic neurotransmitter release.

What are the most important endocannabinoids?

Primarily anandamide (AEA for short) and 2-arachidonoylglycerol (2-AG for short).

What does CB1 do?

CB1 is often located presynaptically and, when activated, can reduce the release of various neurotransmitters.

What does CB2 do?

CB2 plays an important role in immune and inflammatory processes, but also occurs in the central nervous system.

How does THC act in the brain?

THC is a partial agonist at cannabinoid receptors, particularly CB1. By doing so, it alters presynaptic neurotransmitter release and thus numerous neuronal networks.

Does THC increase dopamine?

Acute THC can induce a small increase in dopamine in parts of the striatum. However, human studies are not entirely consistent.

Does dopamine make you happy?

Not directly. Dopamine is involved in, among other things, motivation, learning, reward processing, and the evaluation of relevant stimuli.

Does cannabis influence GABA?

Yes. CB1 is located on GABAergic nerve endings and can reduce their transmitter release.

Does cannabis influence glutamate?

Yes. CB1 can also reduce release at glutamatergic endings. The ECS thus modulates excitatory and inhibitory synapses.

Does CBD have to do with serotonin?

CBD interacts with 5-HT1A-mediated signaling pathways. How exactly this pharmacological relationship functions is still being studied.

Does CBD simply increase serotonin levels?

There is no such simple evidence for this. CBD does not simply act like a classic serotonin reuptake inhibitor.

Can CBD treat anxiety?

There are initial clinical signals, but the evidence base is small and heterogeneous. Larger, methodologically better studies are necessary.

Does THC impair memory?

Acutely, yes. Controlled human studies show impairments in several areas of memory following THC-containing cannabis.

Is high-potency THC psychologically riskier?

Current systematic reviews find less favorable correlations with high-concentration THC products, particularly regarding psychosis/schizophrenia and cannabis use disorder. However, the quality of the underlying evidence varies.

Are cannabinoids well-proven therapeutically for mental illnesses?

For most illnesses, no. A large meta-analysis from 2026 found overall only limited and mostly low-certainty evidence; routine use was rarely considered justified.

Conclusion

Cannabis and neurotransmitters are closely linked – but not through simple one-substance-one-messenger relationships.

At the center is the endocannabinoid system. 2-AG, in particular, can act as a retrograde signal from the postsynaptic nerve cell back to the presynaptic terminal, where it can reduce further neurotransmitter release via CB1. Through this, the ECS regulates GABAergic and glutamatergic synapses, among others.

THC, as a partial CB1 agonist, intervenes directly in this system. The resulting changes can, in turn, influence dopaminergic reward networks. Human studies show rather small and not entirely consistent dopamine effects – far from the simple notion of a massive dopamine kick.

CBD functions differently. Its direct affinity for CB1 is low, while 5-HT1A, TRPV1, and other signaling pathways are being investigated. The link to the serotonergic system is particularly interesting, but mechanistically and clinically not as clearly understood as many popular CBD explanations might suggest.

This distinction is also crucial for mental health. The fact that endocannabinoids are involved in stress, anxiety, reward, and memory does not automatically prove a therapeutic benefit of external cannabinoids. The large RCT meta-analysis of 2026 found only limited or insufficient evidence for most mental illnesses, while also finding more adverse events with cannabinoids.

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