We just wrapped up a thorough review of CBD and the pathways of addiction.
You can't talk addiction without mentioning dopamine.
It's front and center (along with tolerance) to every addictive drug out there but dopamine is so much more.
Especially when it comes to mental health.
The role of dopamine in shaping what we do is fascinating!
It also has effects throughout the body including:
- Initiating movement (hence ties to Parkinson's)
- Slowing down gut movement (anti-nausea drugs)
- Dilating arteries (blood pressure effects)
As important as these are, we want to really focus on interaction with mental health and addiction.
Two sides of the same coin if you read our CBD and addiction review.
Let's zero into research on how dopamine imbalance is implicated in a range of different issues that many people may not suspect.
We'll cover these areas:
- How dopamine work in the brain
- Dopamine and other neurotransmitters
- Dopamine and addiction
- Dopamine and mental health
- Dopamine and anxiety
- Dopamine and depression
- Dopamine and schizophrenia
- Dopamine and bi-polar
- Dopamine and ADHD
- CBD's interaction with dopamine
Let's jump into it!
How dopamine work in the brain
If you are interested in why you do certain things, hold tight. You have to get to know dopamine.
We're going to look at three key effects under the control of dopamine:
- "Do that again"
- Initiating action
- Attention focus
We'll start with the key point for addiction.
"Do that AGAIN!".
Dopamine has been incorrectly given the role of pleasure but that's not really the case.
A better description is "do that again".
Let's get old-school as in a few 100,000 years ago.
As part of the reward circuit, it's tasked with triggering a memory (hippocampus) and reward (VTA) to remember where a good source of food or water is.
In fact, anything tied to survival (food, water, sex) relies on dopamine to fire.
As so, it figures into our learning process directly.
After all, we have to remember where that source of food or water is. If there's a specific set of actions that bring us a reward, this requires learning.
The intertwining of this learning process with the nudge of dopamine is key to addiction.
Addiction is a type of learning and dopamine lies at the heart of it!
We'll get into that below in the addiction section but the key is how do we "un-learn" addiction?
That requires neurogenesis, a fancy word for building new brain and new brain connections.
Again, we'll fully investigate this below.
The next big trick dopamine brings to the brain…
Lift up your arm. Yes, you!
The initiation of any physical or mental action is driven by dopamine.
You can see this effect when dopamine starts to drop with age (which it does) and Parkinson's.
A curious fact with Parkinson's is that there is a rigidity of motion but under a fight/flight situation, motion is similar to someone without Parkinson's.
It's not just lifting up your arm through.
Any change in thought or engagement in a mental direction requires dopamine.
That brings up our next piece.
Let's really get granular here.
The brain is very complicated and there are streams of stimuli coming in at any given second.
You're hopefully reading this sentence and taking in the meaning of the words.
In the background, there may be talking, music, heat, that cut on your finger, etc.
How on earth do you focus on this sentence with all this going on?
Dopamine guides this.
It's called salience or prominence but it basically means what is important at this given moment.
This obviously points to a range of mental health issues (ADHD, etc) and addiction (the drug becomes more and more "prominent" in your brain's awareness).
These three aspects of dopamine function give us a great framework to look at a range of mental health issues and addiction.
Let's quickly touch base on the other neurotransmitters since it's all a big, connected, chemical mess in the brain!
Amazing we can function at all!
Dopamine and other neurotransmitters
We've done huge reviews of glutamate, serotonin, and GABA for a reason.
They're all pieces of the puzzle to mental health.
Some are method actors (serotonin governs behavior) while others have roles across every pathway (glutamate, the "gas pedal" and GABA the "brake pedal").
Dopamine is more of a method actor like serotonin.
That being said, they're all intertwined and also with 100's of other chemicals, hormones, and enzymes.
This is why balance is so key to any of these pathways.
Let's tease out some key interactions tied with mental health and addiction.
We'll start with behavior. Serotonin.
If dopamine is the individual action and reward...a grain of sand...serotonin is the beach!
How do the two interact?
In this relationship, serotonin may be the master (which makes sense...behavior is made up of many actions).
Research is showing that serotonin may inhibit or reduce dopamine in certain pathways.
For example, low serotonin can lead to too much dopamine which results in impulsivity, aggression, and risky behavior.
Again, the goal is to balance as too much or too little of each is tied to mental health issues and pretty nasty side effects.
A rough sketch of examples:
- Too low - depression, anxiety, irritability, impulsivity
- Too high - agitation, serotonin syndrome, loss of pleasure
- Too low - lack of motivation, initiative and motion control
- Too high - impulsivity, aggressiveness, agitation
These two systems are highly interwoven right down to the neurons that produce them.
In some situations, they are opposite:
An influential hypothesis holds that 5-HT controls behavioral inhibition in an aversive context (Soubrié, 1986) such as punishment, monetary losses or omitted rewards, thus ascribing opposite functions to DA and 5-HT
While in others, they work together.
Vice versa, many studies have shown that 5-HT influences the processing of rewards (Kranz et al., 2010), suggesting rather complementary roles for both systems.
Balance is key. We'll look at the system that governs this.
Let's touch base on glutamate because it's becoming the new shining star in mental health.
Glutamate is our brain's "gas pedal" - the key excitatory neurotransmitter.
It's the workhorse of the brain and accounts for the majority of the action in the brain.
It's estimated the glutamate in your body weighs about 4 pounds!
Newer research is pointing to dopamine being a key manager of glutamate:
Although many of these interactions are reciprocal, our approach in this review will be to consider the glutamate system to function as the prime mover, while the DA system provides a strong modulatory influence on responses mediated by glutamate release or activation of glutamate receptors.
This makes sense since dopamine drives action - physical or mental (like driving a car) which requires the gas pedal (glutamate) to be engaged.
It can get very complicated as they are so intertwined!
Glutamate just drives brain activity so if applied in one area, it may have very different effects (even opposite) than other areas.
The research on glutamate and addiction or mental health is so compelling (see the NAC review) that we had to touch base on it.
Back to dopamine.
Let's get specific!
Dopamine and addiction
We have to start here.
Think of what lay at dopamine's feet above:
- Attention - Drug cue, craving
- Action - Drug use
- Reward - do that AGAIN!
We get that the reward circuit aspect of dopamine function would be so present with addiction but let's flip the question.
Why does a certain substance drive addiction while others don't?
No one's getting addicted to broccoli (not the reference for cannabis, mind you).
Your base level dopamine in the brain is probably around 50 ng/dl. A really bad day is around 40.
At your absolute best where everything is firing (remember those awesome days when everything went right!!!). That's about 100 ng/dl.
That's a range from about 40 to 100.
Your favorite food is around 94 ng/dl. Sex clocks in around 92.
There's a great explanation here:
Up to 1,100 ng/dl!
10 times our best day in the chemical that drives what we focus on, what action we'll take, and what we'll learn to do again.
Really watch that video...awesome overview of dopamine in an easy to understand format.
All addictive drugs will drive this dopamine rush:
- Benzos (see CBD versus benzos)
- Stimulants like cocaine, meth, etc
So...what does this do in the brain?
The brain panics...this is not within the range of what's allowable.
It immediately tries to counter this burst by suppressing dopamine function!
The brain will cause a drop in dopamine sensitivity (tonic levels) and actual numbers of receptors.
This is the process of tolerance...why drugs have less and less effective with long term use.
We're only focusing on dopamine but most people are drawn to different drugs for self-medicating other pathways:
- Alcohol - GABA and serotonin (See CBD and alcohol abuse)
- SSRI - serotonin - see CBD and serotonin
- Nicotine - choline, and glutamate (see nicotine)
- Cannabis - anandamide - (see CBD and cannabis addiction)
- Opioids - opioid system and even serotonin, glutamate
- Stimulants - glutamate, adrenaline, and acetylcholine
Dopamine is the real ringleader though in why a substance becomes addictive even if another pathway is why a person is initially drawn to a drug.
With long term use, major architectural changes occur in dopamine pathways along with the three levers we looked at above:
- Prominence - the drug becomes the sole focus for survival
- Action - Craving and desire to use plus the "ritual" of the use
- Repeat - Do that again. Do that again. Do that again.
Let's combine those effects with an extremely elevated juicing of the system from illegal drugs.
There are two phases.
First, as we mentioned, dopamine initiates learning.
Let's go back a few 100,000 years. Your hunters or gatherers find a nice source of food or water.
The brain rewards you with dopamine in order to remember where it was and how to get it again.
Dopamine shapes learning!!
Researchers can even use dopamine to cause rats to learn the wrong thing:
They measured dopamine levels in rats while they performed a decision-making task, and compared it with how motivated the rats were and how much they learned. They also increased dopamine levels to artificially motivate the rats and repeatedly made them learn to perform actions that did not produce rewards.
Drugs or any addictive activity does the same thing.
It literally remodels the brain the way a river carves out a river. Future water naturally flows to the lowest point and follows the river.
All the little streams that feed it are synaptic connections and dendrites (the little branches off our neurons).
This is the physical effect in the brain of learning. Entrenched neural connections that strengthen with use.
The spikes in dopamine from illicit drugs put this process in hyperdrive!
It may take a few years to learn a new language (same process - repetition) but meth can take days or weeks.
That's why early introduction to drugs can accelerate this addiction process since a teenager's brain is primed for learning.
Really check out the review of CBD and addiction to learn more about the tolerance side of it which speaks to why some people can casually have a drink and walk away while others are drawn to drinking to the point of destruction.
It all starts with self-medicating along missing pathways and there's a direct tie with the next section.
Dopamine and mental health
Too much or too little dopamine is tied to a range of different mental health issues.
It's close interaction with serotonin and glutamate make this guaranteed.
We'll drill down into the various mental health issues but understanding serotonin's upstream role is important.
Researchers have destroyed dopamine function to see the effects on serotonin:
Taken together, this research demonstrated that the destruction of dopaminergic system causes the reduction of the serotonergic system resulting in the expression of depressive behavior. The degree of dopaminergic dysfunction was positively correlated with the impairment of the serotonin system.
How do you have behavior without motivation, focus, and action?
Then there are the downstream metabolites of dopamine.
We're going to introduce two very important neurotransmitters:
- Norepinephrine - Your get up and go!!
- Epinephrine - Turn norepinephrine to 11 - Hello adrenaline! - fight or flight operator
First, norepinephrine...the worker bee of dopamine towards a goal.
In the brain, norepinephrine increases arousal and alertness, promotes vigilance, enhances the formation and retrieval of memory, and focuses attention; it also increases restlessness and anxiety.
So...the opposite of depression?
Epinephrine is self-explanatory as adrenaline. Either jump or get hit by the bus!
So...dopamine can be turned into norepinephrine and norepinephrine can turn into epinephrine if needed (tiger in bush situation).
Interestingly, medications that affect dopamine or it's up-river serotonin taskmaster make up a huge number of medications used for mental health:
- SSRIs - boost serotonin
- Antipsychotics - the bulk of them directly affect dopamine
- ADHD medications
The latter is interesting since they're essentially stimulants (amphetamine).
Remember how we said that dopamine drives focus!?!?
Stimulants push glutamate which boosts activity along whatever pathway it activates:
Their main conclusion is that low-dose (1 mg/kg) AMPH administration facilitates both electrical- and cue-evoked vesicular DA release and does not change DA-dependent behaviors in vivo, contrary to what one would expect if AMPH were depleting terminals as shown in vitro.
Essentially, low dose amphetamines boosted dopamine release when triggered.
Hence...the ability to focus!
The downside is that this will burn out glutamate receptors but that's for another review.
In the end, balance is key. Let's get into the research on specific issues.
Dopamine and anxiety
We've covered the mechanisms of anxiety in-depth at our CBD and mechanisms of anxiety here.
Serotonin has a definite effect and therefore, dopamine should be involved.
What does the research show?
There is evidence that dopamine plays an important role in anxiety modulation in different parts of the brain.
They go on to say:
Some evidence has shown that the mesolimbic, mesocortical, and nigrostriatal dopaminergic system is involved in anxiety. Both dopamine D1 and D2 receptor mechanisms are important in mediating anxiety
So our very old brain...the so-called "reptilian brain" where dopamine reigns.
Other researchers then found that mice who had reduced dopamine activity at one of the receptors (d3) directly affected anxiety:
Dopamine receptor D3 deficiency results in chronic depression and anxiety
Dopamine may be a knock-on effect from serotonin, glutamate, GABA, and other major players in anxiety but clearly there's a pathway for dopamine.
The more logical effect of decreased focus, motivation, and action would be….dopamine.
Dopamine and depression
Just look at what dopamine does in the brain in terms of behavior.
- It shapes what you want to focus on.
- It shapes what you want to act on.
It is literally the stuff of motivation!
Then you look at dopamine's downstream metabolite, norepinephrine.
Lust for life. Engagement. We'll end on the one description that directly counters depression.
What do the antidepressants on the market do?
All of these mechanisms result in enhanced neurotransmission of 5-HT and/or NE.
5-HT is serotonin and NE is norepinephrine.
After all, depression has been tied to anhedonia.
What does anhedonia mean?
Oh, just a lack of feeling of joy.
Research has pinpointed this directly to the dopamine pathway and as a result:
Prevention techniques that can restore homeostatic balance via physiological activation of dopaminergic receptors (D2/D3) may be instrumental for targeting not only anhedonia per se but also drug craving and relapse.
That's a mouthful but it's critical to CBD's effect later.
Homeostatic just means balanced. That's the role of the endocannabinoid system where CBD works. We'll look at that area later but let's jump to some of the most debilitating and brutal mental health diseases.
Dopamine and schizophrenia
Most of the anti-psychotic medications...both typical and atypical (as they're called) affect the dopamine pathway.
Here's the rub...they pretty much reduce dopamine in one direction across the brain regions.
That's helpful for only part of the problem.
See, the "positive" symptoms such as hallucinations, delusions, etc are driven by too much dopamine in one pathway (striatum).
The "negative" symptoms such as anhedonia, low affect, etc are driven by too little dopamine in another pathway (the cortex).
Great….so when we reduce dopamine with those drugs, we improve on the positive symptoms but we can make the negative ones worse or have no effect (best case).
Then there's the third pathway for body movements where we can literally cause Parkinsonism.
Remember how dopamine is needed for body movement and control.
The point is...dopamine function is all over schizophrenia in terms of how it manifests.
The true imbalance may be further up in the serotonin or glutamate pathways.
Check out CBD and schizophrenia for more detail.
The fact that CBD has such a profound effect on schizophrenia and psychosis is a critical clue to us regarding dopamine and we'll look at that below.
Read the review on CBD and schizophrenia...it's some of the most fascinating research out there for the seemingly intractable disease.
Let's look at a cousin of schizophrenia with shared risk.
Dopamine and bi-polar
The clues here are interesting on the mania side...a distinct aspect of bipolar that you don't find in other mental health diseases such as depression, anxiety, and schizophrenia.
Think about what too much dopamine might look or feel like?
Excessive Focus. Modification. Energy. Action.
Might be relevant?
What does the research show?
Converging findings from pharmacological and imaging studies support the hypothesis that a state of hyperdopaminergic, specifically elevations in D2/3 receptor availability and a hyperactive reward processing network, underlies mania.
On the flip side, studies are showing too much dopamine transporter activity during the depression side.
Transporters are chemicals in the brain that shuttle a given neurotransmitter out of action.
Interestingly, would an explosion in dopamine cause a knee-jerk reaction to clear it out? Or an exhaustion?
It's not beyond the brain to overshoot this way (check out CBD and tolerance).
Then there's the question of lithium.
How exactly does it work?
Turns out that rather than micromanaging pathways for these various neurotransmitters (dopamine, serotonin, and glutamate), lithium promotes brain growth!
Literally, it drives neurotropic which are agents that lead to growth in brain tissue and connections.
Check out CBD and BDNF to understand why this is so important across a range of issues.
It's the whole new world of neurogenesis.
After all, the reason SSRI's take a few weeks to work is because their real effect is via neurogenesis (see how do SSRI's work).
What about lithium? Is its effect immediate (neurotransmitters) or longer-term (neurogenesis)?
1-3 weeks...just like SSRIs.
So lithium is in the business of repairing and growing pathways.
Lithium has shown neuroprotective effects in a number of brain regions. This has been suggested by changes in grey matter volume.
"Changes in grey matter volume". This is either reducing damage or repairing/rebuilding from prior damage.
Remember that there are ties with early infection (even in utero), trauma, and chronic stress tied to risk for bipolar (and schizophrenia).
Let's jump to a disease tied to focus.
Dopamine and ADHD
We can look at genetic clues here.
There's a specific gene that's tied to ADHD and it's role:
Moreover, this genetic trait is due in part to a form of a gene (DRD2 A1 allele) that prevents the expression of the normal laying down of dopamine receptors in brain reward sites.
Research is pointing to hypo or too little dopamine with ADHD. This makes sense since dopamine is involved with "salience" or figuring out what's important to focus on.
Of course, don't discount the power of glutamate which we cover in our Glutamate and mental health review.
The current course of treatments, however, are amphetamines that boost dopamine function:
psychostimulants, like amphetamine and methylphenidate, that are used for the treatment of attention-deficit/hyperactivity disorder (ADHD) elevate DA tones.
"DA tone" means your baseline dopamine levels (not spikes after great food or sex).
The issue is tolerance or your body pushing back!
Let's take a quick stop to the endocannabinoid system before jumping into CBD.
Endocannabinoid system and dopamine balance
Every animal has one. It dates back about 600 million years ago.
This naturally occurring system is tasked with balancing other key systems during and after stress:
- Endocrine system - hormones such as cortisol that deal with stress response
- Immune system - including inflammatory agents in the brain and nervous system
- Nervous system - neurotransmitters such as serotonin, glutamate, and….dopamine!
The goal of this system is balance.
Outside stress (using the term generically for anything that pushes on these systems one way or the other) might cause a given pathway to boost or drop.
The endocannabinoid system is tasked with bringing it back to balance.
What about dopamine?
First, a little brain science (we won't go too deep).
There's a major hub of dopamine creation in the middle of the brain that then sends dopamine signaling out to different areas.
Remember how schizophrenia had too much going to the striatum but not enough going to the cortex?
Think of the endocannabinoid as a traffic cop for all this traffic:
The endocannabinoid (eCB) system serves as an important filter of afferent input that acts locally at midbrain and terminal regions to shape how incoming information is conveyed onto DA neurons and to output targets.
That gets pretty technical but basically, the endocannabinoid system monitors and adjusts dopamine pathways.
Traffic cop...waiving some through...stopping others. Balance.
Let's take one example of a very complex case...schizophrenia.
- There are associations between the main cannabinoid receptor (CB1) gene and schizophrenia.
- Excessive CB1 activity can result in psychosis (think of cannabis overdose) with similar symptoms
- CB1 receptors are found in higher amounts in a certain part of the brain tied to the disease
As researchers put it:
This endocannabinoid system is disturbed in schizophrenia.
This leads us to the final section and what a great segue.
CBD's interaction with dopamine
If the role of the endocannabinoid system is balance including dopamine function, how does CBD fit into this?
CBD is fascinating.
We'll use its cousin THC as a comparison.
THC boosts CB1 activity directly as if it were the naturally occurring anandamide.
Anandamide is our main endocannabinoid in the brain and it's named after the Hindu goddess of bliss, Anand.
You can think of anandamide as a stress response buffer.
The problem is that the brain doesn't like outside boosts to key systems long term and indeed, too much THC can lead to psychosis.
CBD doesn't push in one direction like CBD.
Technically, it's called a allosteric negative modulator.
Goodness, what does that mean?
It works like a feedback mechanism in the endocannabinoid system.
Where THC pushes one way from neuron A to neuron B, CBD sends a message back the other way.
- We're all fine here...stop sending
- We're running low, send more
This is why there can be different responses depending on the state of the system.
Let's look at dopamine specifically.
Finally...what is CBD's effect here?
Let's start with the trickiest disease...schizophrenia which shows both hypo and hyper dopamine function depending on the brain area.
The results are in:
However, evidence has demonstrated that CBD strongly modulates the mesolimbic dopamine (DA) system and may possess promising antipsychotic properties.
This is the exact opposite of THC.
There is a question on whether it is a direct effect on dopamine or from serotonin management above which is well established in CBD research.
Remember...the two are intimately linked.
Studies on CBD and serotonin are well-defined such as:
Seven days of treatment with CBD reduced mechanical allodynia, decreased anxiety-like behavior, and normalized 5-HT activity.
Essentially, a mouse model of pain, CBD was able to "normalize" serotonin function which was impaired due to the injury.
Ever wonder why your mood suffers when you're in pain?? or sick?? Now you know!
Reduced anxiety and pain were just knock-on effects.
Back to schizophrenia...the research on CBD there is very interesting.
The whole push-started off with a study and the effects were as follows:
Either treatment was safe and led to significant clinical improvement, but cannabidiol displayed a markedly superior side-effect profile.
They were comparing it to a leading anti-psychotic, Amisulpride.
How does Amisulpride work?
Amisulpride is believed to work by blocking, or antagonizing, the dopamine D2 receptor, reducing its signaling.
CBD was as effective but without the nasty side effect profile.
Here's where it gets interesting.
One study found that CBD would block dopamine function in the striatum where too much dopamine can lead to positive symptoms (hallucinations, delirium, etc).
It was found that cannabidiol inhibited the binding of radio-domperidone with dissociation constants of 11 nm at dopamine D2High receptors and 2800 nm at dopamine D2Low receptors, in the same biphasic manner as a dopamine partial agonist antipsychotic drug such as aripiprazole.
But what about the cortex where the disease reflects too little dopamine?
We don't want to drop it there.
Remember, the symptoms of low dopamine in the cortex are loss of joy, feeling, and emotional effect.
- The so-called negative symptoms.
- These are also present with depression.
Does CBD appear to cause any of these issues which would reflect a drop in dopamine?
Quite the opposite.
In fact, read the CBD and depression review to see how this is one of the key mental health issues pointing to CBD.
We can look to its effect on upstream serotonin specifically:
Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex
Let's break that down because it's too cool.
BDNF is our brain's fertilizer and lies at the heart of how antidepressants work (see CBD and BDNF) till tolerance kicks in.
Synaptogenesis is the important part...building of new connections in the brain!
Where in the brain? The prefrontal cortex!
Serotonin governs dopamine so we have our answer.
More importantly, reduced dopamine in another pathway leads to parkinsonism.
Remember that dopamine controls movement.
Do we see any impact from CBD on this dopamine pathway?
Here is a full review on CBD and Parkinson's but the effects are all positive.
One trial found the following...
First, treatment with 300mg of CBD:
the groups treated with placebo and CBD 300 mg/day had significantly different mean total scores in the PDQ-39 (p = 0.05).
Parkinson's is a disease primarily of reduced dopamine function in that third pathway.
That's why the most common course of treatment is Dopa, a form of dopamine given directly.
More importantly, the symptoms of reduced dopamine do not show in the CBD safety profile even for the long term, chronic use.
Very fascinating...how can it decrease dopamine in one pathway (striatum) but not in others?
Again, CBD bolsters the endocannabinoid system which is tasked with balancing neurotransmitters.
As we have shown in our CBD and serotonin review, the response can be different depending on the state of the system!
Finally, we have to ask what does it mean to have reduced dopamine function?
Now we're talking structure. Tracts of white brain matter and even number of neurons specific to dopamine function.
Dopamine is really produced in a specialized area of the brain and then sent out along the pathways we mentioned above (plus a 4th one to the hypothalamus for hormone interaction).
Researchers looked at dopamine neurons specifically under assault from a known brain toxin, cadmium.
Cannabidiol Protects Dopaminergic Neuronal Cells from Cadmium
As for how much CBD, the studies on more serious issues were at 600-800 mg doses per day but research is pointing to a different level.
The studies on neurogenesis (building new brain connections - see CBD and brain repair) point to 300 mg as the dose for maximum effects.
This is key to the white matter tracts that connect brain areas as well as the individual neurons (some of which are dopamine) and their connections (synaptogenesis).
We look forward to furthering research on CBD and dopamine specifically since it's the very reason you made it to the end of this long, windy review.
Make sure to check out or dopamine rescue review.
Always work with a doctor or naturopath with any supplement!
The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.
Always work with a doctor or naturopath with any supplement!
The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.