Research on CBD and the Pathways of Paranoia
We wrapped up an in-depth review of CBD and schizophrenia recently.
One of the most frustrating elements of that disease can be paranoia.
As complicated as paranoia is in terms of behavior, research is starting to really understand the underpinnings of it in the brain.
Even the neurotransmitters at work are coming to light.
The question then is...can we impact those in any meaningful way?
More importantly, there's new research on CBD and these pathways which is fascinating.
We'll dive into all of it.
These are the topics we'll cover:
- What is happening in the brain with paranoia
- Genes tied to paranoia
- Clues from triggers for paranoia
- The dopamine connection with paranoia
- Amphetamines, THC, and cocaine and paranoia
- Early trauma and paranoia
- Stress and paranoia
- CBD and paranoia
- How much CBD for paranoia
- What's the best CBD for paranoia
Let's get started.
What is happening in the brain with paranoia
There's a great deal of interesting research on this topic.
We'll focus on two critical areas:
- Hyperactive amygdala - our fear and threat detection area
- Excessive dopamine especially in the striatum
We've covered the amygdala in-depth at our CBD and anxiety mechanics review.
Anxiety is closely linked issue with paranoia and in fact, social anxiety is generally considered at the lowest end of the paranoia spectrum.
A hyper awareness of how others view you.
The amygdala is our fear and threat detection brain area and it's too strong or getting push back from the prefrontal cortex (our rational brain), anxiety or paranoia can result.
Just look at this descriptions:
Accumulating evidence of the amygdala’s role in associative learning and the rapid processing of positive, negative, and even unusual stimuli suggest that the amygdala acts as a “scout,” detecting information that is relevant, interesting, or salient to the organism.
Brain scans are finding differing activity levels there with paranoia:
Overall, these results suggest that paranoia is related to higher resting neuronal activity in the amygdala, as well as in broader sensory and frontal regions.
We say different because there are some studies that show reduced response to fearful faces, etc.
The "resting state" is the important piece. It's a brain area running too hot...looking for a threat whether it's there or not.
The other brain areas they mention deal primarily with the cortex, our "thinking" brain which is supposed to take these signals from the amygdala and determine if they're real or not.
The amygdala can definitely by trauma, pyschosocials stress, and early abuse.
We'll touch on those below in the clues to paranoia below.
Next up, the striatum and dopamine.
The dopamine connection with paranoia
This is more a focus on dopamine itself than the brain area but don't discount the striatum.
First, excessive activity in this area for dopamine is a main driver behind the "positive" symptoms of psychosis including delusions and paranoia.
Take a look at what happens in the striatum:
Functionally, the striatum coordinates multiple aspects of cognition, including both motor and action planning, decision-making, motivation, reinforcement, and reward perception
"Reinforcement" ….a key component of paranoia where initial beliefs slowly become dogma.
Then there's dopamine. This may be the most important takeaway from this article.
Dopamine is our primary "reward circuit" neurotransmitters.
Reward doesn't have to be something good for us!
Dopamine and the reward circuit is the basis for addiction after all (see CBD and addiction).
People think of dopamine as a measure of pleasure, but really it's more akin to "do that again".
There's lots of interesting research on what happens when we have too much dopamine with paranoia.
Just a taste:
High levels of free dopamine in the brain generally enhance mood and increase body movement (i.e., motor activity), but too much dopamine may produce nervousness, irritability, aggressiveness, and paranoia that approximates schizophrenia, as well as the hallucinations and bizarre thoughts of schizophrenia.
Drop mic now?
Excessive dopamine a key driver of paranoia.
Another study pinpointed dopamine as the main processor of "dread" as well as pleasure.
They blocked it from reaching certain brain areas and put mice in a place where they should have been scared out of their minds. Nothing.
This suggests that too much dopamine in the rear of the nucleus accumbens (linked to dread) may at least be partly responsible for the paranoia that many schizophrenia patients experience, study co-author Kent Berridge says.
Dopamine is fascinating. So much so that we did a major review of it in our CBD and dopamine pathways article.
Outside the reward circuit, dopamine drives salience.
Salience is simply the ordering of what's important to make a decision based on.
This is highly intertwined with paranoia as "salience" is all askew.
That look from a colleague may be indigestion but it's taken as a slight or insult.
Now combine this misappropriation of importance with a negative bent (the amygdala).
Negative affect and aberrant salience appear to drive and exacerbate paranoia, rather than being merely the sequelae of the symptom.
They found that the negative coloring (amygdala) and the off salience (dopamine) drove paranoia. They were not simply a result of the condition.
The brain is simply a prediction machine. It's trying to reduce surprise in the future since surprise was usually a tiger jumping out of the bush.
Life and death.
Part of this is to anticipate threats (amygdala) and decide if they're important or not (dopamine).
Let's see if this basic understanding matches clues we have with paranoia.
Clues from triggers for paranoia
There are some basic triggers for paranoia that are well-established.
- Genes - we'll touch on that next section
- Certain drugs - THC, amphetamines, cocaine
- Trauma - especially early in life and or PTSD later
- Stress - war prisoners, etc who experience long term stress
- Illness - schizophrenia, dementia, and certain specific illnesses
Okay, let's walk through some of these.
First, the drugs.
Amphetamines, THC, and cocaine and paranoia
Amphetamines and cocaine are interesting in that they both drive up activity in the brain including...wait for it….dopamine!
Amphetamines inhibit dopamine reuptake by interacting with the dopamine transporter (DAT), thereby increasing the concentration of dopamine in the synaptic cleft
Cocaine has numerous effects on many important neurotransmitters in the brain; however, the most dramatic effect is on the increase as well as the release of dopamine.
What about THC from cannabis?
The endocannabinoid system (where THC operates) helps to balance all neurotransmitters.
Pumping up THC offsets this level if too high:
THC and cannabinoid agonists enhance striatal and mesocorticolimbic dopamine levels
Check out CBD versus THC since CBD has opposing effects on this pathway to THC.
In fact, many people look at CBD for greening out (too much THC).
Interestingly, THC is more of a depressant (see THC used to calm glutamate) while cocaine and amphetamines are stimulants.
Yet...they all disrupt dopamine function.
That's a big clue!
What about Trauma?
Early trauma, PTSD, and paranoia
Hello amygdala, our fear and threat processor.
Post-traumatic stress disorder (PTSD) has been associated with excessive amygdala and a lack of MPFC activity in response to nonconscious facial signals of fear, but responses to consciously processed facial fear stimuli have not been examined.
Okay, so exposure to trauma can "prime" the amygdala to be over-reactive.
Remember our hyperactive threat detection theory above?
The brain doesn't like surprises so if something came along that almost killed us early on, it's not going to let that happen again.
Then, there's early life trauma (ELT):
This cohort exhibited increased amygdala functional connectivity with the prefrontal cortex and decreased functional connectivity with the parahippocampal gyrus when compared to those without I‐ELT.
This means that the "fear center" is more wired into our thinking process (the prefrontal cortex) and has less connection with the hippocampus, a key mood regulator and seat of memory.
There are ways to unwind this which we'll look at below (including CBD).
What's fascinating is that stress can exacerbate these connections.
What about stress and paranoia?
Stress and paranoia
Just look at how this all comes together:
The striatum is functionally connected to the threat detection system (Haber, 2014). Animal research has demonstrated that acute stressors including aversive stimuli induce a pronounced activation of the dopamine system
There's the striatum (where dopamine is prominent). Stress drives dopamine activation.
Lots of research is pointing to this result:
In humans, childhood sexual abuse is associated with elevated urinary dopamine metabolites in childhood
Then, there's the connection with the drugs that drive paranoia:
Stress-induced elevations in cortisol levels have been directly correlated with amphetamine-induced dopamine release
Finally, CBD and illness
Schizophrenia or psychosis show heavy connections with the dopamine excess for positive issues like paranoia and delusions.
Check out CBD and schizophrenia for a full review.
Interestingly, the "positive" symptoms of schizophrenia like delusions and paranoia are driven by too much dopamine in the striatum. Remember, it's tied directly to the threat detection system.
The "negative symptoms" like depression, low response, etc are driven by too little dopamine in the cortex (our higher thinking area).
This is a perfect segue into paranoia from dementia.
Dementia and paranoia
We discussed the amygdala, our fear and threat detector area of the brain which can too active after trauma or stress.
This is a very old part of our brain, evolutionarily speaking. The "reptilian" brain.
Our newest addition, the cortex, is in charge of keeping our "animal" instincts at bay.
This is our thinking brain and it's under direct assault with dementia:
neuroimaging studies indicate that delusional thoughts may be associated with dysfunction in frontal and temporal cortex in patients with AD
This area is literally losing brain mass and connectivity.
It's like the hen is leaving the henhouse and fears, threats, etc can run amok.
Let's turn our attention to genes.
Genes tied to paranoia
A study looked at people with delusional paranoia disorder versus healthy controls and even people with schizophrenia for a particular gene that drives dopamine function.
Their results were interesting:
The genotype frequency of the DRD2 gene Ser311Cys was significantly higher in patients with persecution-type delusional disorder (21%), compared with schizophrenic patients (6%) or controls (6%).
That's over a 3 times difference for one gene that affects dopamine function.
Interestingly, this particular gene was different from schizophrenia.
Another gene was tied directly to paranoia for Prader William disease here:
This gene variant is more specific.
Paranoia is a complicated result of many interactions (as is most behavior) so it would likely result from many genes that perhaps, make a person vulnerable to environmental effects (trauma, stress, etc).
Finally, CBD. How does it affect these pathways above and more importantly, is there any research on CBD and paranoia directly?
Let's go there.
CBD and paranoia
First, we'll look at CBD and the pathways above:
CBD and dopamine function
Since excess dopamine is a main driver of paranoia, let's start there.
We did a full review of CBD and dopamine since it's so tied into addiction (see CBD and addiction).
In fact, a big reason for a substance's ability to be addictive is directly tied to how it boosts dopamine.
Dopamine drives what the brain focuses on. Too much dopamine drives hyper focus or hypervigilance.
You combine this with an overactive fear center (amygdala) and you see why this might be an issue.
What does CBD do here?
We can look at clues from two different areas:
CBD has shown powerful effects on addiction. Let's focus on the drug focus part since that speaks to salience which we discussed above (hyper focus).
One result (of many) with nicotine:
A single 800‐mg oral dose of cannabidiol reduced the salience and pleasantness of cigarette cues, compared with placebo, after overnight cigarette abstinence in dependent smokers.
There's that word...salience.
Remember, the "focus" or fixation (a better word here) on cigarettes is driven by an established pathway where the currency is dopamine.
Again, check out CBD and addiction to learn all about this.
Psychosis is another issue marked by too much dopamine to the striatum.
Paranoia, delusions, and hallucinations are directly attributed to this effect in this brain area.
The effects of CBD on psychosis are pretty fascinating.
We did a full review of CBD and schizophrenia or psychosis to go through the research.
One double-blind, placebo study results:
Positive psychotic symptoms (measured using the PANSS positive subscale) were significantly reduced from baseline to end of treatment in the CBD group compared with the placebo group
How is CBD having this effect on the so-called positive symptoms?
Interestingly, the effect may be further upstream to the master regulator...serotonin.
CBD's greatest trick may be to act as a feedback mechanism on serotonin.
Why does this matter for dopamine?
Considering the functional regulation of serotonin over the dopamine system, deficient serotonergic function may result in hyperactivity of the dopamine system, promoting impulsive behavior.
Too much dopamine is also tied to aggression, impulsive behavior, compulsive behavior.
All of these fit in framework of paranoia. A repetitive and antagonistic framework.
CBD's effect on serotonin balance is pronounced.
Just look at one example from our CBD and serotonin pathway reviews:
Overall, repeated treatment with low-dose CBD induces analgesia predominantly through TRPV1 activation, reduces anxiety through 5-HT1A receptor activation, and rescues impaired 5-HT neurotransmission under neuropathic pain conditions.
Let's break that down because it's fascinating.
They essentially gave a significant injury to animals. Serotonin manages our pain sensitivity so it was quickly exhausted from the injury.
CBD reduced the pain (analgesia), reduced anxiety (see CBD and anxiety), and "rescued" 5-HT (short for serotonin) function.
The "rescue" part is critical. We don't want too much serotonin as that's a whole host of other serious issues (see CBD and serotonin syndrome).
We have lots of studies at our CBD and serotonin review but the key is that serotonin directly interacts with dopamine and low serotonin leads to high dopamine.
Let's turn our attention to fear.
CBD and amygdala fear and threat detection
Deep in the amygdala, they just found a switch that flips in mice for aggression towards a male rival.
We have no doubt, they'll find specific circuitry tied to paranoia (a defensive stance of a different sort).
Let's turn our attention to CBD and anxiety since the amygdala is so tied in there.
Too much amygdala activity actually.
If you think about it, there's a close connection with paranoia and anxiety...especially social anxiety where we have a hyperfocus on how others are viewing (and judging) us.
We have a full review on CBD and social anxiety.
In a study of panic attacks, brain scans look at this area:
CBD decreased the activity of the left amygdala-hippocampal complex
It gets more interesting though.
They looked at CBD's effect on this brain area when looking at fearful faces specifically.
CBD blunted the amygdala's threat detection response to psycho-social stimuli.
Speaking of social anxiety, there's a fascinating result on CBD and public speaking.
The full review is here but a quick take away which we'll explain after:
The SSPS-N scores evidenced significant increases during the testing of placebo group that was almost abolished in the CBD group.
The key there is the SSPS-N. It's short for Negative Self Statement Test.
This means...how did the speaker view themselves in terms of negativity.
Did they feel like they were being judged or performing poorly.
CBD "abolished" this effect with people who had a known social anxiety diagnosis.
Let's continue on so we can get to CBD and paranoia directly.
CBD and stress response
One of the key drivers of paranoia was stress response.
Remember that our stress response system drives up dopamine.
Stress is a natural response to danger and dopamine gets converted to adrenaline. You can see why dopamine might spike in times of stress!
Let's introduce one of our primary endocannabinoids.
Anandamide. It's named after the Hindu goddess of bliss, Anand.
Anandamide does many things but you can think of it as our primary stress response buffer.
It generally acts like a wet blanket to calm activity in the brain and nervous system.
The endocannabinoid system in general is a primary system to balance other key systems including:
- Immune system - inflammatory response
- Endocrine system - hormones including stress hormones
- Nervous system - neurotransmitters like serotonin and dopamine!
Balance is its key role.
How does CBD (which is also a cannabinoid) affect this "bliss" molecule?
It supports it level when running low!
In fact, a study on paranoid schizophrenics pinpointed CBD's effects on anandamide as being the driver (a large number of the participants were paranoid schizophrenics):
Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia
Interestingly, it went head to head against a powerful antipsychotic (amulsipride) and had equal results without the side effects profile.
Amulsipride directly reduces dopamine which affects positive symptoms like paranoia and delusions.
CBD did not directly affect dopamine in that study but had a significant effect on anandamide.
To bring it all back around, anandamide is our primary stress response buffer and we use the word stress to mean any swing up or down in key pathways such as dopamine.
Balance is its goal!
Let's turn to THC paranoia.
CBD and THC paranoia
It's a known side effect of too much THC from cannabis. Paranoia.
It's part of "greening out" or essentially overdosing on cannabis.
A study looked at intravenous THC administration and reviewed the results:
THC significantly increased paranoia, negative affect (anxiety, worry, depression, negative thoughts about the self), and a range of anomalous experiences, and reduced working memory capacity.
So...there's a term that used in the cannabis world. The entourage effect.
These days, it's used to sell full spectrum CBD (more on that below) but it's origin is completely different.
The godfather of CBD discovered that CBD would offset the negative psychological impacts of THC.
THAT's the entourage effect.
some individuals cannabis use leads to undesirable effects: cognitive impairment, anxiety, paranoia, and increased risks of developing chronic psychosis or drug addiction. Studies examining the protective effects of CBD have shown that CBD can counteract the negative effects of THC.
A big review of medical cannabis looked at the ratio of CBD to THC directly:
Avoidance of higher THC formulas should occur in youth and in those with paranoid personalities;
Check out CBD versus THC.
Let's turn our attention to PTSD and trauma.
CBD and PTSD trauma with paranoia
First, we have research now on CBD and PTSD directly.
For example, one review:
From the total sample of 11 patients, 91% (n = 10) experienced a decrease in PTSD symptom severity, as evidenced by a lower PCL-5 score at 8 weeks than at their initial baseline.
Remember the study on fearful faces? This is about how our brain perceives outside social stimuli...it incorporates many brain pathways.
Studies looked at CBD and fear extinction...essentially the ability to forget negative emotional perceptions.
This is important for paranoia where negative beliefs generally grow and reinforce with time.
CBD given post-extinction enhanced consolidation of extinction learning as assessed by shock expectancy.
This is especially important for PTSD where past trauma has been engrained in the brain. The opposite of forgetting...especially the emotional coloring of that event.
Let's jump to the final piece...what really matters.
CBD and paranoia research
First, we have the studies on high CBD and THC. When CBD is higher in cannabis, there's a direct effect on reduced paranoia:
In agreement, post-THC paranoia, as rated with the State Social Paranoia Scale (SSPS), was less in the CBD group compared with the placebo group (t=2.28, p<0.05).
Another larger study found similar results:
A larger between-group study (n = 48) showed that relative to placebo, pretreatment with 600 mg oral CBD reduced the paranoia and impairments in episodic memory elicited by 1.5 mg intravenous THC.
A small study looked at two children age 16 and 9:
Upon treatment with CBD and cessation of the antidepressant medication, the patient improved regarding depressive as well as anxiety symptoms including simple phobias and symptoms of paranoia and dissociation.
Most of the studies are on CBD and paranoia as a result of psychosis or THC use.
We look forward to studies on paranoia disorder or the behavior itself.
One note...these studies point to long term, sustained use of CBD at higher doses.
This isn't surprising considering research we've seen on neurogenesis, or the process of brain repair and remodeling.
Let's go there now.
How much CBD for paranoia
Interestingly, there's a study that used one dose and looked at CBD's effect on persecutory ideation which fits in line with paranoia.
It didn't have much effect and the dose was really high.
Other research looks at the long term effects of CBD (6-8 weeks plus) and shows very different results.
This is likely due to neurogenesis, the same basis basis behind exercise, mindful meditation, medications (lithium, SSRIs, etc) and even CBT (cognitive behaviorial therapy).
The process of building new pathways and even forgetting old ones.
Studies show that this effect of CBD peaks at 300 mg daily. After that, it starts to go down.
The big studies on psychosis were generally at 600-800 mg.
Our bet is on neurogenesis as it's going to the next big thing in mental health (till CRSPR catches up) for a decade.
One side note, Vitamin C at higher doses is shown to be a major regulator for dopamine and other neurotransmitters as well as a direct reducer of cortisol, our primary stress hormone.
Who knew Vitamin C has so many tricks!
NAC (N acetyl cysteine) is also gaining some recognition for psychosis including the "negative" symptoms which speak to the cortex, an area that is not fully functioning with paranoia.
Remember, its role is to interpret and make sense of incoming signals from our threat detection area (amygdala). This is clearly off with paranoia.
Check out review on NAC here.
As for CBD, peak levels at 300mg reflects what we see in the research. The studies above were generally around 400 mg so that fall in line.
But what type of CBD?
What's the best CBD for paranoia
First, we have the basic requirements:
- Organically grown industrial hemp in the USA at an FDA registered farm
- 3rd party tested
- CO2 processed
- No THC (zero!!!)
- No heavy metals
- No solvents
- No pesticides
- No bacteria
- No mold
We test ours twice since our whole family uses it.
That's just the start.
Then there's the whole question of CBD isolate versus full spectrum.
The dozens of NIH studies we reference on this site including those above are based on CBD isolate.
Full spectrum can have lots of other plant materials and even a small amount of THC.
There's no real research on this but more importantly, many people have histamine issues.
40-60% of the population has histamine issues and this number goes up as we get older and for women.
All that plant material in full spectrum is going the wrong direction.
Check out CBD isolate versus full spectrum for anxiety since there's an element of social anxiety that dovetails with paranoia.
FInally, there's cost.
This is a big one and lots of brands out there are just plain ripping people off.
The key is cost per mg of CBD. We price our 6000 mg bottles at about 2-3 cents per mg BEFORE discounts up to 30%.
This makes us the lowest priced CBD isolate we can find and for a reason.
If you read our founder's story here, we've been there. Various medications that doctors put me sent me into a psychotic break (SSRI plus nausea ER drug caused serotonin syndrome).
It's the worst day of my life and if we can reduce suffering by reducing cost...so be it.
Be well and take care of each other. Take care of yourself first though.
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.