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This post will explain the mechanisms why some people get psychosis symptoms from pot/marijuana. THC has been one of my favorite substances for food sensitivities and sleep quality, I know a lot of my clients don’t do well on THC so I wrote this post to explain the reasons why they get these negative reactions and some things they can do to mitigate them. You can also find many other substances I have tried to get rid of my food sensitivities and improve my sleep if you think THC is not for you in my ebooks, SelfHacked Secrets and Biohacking Insomnia.


There are a number of anecdotal reports that cannabis can produce a range of acute psychotic symptoms that include depersonalization, derealization, paranoia, flight of ideas, disorganized thinking, persecutory delusions, grandiose delusions, auditory and visual hallucinations, and impairments in attention and memory in an otherwise clear consciousness (R).

Studies show that in healthy volunteers, THC (from cannabis) can induce psychosis (R).  However, some people experience more negative effects than others and in some cases result in long-lasting changes.

In recent years, there has been research linking cannabis use and schizophrenia-like psychotic disorders, and epidemiological evidence consistently suggest that the use of cannabis during adolescence increases the risk for psychotic disorders by 2-fold.  However, no one knows for sure if cannabis causes schizophrenia.

Whether it causes schizophrenia or not, some people experience more negative psychotic effects (such as paranoia) and this post will address why this might be the case.

Cannabis Induced Psychosis and Neurotransmitters



THC increases dopamine in the striatum, which is a biological feature of schizophrenia and psychosis (R).  Dopamine in the striatum is good in that it increases motivation and probably happiness, but if someone already has high dopamine in the striatum, cannabis can bring them over the edge.

CB1 receptor activation also increases dopamine in the Prefrontal Cortex, which might lead to non-specific activation and disrupt normal signal processing and result in poor cognitive integration of inputs. Too high levels of dopamine may contribute to working memory deficits associated with cannabis exposure (R).

Structural and functional imaging studies have shown that chronic cannabis causes the same negative changes in brain structure as schizophrenia, such as volume reduction in the hippocampus and the amygdala (R).  This might be due to the neurotoxic effects of chronically elevated dopamine (R).


Activation of the CB1 receptor reduces GABA release in hippocampal neurons.  This disrupts the synchronization of neuronal activity, which interferes with memory consolidation and brain’s ability to make normal associations, eventually leading to psychotic symptoms (R).

In other words, GABA puts the breaks on ‘crazy’ thoughts, and when CB1 receptors are activated, GABA is reduced in some key places(R).

Schizophrenics, likewise, have less GABA.


Cognitive gating functions in the brain prevent illogical or crazy thoughts from entering the conscious brain.

Several studies show that cannabinoids reduce glutamate (and NMDA activation) in several brain regions involved in the regulation of gating functions, such as the hippocampus, the prefrontal cortex, the nucleus accumbens, and the amygdala (R).

Ketamine, an NMDA blocker, also causes psychosis, demonstrating the role of lower glutamate in certain regions and psychosis.

Genes and Cannabis-Induced Psychosis

You can upload your genetic data to SelfDecode to see if you have these genes.

DRD2 (Dopamine Gene)

A large series of experimental data indicate that dopamine D2 receptors and schizophrenia are tightly related.

There is an association between psychosis and relatively greater D2 receptors in the striatum, a dopamine-rich area of the brain (R).

The DRD2 receptors are blocked of antipsychotic drugs and is their most important mechanism of action (R).

Relatively excessive dopamine D2 activation may lead to reduced ‘gating’ functions: reduced filtering of relevant information (reduced signal to noise ratio), as well as blocking out distractions (RR).

These brain processes contribute to different higher-order cognitive functions and are strongly involved in control of attention (R, R).

Patients with schizophrenia performing attentional tasks have less activity and lower grey matter in the cingulate, a brain region that heavily influences attentional processing and executive function (R). This region is influenced by D2 receptors (R, R).

The “A” allele of rs1076560 in the Dopamine DRD2 gene is associated with Cannabis-induced psychosis (R).

It’s associated with a 10X higher risk of developing psychosis in daily cannabis users (R).

This SNP has also been associated with behavior and brain activity during cognitive and emotion processing in healthy humans and in patients with schizophrenia (R, R, R).

rs1076560 is associated with neuronal connectivity in the amygdala, dorsolateral prefrontal cortex and striatal regions (RR), and differences in EEG results (R).

Brain activity in the left basal ganglia and thalamus was also found to be associated with rs1076560 (R).

These differences in brain function have been found to correlate with alterations in working memory, reaction time and impairments in negative decision making (RRRR).

The A allele increased DRD2 function by making the DRD2 protein longer (decreases the ratio of D2S and D2L) (R)

The D2 long form (D2L) is mainly postsynaptic and is a target for antipsychotics (R).  Mice without D2L receptors have reduced D2 activity (R). The D2 short (D2S) form is mainly a presynaptic autoreceptor that inhibits dopamine synthesis and release (R).

The A allele has been associated with less efficient prefrontal-striatal activity during working memory (R) and with greater levels of striatal dopamine (R).

In healthy subjects, the interaction between the A allele of DRD2 rs1076560 and the A allele of AKT1 rs1130233 was associated with reduced AKT1 protein levels and increased GSK-3β, as well as with altered cingulate response and impaired cognitive function during attentional processing (R).

GSK3b is a protein that increases oxidative stress, inflammation and harms proper neuronal function, so inhibiting it is important.

D2 stimulation by dopamine inhibits AKT1, which increases GSK3b, which can cause psychosis (R, RRR).

AKT1 levels in the prefrontal cortex of patients with schizophrenia are indeed reduced (R, R) and antipsychotics help by increasing AKT1 and reducing GSK-3β (R).

(Technical: AKT1 (and antipsychotics) phosphorylates GSK-3β at the Ser-9 residue, and inhibits its activity (R, R). Chronic anti-psychotics and lithium cause inhibitory phosphorylation of GSK-3β in the rat prefrontal cortex and striatum (R, R, R, R, R).)

COMT (Dopamine-Related Gene)

The COMT gene plays an important role in the degradation of dopamine in brain.

The “GG” variant of rs4680 is associated with increased COMT activity, which results in a combination of reduced dopamine in the prefrontal cortex and increased levels of dopamine in mesolimbic areas.

Individuals with “GG” display psychotic symptoms after use of cannabis during adolescence (R).

Another study reported that COMT genotypes only influenced development of psychotic disorders among individuals exposed to childhood abuse, indicating that environmental exposure and genetic factors may interact in a more complex way than expected (R) .

CB1 Receptor (Cannabinoid Gene)

Cannabinoid receptor type 1 (CB1) is the most well-characterized cannabinoid receptor.  It seems that changes in this receptor can increase the risk of schizophrenia.

The cannabinoid system plays an important role in brain maturation during adolescence, which is a critical period for maturation of many neurotransmitters, including dopamine (R).

Some scientists suggest that abnormal CB1 function may hamper maturation of the neuronal networks during adolescence, which might underline the later development of psychosis (R).

In schizophrenia, it’s interesting that some studies have reported an increase in cannabinoid receptor (CB1) function in the dorsolateral prefrontal cortex and cingulate, which are associated with volume loss in these areas (R, R).

The CB1 Receptor SNP rs12720071 (the “C” allele) is associated with lower white matter volumes (frontal and temporal) (R) and an increased schizophrenia risk with marijuana misuse (R).

Counteracting The Psychotic Effects of Cannabis

It seems like inhibiting GSK3b is the best bet to counteracting cannabis-induced psychosis.

People with schizophrenia have less alpha 7 nicotinic receptors in their hippocampus, cortex and thalamus (R, R). In animal models, impaired auditory sensory gating has been linked to the alpha7 nicotinic receptor gene, and in turn, introducing alpha7 nicotinic agonists has been found to enhance auditory sensory gating (R, R).

One SNP (rs6494223) of this gene was associated with delusions in Alzheimer’s disease.

Alpha 7 nicotinic activators, such as nicotine and galantamine, may help counteract the working memory issues people face with schizophrenia (R).


Find out if any of these gene variations could be affecting your mental and physical health with SelfDecodeYour genes have a lot to tell you. Now you can finally start listening.

Health Tools I Wish I Had When I Was Sick

At SelfHacked, it’s our goal to offer our readers all the tools possible to get optimally healthy. When I was struggling with chronic health issues I felt stuck because I didn’t have any tools to help me get better. I had to spend literally thousands of hours trying to read through studies on pubmed to figure out how the body worked and how to fix it.

That’s why I decided to create tools that will help others cut down the guesswork:

  • Lab Test Analyzer – a software tool that will analyze your labs and tell you what the optimal values are for each marker — as well as provide you with actionable tips and personalized health and lifestyle recommendations to help you get there.
  • SelfDecode – a software tool that will help you analyze your genetic data from companies such as 23andme and ancestry. You will learn how your health is being impacted by your genes, and how to use this knowledge to your advantage.
  • SelfHacked Secrets – an ebook where we examine and explain the biggest overlooked environmental factors that cause disease. This ebook is a great place to start your journey if you want to learn the essential steps to optimizing your health.
  • SelfHacked Elimination Diet course – a video course that will help you figure out which diet works best for you
  • Selfhacked Inflammation course – a video course on inflammation and how to bring it down
  • Biohacking insomnia – an ebook on how to get great sleep
  • Lectin Avoidance Cookbook – an e-cookbook for people with food sensitivities
  • BrainGauge – a device that detects subtle brain changes and allows you to test what’s working for you
  • SelfHacked VIP – an area where you can ask me (Joe) questions about health topics

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  • Viktor Tikka

    I would belive most of the paranoia is from THC blocking GABA

  • Nattha Wannissorn, PhD

    You can ask Joe inside of VIP: or over a consult at

  • Viktor

    Eduardo, have you tried ayahuasca? How many times? And it didn’t help with this marijuana side-effects?

  • Eduardo

    It happens to me everytime I smoke marijuana: listen to voices very clearly in my head, talking to me, sometimes laughing. I used to believe they were spirits. That never ever happens to me unless I smoke marijuana. Visual hallucinations also happen. Even other drugs considered “stronger” (like ayahuasca) don’t give me such crazy effects, only marijuana… so I stay away from it.

  • Rob

    What about Cannibis induced Derealization/Depersonalization (DP/DR)? Any theories about why that occurs and persists? Is it related to similar neurotransmitter disruptions?

  • Doug

    Is all of this mainly applicable to high THC strains? I use high CBD strains that have little or no psychoactive effect, but I’m not clear to what extent these strains have the potential to affect cognition or mood or brain function. I don’t notice much subjectively.

  • dsaulw

    Would these effects not depend, at least in part, upon using an imbalanced cannabis extract, i.e. one with high THC and low CBD? My understanding is that CBD is protective against potential harm from THC.

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