This post will explain the mechanisms why some people get psychotic symptoms from pot/marijuana. THC has been one of my favorite substances for food sensitivities and sleep quality, however, 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.

Problems That May Come From THC

There are a number of anecdotal reports that cannabis can produce a range of acute psychotic symptoms that include depersonalization, derealization, paranoia, anxiety, a flight of ideas, disorganized thinking, persecutory delusions, grandiose delusions, auditory and visual hallucinations, and impairments in attention and memory [1].

Studies show that in healthy volunteers, THC (from cannabis) can induce psychosis [2]. However, some people experience more negative effects than others and in some cases result in long-lasting changes.

There is growing research linking cannabis use and schizophrenia-like psychotic disorders. Epidemiological evidence consistently shows that the use of cannabis during the teenage years increases the risk of psychotic disorders by 2-fold. However, no one knows for sure if cannabis causes schizophrenia. It’s possible that people who are predisposed to schizophrenia are more likely to consume cannabis.

Whether it causes schizophrenia or not, it’s clear that some people experience psychotic effects (such as paranoia). Other people get anxiety. In some cases, I’ve seen people who had lasting effects from consuming pot.

One study with 6,700 people found that if you had marijuana-induced psychosis, there’s a 47% chance that you will end up getting bipolar or schizophrenia. Out of the people who ended up getting these conditions, half got schizophrenia within 3 years or bipolar within 4.5 years. Young age after a substance-induced psychosis was associated with a higher risk of converting to schizophrenia. Self-harm after a substance-induced psychosis was associated with a higher risk of both schizophrenia and bipolar disorder [3].

Cannabis-Induced Psychosis and Neurotransmitters


THC increases dopamine in the striatum, which is a biological feature of schizophrenia and psychosis [1]. 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 [1].

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 [4]. This might be due to the neurotoxic effects of chronically elevated dopamine [5].


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 [1].

In other words, GABA puts the breaks on ‘crazy’ thoughts, and when CB1 receptors are activated, GABA is reduced in some key places [1].

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 [1].

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

Genes and Cannabis-Induced Psychosis

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 [6].

The DRD2 receptors are blocked by antipsychotic drugs, which helps decrease psychosis [7].

Relatively excessive dopamine D2 activation may lead to reduced ‘gating’ functions. This means that people have reduced filtering of relevant information (reduced signal to noise ratio), as well as blocking out distractions [89].

These brain processes contribute to different higher-order cognitive functions and are strongly involved in the control of attention [10, 11].

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 [11]. This region is influenced by D2 receptors [12, 13].

The “A” allele of rs1076560 in the Dopamine DRD2 gene is associated with Cannabis-induced psychosis [14].

It’s associated with a 10X higher risk of developing psychosis in daily cannabis users [14].

This SNP has also been associated with behavior and brain activity during cognitive and emotion processing in healthy humans and in patients with schizophrenia [15, 16, 17].

rs1076560 is associated with neuronal connectivity in the amygdala, dorsolateral prefrontal cortex and striatal regions [1819], and differences in EEG results [20].

Brain activity in the left basal ganglia and thalamus was also found to be associated with rs1076560 [21].

These differences in brain function have been found to correlate with alterations in working memory, reaction time and impairments in negative decision making [22232425].

The A allele increased DRD2 function by making the DRD2 protein longer (decreases the ratio of D2S and D2L) [26].

The D2 long form (D2L) is mainly postsynaptic and is a target for antipsychotics [27]. Mice without D2L receptors have reduced D2 activity [28]. The D2 short (D2S) form is mainly a presynaptic autoreceptor that inhibits dopamine synthesis and release [27].

The A allele has been associated with less efficient prefrontal-striatal activity during working memory [17] and with greater levels of striatal dopamine [29].

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 [30].

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 [31, 283233].

AKT1 levels in the prefrontal cortex of patients with schizophrenia are indeed reduced [34, 35] and antipsychotics help by increasing AKT1 and reducing GSK-3β [36].

(Technical: AKT1 (and antipsychotics) phosphorylates GSK-3β at the Ser-9 residue, and inhibits its activity [37, 38]. Chronic anti-psychotics and lithium cause inhibitory phosphorylation of GSK-3β in the rat prefrontal cortex and striatum [39, 40, 41, 42, 43].)

COMT (Dopamine-Related Gene)

The COMT gene plays an important role in the breakdown of dopamine in the 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 [44].

Another study reported that COMT genotypes only influenced the 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.

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 [45].

Some scientists suggest that abnormal CB1 function may hamper maturation of the neuronal networks during adolescence, which might underline the later development of psychosis [46].

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 [47, 48].

The CB1 Receptor SNP rs12720071 (the “C” allele) is associated with lower white matter volumes (frontal and temporal) [49] and an increased schizophrenia risk with marijuana misuse [49].

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 [50, 51]. 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 [52, 51].

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 [53].

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