<p>Research into the "how" is ongoing. From the most <a href="https://www.ncbi.nlm.nih.gov/pubmed/26970363" rel="nofollow noreferrer">recent review</a> I could find, the effect of cannabis on the dopamine system is not entirely elucidated, even on a quantitative level:</p>

<blockquote>
  <p>The onset of effects of THC appears to be delayed relative to the onset
  of other psychotomimetic drugs, suggesting that the effects of THC may be downstream to its
  primary site of action. Given that the endocannabinoid system is principally a neuromodulatory
  system, perhaps the psychosis-relevant effects of THC are related to the consequences of CB1R
  activation on other neurotransmitter systems implicated in the neurobiology of psychosis.
  Cannabinoid Dopaminergic Interactions: Single doses of dopamine (D2) receptor antagonists
  (olanzapine and haloperidol) have been shown to reverse the acute psychotomimetic effects of
  THC in healthy subjects in two HLS (5, 6) although not in the third (7). Furthermore, chronic D2
  antagonist treatment failed to protect schizophrenia patients from the symptom exacerbating
  effects of THC (32).</p>
  
  <p>Preclinical studies demonstrate that THC administration increases striatal dopamine
  release by 25-100%, but the human data are mixed with two studies reporting no significant
  increase (91, 92) and one study reporting a 3.9% increase in striatal dopamine release (93).
  These studies had small sample sizes and differed in the THC doses, routes of administration
  and imaging methodology. A re-analysis combining data from two studies (91, 93) reported a
  significant but small increase in THC-induced dopamine release (94). Of note, in contrast to
  amphetamine and cocaine, which induce large increases in striatal DA release (10-30%) in
  humans, THC at doses that produce robust behavioral effects induces small (2-5%) increases in
  dopamine release. More recently, Kuepper et al, 2013 reported that individuals with psychosis as
  well as those with a family history of psychosis demonstrated THC-induced striatal dopamine
  release, but this was not observed in the controls suggesting that dopamine may be involved
  particularly in the effects of THC in those with an increased risk for psychosis (95).</p>
</blockquote>

<p>The review also covers several genes that have been implicated in both schizophrenia and vulnerability to THC-induced psychosis:</p>

<blockquote>
  <p>In the striatum, clearance of synaptic dopamine is highly dependent on the dopamine
  transporter (DAT). A polymorphism of the DAT1 gene is associated with lower enzymatic activity
  and thus, higher dopamine levels in the striatum, and has previously been associated with
  schizophrenia (81). Bhattacharyya et al. reported that individuals with the 9-repeat allele showed
  increased sensitivity to acute THC-induced psychotic symptoms (82).</p>
  
  <p>The enzyme AKT1 inactivates glycogen synthase kinase by phosphorylation and their
  interaction has been implicated in schizophrenia (83, 84). Cannabinoids stimulate the AKT1
  pathway via CB1Rs and CB2Rs. Bhattacharyya et al found that a polymorphism of the AKT1
  gene (the GG genotype of the SNP rs1130233) moderated sensitivity to the acute psychosisinducing
  effect of THC (82). Furthermore, a synergistic influence of DAT1 and AKT1 genotypes
  on THC-induced psychotomimetic effects was also reported. </p>
</blockquote>

<p>All the DAT/AKT1 data on healthy individual using cannabis with is based on <a href="https://www.nature.com/mp/journal/v17/n12/full/mp2011187a.html" rel="nofollow noreferrer">exactly one study</a>, so I reproduce their graphical finding below:</p>

<p><a href="https://i.sstatic.net/M6O4X.png" rel="nofollow noreferrer"><img src="https://i.sstatic.net/M6O4X.png" alt="enter image description here"></a></p>

<p>Alas they only reported total <a href="https://en.wikipedia.org/wiki/Positive_and_Negative_Syndrome_Scale" rel="nofollow noreferrer">PANSS</a>.</p>

<p>In the review, there's more discussion of COMT, which has seen more attention, but suffice to say the results on that have been mixed. It remains to be seen in  the DAT1/AKT1 study can be replicated. It does seem that AKT1 alone has an impact, based on more studies that found the same polymorphism of AKT1 impacts <a href="https://www.ncbi.nlm.nih.gov/pubmed/228319800" rel="nofollow noreferrer">first-episode psychosis in cannabis users</a> and <a href="http://www.nature.com/tp/journal/v6/n2/full/tp2015219a.html" rel="nofollow noreferrer">psychotomimetic effects in healty cannabis smokers</a>.</p>

<p>I find it interesting that yet another study on first-episode psychosis has implicated AKT1 polymorphism, however, this time with an interaction that enhanced its effect... except that the other gene involved was not DAT1 (as in the case of psychotomimetic effects on healthy individuals) <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849451/" rel="nofollow noreferrer">but rather with DRD2</a>.</p>

<p>Perhaps 10 years from now, this question will have a less tentative answer.</p>

<p>To further complicate the issue, cannabis has more than one active substance:</p>

<blockquote>
  <p>CBD is the second most prominent
  cannabinoid in cannabis. Unlike THC, CBD displays CB1R antagonism/inverse agonism
  amongst several other modulatory effects on the endocannabinoid system. The potential
  antipsychotic effects of CBD have drawn increasing attention (20) and some HLS have
  examined the interactive effects of THC and CBD. Pretreatment with CBD is associated with
  lower THC-induced psychotomimetic effects, paranoia and verbal memory impairments (12, 21).
  Furthermore, while THC resulted in increased psychotic symptoms and skin conductance
  responses during processing of fearful faces; CBD, led to a reduction in anxiety and a decrease
  in skin conductance response (22). </p>
</blockquote>

<p>For more, there's a slightly older review that's <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4033190/" rel="nofollow noreferrer">freely available in PMC</a>.</p>

<p><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123717/" rel="nofollow noreferrer">Yet another review</a> that focuses only on THC's effect on dopamine mentions some of the challenges in observing dopamine changes in humans following THC administration: insufficient PET camera resolution and doses that are substantially less than those used in animal models.</p>

CC BY-SA 3.0
2017-11-08T21:17:04.793Z
2017-11-09T10:53:46.610Z
2017-11-09T10:53:46.610Z
got trolled too much this week
<p>Cannabis induced psychosis is very prevalent. Statistically Cannabis use doubles the risk of developing psychosis in vulnerable people. There even exists a relationship regarding the dose used and the age of first use. Gene-environment interactions that modulate the association between cannabis use and the presence of psychosis have also been described. <sup><a href="https://pubmed.ncbi.nlm.nih.gov/30442059/" rel="nofollow noreferrer">1</a></sup> and Cannabis is involved in approximately 50% of psychosis, schizophrenia, and schizophreniform psychosis cases.<sup><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927252/" rel="nofollow noreferrer">2</a></sup></p>
<p>Here are more sources on NCBI and Nature indicating that heavy cannabis use can induce psychosis. <sup><a href="https://www.nature.com/articles/s41398-022-02112-8" rel="nofollow noreferrer">3</a></sup> <sup><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927252/" rel="nofollow noreferrer">4</a></sup></p>
<p>From my perspective, the reason why cannabis can cause psychosis is because THC binds to CB1/2 receptors in the brain and directly affects dopamine transmission in the mesolimbic area<sup><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405830/" rel="nofollow noreferrer">5</a></sup>. THC also causes dopamine from the VTA to be released in to the NAcc, your reward centre of the brain. <sup><a href="https://www.jneurosci.org/content/24/18/4393" rel="nofollow noreferrer">6</a></sup></p>
<p>Chronic artificially elevated levels of dopamine in the mesolimbic area obviously also affect the activity of D2 receptors in the mesolimbic area where a hyperactivity is part of the condition of schizophrenia patients.</p>
<p>To understand why, you would want to take a look at the <strong>D</strong>opamine <strong>H</strong>ypothesis which postulates that psychotic symptoms are caused by a D2 hyperactivity in the mesolimbic area and a hypoactivity in the prefrontal cortex<sup><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032934/" rel="nofollow noreferrer">7</a></sup>.</p>
<p>Heavy use of THC probably causes constantly elevated dopamine levels in the NAcc.</p>
<p>I can say from experience that heavy use of Cannabis can cause psychosis after ~3-6 months and D2 blockers completely negate the psychotic effects, suggesting that elevated dopamine levels in the NAcc/mesolimbic area might lead to sufficient D2 hyperactivity to cause positive symptoms of psychosis as postulated by the DH.</p>

CC BY-SA 4.0
2023-12-19T21:52:58.077Z
I am positive that cannabis causes psychosis in young people, have seen it more than once, in some cases permanent. But isn't the dopamine hypothesis being put into question now?
user1721135
CC BY-SA 4.0
2023-12-19T22:02:05.390Z
AFAIK it's still what's being practiced. At least that's what my psychiatrist told me. I can also confirm from personal experience that D2 blockers completely negate the psychotic state THC induces LT at heavy use. Which suggests that in some cases a D2 hyperactivity is indeed the cause for psychotic symptoms, natural or drug induced, it's present in most patients with schizophrenia so it plays a role at least. I will read up on any news.
Moritz Roessler
CC BY-SA 4.0
2023-12-13T11:32:51.533Z
2023-12-19T20:05:49.770Z
2023-12-19T20:05:49.770Z
Moritz Roessler
<p>Whenever I research cannabis induced psychosis, I mostly get two types of results:</p>

<p>1) Cannabis causes psychosis directly and a bunch of other issues (mostly misleading propaganda)</p>

<p>2) There is no evidence that cannabis actually causes psychosis directly, rather it seems to be a correlation issue. (also misleading propaganda)</p>

<p>However, my two best friends experienced permanent psychosis immediately after a heavy cannabis use episode (on separate occasions).</p>

<p>I am convinced that cannabis is perfectly capable of causing or "unlocking" psychosis. I don't think that there is any question to this.</p>

<p>But how does it actually work?</p>

<p>In one of the cases, my friend had some very strong cannabis to smoke, after which he started to hear voices, and this never ended, even months after stopping smoking. Only after anti psychotic medication (Seroquel) did the symptoms stop, and they seem to be permanent, stopping the medication causes the symptoms to come back.</p>

<p>From what I understand, Seroquel suppresses dopamine, while cannabis has nothing to do with dopamine.</p>

<p>So how does cannabis induce a dopamine related disorder?</p>

CC BY-SA 3.0
2017-11-08T20:12:19.443Z
The controversy is not whether it can trigger transient psychosis in some individuals, but whether it can trigger the onset of schizophrenia. http://bjp.rcpsych.org/content/184/2/110
got trolled too much this week
CC BY-SA 3.0
2017-11-13T15:42:20.037Z
The question is how did they use it? If they smoked it - then it looks like an unlucky case of "to catch the pale".
Thick smoke blocks the lungs from oxygen for several minutes. Then active components increase the adrenaline level, 
which in turn causes more and more need for oxygen. Google for  "Hypercapnia". This causes strong death fear and as a result - anxiety, paranoia, etc. Probably this can cause long-term trauma also.
So I doubt this can be reproduced in an experiment with more 'civilized' usage through vaporizing or swallowing.
Mikhail V
CC BY-SA 3.0
2017-11-14T17:32:27.883Z
Hypercapnia is CO2 retention right? It seems to me this shouldn't be an issue, when you smoke you do exhale after all. Maybe you mean hypoxia? Yes the ROA was smoking, but I am not sure how this would cause psychosis. For example I am a diver and read a lot about hypoxia and have never heard about anyone with psychosis because of a diving accident.
user1721135
<psychosis>
How does Cannabis cause psychosis?
user1721135
# How does Cannabis cause psychosis?

(Asked by: username_0 on 2017-11-08)

Whenever I research cannabis induced psychosis, I mostly get two types of results:

1) Cannabis causes psychosis directly and a bunch of other issues (mostly misleading propaganda)

2) There is no evidence that cannabis actually causes psychosis directly, rather it seems to be a correlation issue. (also misleading propaganda)

However, my two best friends experienced permanent psychosis immediately after a heavy cannabis use episode (on separate occasions).

I am convinced that cannabis is perfectly capable of causing or "unlocking" psychosis. I don't think that there is any question to this.

But how does it actually work?

In one of the cases, my friend had some very strong cannabis to smoke, after which he started to hear voices, and this never ended, even months after stopping smoking. Only after anti psychotic medication (Seroquel) did the symptoms stop, and they seem to be permanent, stopping the medication causes the symptoms to come back.

From what I understand, Seroquel suppresses dopamine, while cannabis has nothing to do with dopamine.

So how does cannabis induce a dopamine related disorder?

**Tags:** psychosis

> **Comments:**
> **username_1**: The controversy is not whether it can trigger transient psychosis in some individuals, but whether it can trigger the onset of schizophrenia. http://bjp.rcpsych.org/content/184/2/110  
> **username_2**: The question is how did they use it? If they smoked it - then it looks like an unlucky case of "to catch the pale". Thick smoke blocks the lungs from oxygen for several minutes. Then active components increase the adrenaline level,  which in turn causes more and more need for oxygen. Google for  "Hypercapnia". This causes strong death fear and as a result - anxiety, paranoia, etc. Probably this can cause long-term trauma also. So I doubt this can be reproduced in an experiment with more 'civilized' usage through vaporizing or swallowing.  
> **username_0**: Hypercapnia is CO2 retention right? It seems to me this shouldn't be an issue, when you smoke you do exhale after all. Maybe you mean hypoxia? Yes the ROA was smoking, but I am not sure how this would cause psychosis. For example I am a diver and read a lot about hypoxia and have never heard about anyone with psychosis because of a diving accident.  

---

## 2 answers

### Answer by username_1 on 2017-11-08. Score: 2

Research into the "how" is ongoing. From the most [recent review](https://www.ncbi.nlm.nih.gov/pubmed/26970363) I could find, the effect of cannabis on the dopamine system is not entirely elucidated, even on a quantitative level:

> The onset of effects of THC appears to be delayed relative to the onset
> of other psychotomimetic drugs, suggesting that the effects of THC may be downstream to its
> primary site of action. Given that the endocannabinoid system is principally a neuromodulatory
> system, perhaps the psychosis-relevant effects of THC are related to the consequences of CB1R
> activation on other neurotransmitter systems implicated in the neurobiology of psychosis.
> Cannabinoid Dopaminergic Interactions: Single doses of dopamine (D2) receptor antagonists
> (olanzapine and haloperidol) have been shown to reverse the acute psychotomimetic effects of
> THC in healthy subjects in two HLS (5, 6) although not in the third (7). Furthermore, chronic D2
> antagonist treatment failed to protect schizophrenia patients from the symptom exacerbating
> effects of THC (32).
>
> Preclinical studies demonstrate that THC administration increases striatal dopamine
> release by 25-100%, but the human data are mixed with two studies reporting no significant
> increase (91, 92) and one study reporting a 3.9% increase in striatal dopamine release (93).
> These studies had small sample sizes and differed in the THC doses, routes of administration
> and imaging methodology. A re-analysis combining data from two studies (91, 93) reported a
> significant but small increase in THC-induced dopamine release (94). Of note, in contrast to
> amphetamine and cocaine, which induce large increases in striatal DA release (10-30%) in
> humans, THC at doses that produce robust behavioral effects induces small (2-5%) increases in
> dopamine release. More recently, Kuepper et al, 2013 reported that individuals with psychosis as
> well as those with a family history of psychosis demonstrated THC-induced striatal dopamine
> release, but this was not observed in the controls suggesting that dopamine may be involved
> particularly in the effects of THC in those with an increased risk for psychosis (95).

The review also covers several genes that have been implicated in both schizophrenia and vulnerability to THC-induced psychosis:

> In the striatum, clearance of synaptic dopamine is highly dependent on the dopamine
> transporter (DAT). A polymorphism of the DAT1 gene is associated with lower enzymatic activity
> and thus, higher dopamine levels in the striatum, and has previously been associated with
> schizophrenia (81). Bhattacharyya et al. reported that individuals with the 9-repeat allele showed
> increased sensitivity to acute THC-induced psychotic symptoms (82).
>
> The enzyme AKT1 inactivates glycogen synthase kinase by phosphorylation and their
> interaction has been implicated in schizophrenia (83, 84). Cannabinoids stimulate the AKT1
> pathway via CB1Rs and CB2Rs. Bhattacharyya et al found that a polymorphism of the AKT1
> gene (the GG genotype of the SNP rs1130233) moderated sensitivity to the acute psychosisinducing
> effect of THC (82). Furthermore, a synergistic influence of DAT1 and AKT1 genotypes
> on THC-induced psychotomimetic effects was also reported.

All the DAT/AKT1 data on healthy individual using cannabis with is based on [exactly one study](https://www.nature.com/mp/journal/v17/n12/full/mp2011187a.html), so I reproduce their graphical finding below:

[![enter image description here](https://i.sstatic.net/M6O4X.png)](https://i.sstatic.net/M6O4X.png)

Alas they only reported total [PANSS](https://en.wikipedia.org/wiki/Positive_and_Negative_Syndrome_Scale).

In the review, there's more discussion of COMT, which has seen more attention, but suffice to say the results on that have been mixed. It remains to be seen in the DAT1/AKT1 study can be replicated. It does seem that AKT1 alone has an impact, based on more studies that found the same polymorphism of AKT1 impacts [first-episode psychosis in cannabis users](https://www.ncbi.nlm.nih.gov/pubmed/228319800) and [psychotomimetic effects in healty cannabis smokers](http://www.nature.com/tp/journal/v6/n2/full/tp2015219a.html).

I find it interesting that yet another study on first-episode psychosis has implicated AKT1 polymorphism, however, this time with an interaction that enhanced its effect... except that the other gene involved was not DAT1 (as in the case of psychotomimetic effects on healthy individuals) [but rather with DRD2](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849451/).

Perhaps 10 years from now, this question will have a less tentative answer.

To further complicate the issue, cannabis has more than one active substance:

> CBD is the second most prominent
> cannabinoid in cannabis. Unlike THC, CBD displays CB1R antagonism/inverse agonism
> amongst several other modulatory effects on the endocannabinoid system. The potential
> antipsychotic effects of CBD have drawn increasing attention (20) and some HLS have
> examined the interactive effects of THC and CBD. Pretreatment with CBD is associated with
> lower THC-induced psychotomimetic effects, paranoia and verbal memory impairments (12, 21).
> Furthermore, while THC resulted in increased psychotic symptoms and skin conductance
> responses during processing of fearful faces; CBD, led to a reduction in anxiety and a decrease
> in skin conductance response (22).

For more, there's a slightly older review that's [freely available in PMC](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4033190/).

[Yet another review](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123717/) that focuses only on THC's effect on dopamine mentions some of the challenges in observing dopamine changes in humans following THC administration: insufficient PET camera resolution and doses that are substantially less than those used in animal models.


---

### Answer by username_3 on 2023-12-13. Score: 1

Cannabis induced psychosis is very prevalent. Statistically Cannabis use doubles the risk of developing psychosis in vulnerable people. There even exists a relationship regarding the dose used and the age of first use. Gene-environment interactions that modulate the association between cannabis use and the presence of psychosis have also been described. [1](https://pubmed.ncbi.nlm.nih.gov/30442059/) and Cannabis is involved in approximately 50% of psychosis, schizophrenia, and schizophreniform psychosis cases.[2](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927252/)

Here are more sources on NCBI and Nature indicating that heavy cannabis use can induce psychosis. [3](https://www.nature.com/articles/s41398-022-02112-8) [4](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927252/)

From my perspective, the reason why cannabis can cause psychosis is because THC binds to CB1/2 receptors in the brain and directly affects dopamine transmission in the mesolimbic area[5](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405830/). THC also causes dopamine from the VTA to be released in to the NAcc, your reward centre of the brain. [6](https://www.jneurosci.org/content/24/18/4393)

Chronic artificially elevated levels of dopamine in the mesolimbic area obviously also affect the activity of D2 receptors in the mesolimbic area where a hyperactivity is part of the condition of schizophrenia patients.

To understand why, you would want to take a look at the **D**opamine **H**ypothesis which postulates that psychotic symptoms are caused by a D2 hyperactivity in the mesolimbic area and a hypoactivity in the prefrontal cortex[7](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032934/).

Heavy use of THC probably causes constantly elevated dopamine levels in the NAcc.

I can say from experience that heavy use of Cannabis can cause psychosis after ~3-6 months and D2 blockers completely negate the psychotic effects, suggesting that elevated dopamine levels in the NAcc/mesolimbic area might lead to sufficient D2 hyperactivity to cause positive symptoms of psychosis as postulated by the DH.

> **Comments:**
> **username_0**: I am positive that cannabis causes psychosis in young people, have seen it more than once, in some cases permanent. But isn't the dopamine hypothesis being put into question now?  
> **username_3**: AFAIK it's still what's being practiced. At least that's what my psychiatrist told me. I can also confirm from personal experience that D2 blockers completely negate the psychotic state THC induces LT at heavy use. Which suggests that in some cases a D2 hyperactivity is indeed the cause for psychotic symptoms, natural or drug induced, it's present in most patients with schizophrenia so it plays a role at least. I will read up on any news.  

---

