zxvxv,

1. Cannabis
and
psychosis
Presenter:
Dikendra sanjyal
Resident
Department of psychiatry

2. Cannabis and Psychosis
Central Concern
The relationship between recreational cannabis use and psychosis, especially the
development of primary psychotic disorders (PPD) such as schizophrenia, has been
widely debated.
Cannabis may induce psychotic symptoms, worsen existing psychosis, or even
precipitate a first episode psychosis (FEP) in vulnerable individuals.
Cannabis may cause: Short-lived, mild psychotic experiences after intoxication Or
more severe, persistent psychotic episodes like *Cannabis-Induced Psychotic Disorder
(CIPD)

3. Definitions and Diagnostic Clarity
Transient Psychotic Symptoms
Occur during acute intoxication.
Symptoms resolve within 24 hours.
Insight is usually preserved (the person knows the symptoms are unusual).
Do not constitute a full psychotic episode.

4. Cannabis-Induced Psychotic Disorder (CIPD)
A diagnosable psychiatric condition.
Develops when psychotic symptoms persist beyond the intoxication period, typically:
Lasting days to weeks post-use.
No prior prodromal symptoms are expected.
Diagnosed according to DSM-5 if:
The episode lasts ≤4 weeks after last cannabis use.
Primary psychotic disorder (PPD) is excluded.
Often difficult to distinguish from First-Episode Psychosis (FEP) or PPD with comorbid Cannabis
Use Disorder (CUD).

5. Epidemiological Association
Consistent evidence from community and clinical samples shows an
association between schizophrenia and dependent cannabis use.
Longitudinal studies support a dose-response relationship:
Higher frequency and earlier age of cannabis use → increased risk of developing psychotic
disorders.
These findings hold even after adjusting for confounding variables (e.g., other substance
use, pre-existing vulnerability).

6. Causal Hypothesis and Alternatives
The idea that cannabis is a contributory cause of schizophrenia is more
plausible than:
◦ (a) The self-medication hypothesis (i.e., individuals use cannabis to manage symptoms).
◦ (b) Cannabis is simply a marker for other risks (e.g., stimulant use, genetic vulnerability).
Epidemiological studies across multiple countries (e.g., Sweden, France,
Germany, Netherlands, New Zealand) support this causal role, especially in
vulnerable populations.

7. Explaining the Association: Hypotheses
1.Common Vulnerability Hypothesis
Shared risk factors (genetic, neurodevelopmental, psychosocial) predispose
individuals to both cannabis use and psychosis.
Cannabis is a behavioral expression of underlying vulnerability.
2. Self-Medication Hypothesis
Patients use cannabis to cope with prodromal or active symptoms, such as:
◦ Anxiety
◦ Dysphoria
◦ Negative symptoms

8. 3.Cannabis as an Environmental Trigger (Most Plausible)
Cannabis use (especially early and heavy use) acts as a late environmental
risk factor.
In individuals with genetic vulnerability, it may:
◦ Trigger FEP
◦ Accelerate onset
◦ Contribute to pathogenesis

9. Tetrahydrocannabinol (THC) and Psychosis: Neurobiological
Insights
THC as the Active Compound
Δ9-Tetrahydrocannabinol (THC) is the primary psychoactive constituent of
cannabis.
Its discovery led to the identification of G-protein-coupled cannabinoid
receptors—primarily CB1 receptors in the brain.
THC binds specifically and saturably to CB1, indicating the existence of an
endogenous cannabinoid system.

10. Pharmacokinetics and Brain Effects
THC is lipophilic: it accumulates in lipid membranes, slowly releasing and
producing long-lasting effects.
It interacts with CB1 receptors, especially in brain areas rich in spare receptors
(e.g., prefrontal cortex).
Leads to:
◦ Positive psychotic symptoms
◦ Neurocognitive impairments
◦ Reduced synaptic density and efficiency, particularly in the prefrontal cortex (PFC)

11. Neurodevelopmental and Addictive Properties
oTHC exposure during prenatal development can disrupt interneuron
positioning during corticogenesis.
oIt can induce withdrawal and tolerance, and potentiate alcohol and opioid
dependence.

12. Cannabis and Transition to Psychosis
Epidemiological Context
Cannabis is implicated in ~50% of psychosis cases, including schizophrenia and
schizophreniform disorder.
Cannabis use is notably high in First-Episode Psychosis (FEP) and Ultra-High
Risk (UHR) populations.
Among FEP individuals, cannabis use does not differentially predict
schizophrenia development, implying non-specific impact on vulnerability.

13. FEP patients and individuals with schizophrenia use cannabis more frequently
than the general population.
Cannabis users have a 1.4 to 4x increased risk of developing schizophrenia.
Early and intense use → Higher risk
Cannabis use typically precedes psychotic symptom onset.

14. Neurobiological Parallels
oNeurobiological changes from cannabis use mirror those seen in schizophrenia
(e.g., dopaminergic alterations, synaptic deficits), but:
These similarities are insufficient to establish causality.
Many individuals with these brain changes do not develop psychosis.
Unresolved Mechanisms
 The sequence of biological events leading from cannabis exposure to psychosis is still
uncertain.
 Multiple factors—genetic, environmental, developmental—likely modulate the
transition to psychosis.

15. Modulating Factors
Cannabidiol (CBD), another cannabinoid, may have antipsychotic properties,
potentially offsetting THC's propsychotic effects.
Cannabis preparations differ in THC:CBD ratios, influencing psychosis risk.
A dose-response relationship is evident: higher THC content and frequency of
use increase psychosis risk.

16. Neurobiology of Cannabis and Psychosis
1. Prenatal Exposure and Early Brain Development
Prevalence: 2–5% in Europe; ~13% in high-risk groups; 75% of pregnant substance users in the
U.S. use cannabis.
Placental Transfer: ~1/3 of THC crosses the placenta, potentially impairing fetal growth and
neurotransmitter system maturation.
Neurodevelopmental Effects:
◦ Midgestation growth retardation.
◦ Long-term impact on serotonergic and dopaminergic systems.
◦ Infant outcomes: tremors, heightened startle, poor habituation.
◦ Persistent effects on mesocorticolimbic circuitry into adulthood.

17. 2. Adolescent Cannabis Use
Critical Phase: Brain undergoes major changes (myelination, synaptic pruning,
dendritic plasticity).
THC during adolescence:
◦ Disrupts endocannabinoid-mediated developmental processes (cell migration, proliferation).
◦ Associated with greater risk of psychosis when used before age 15.
◦ Impairs DLPFC-dependent cognition (e.g., working memory, executive function).
Enduring Changes:
◦ Early cannabis exposure → lasting neurofunctional alterations, despite compensatory
mechanisms.
◦ Increased CB1 receptor expression during adolescence may heighten sensitivity.

18. 3. Endocannabinoid System (ECS)
Core Components: CB1 and CB2 receptors, endocannabinoids, synthetic/degradative
enzymes.
CB1 Receptors:
◦ Highly expressed in GABAergic neurons, localized at presynaptic terminals.
◦ Involved in retrograde signaling: modulate synaptic transmission and plasticity.
◦ Affect memory, pain, motivation, cognition.
Functional Role:
◦ Present during gestation—critical for neural differentiation and migration.
◦ THC impairs memory via CB1 modulation, particularly affecting GABAergic neurons.
◦ Plays a neuroprotective and antioxidant role, yet chronic exposure alters homeostasis.

19. 4. Neurochemistry
oNeurotransmission: ECS regulates inhibitory and excitatory synapses.
oUnique signaling: Endocannabinoids are synthesized on demand (not stored in
vesicles).
oBDNF & Neuregulin:
◦ THC reduces BDNF, critical for neuroplasticity.
◦ Possible link between cannabis, neurotrophic factors, and schizophrenia susceptibility.

20. 5. Dopaminergic System
THC increases dopamine release in:
◦ Striatal and prefrontal areas (implicated in psychosis).
◦ Enhances mesocorticolimbic activity, possibly disrupting emotional and cognitive processing.
THC-induced psychotic-like states in healthy volunteers mimic schizophrenic
symptoms.

21. 6. Genetic Vulnerability
Cannabis use disorder (CUD) is highly heritable, though genes are still being identified.
Involves chromosomes 1, 3, 4, 6, 7, 9, 14, 17, 18.
Gene × cannabis interactions:
◦ COMT Val158Met polymorphism modulates risk:
◦ Met allele + cannabis use → earlier onset of psychosis.
◦ Cannabis may suppress protective delay effects in genetically vulnerable individuals.
7.Genetic Complexity
While genetic risk plays a role, GWAS studies suggest schizophrenia involves many genes of
small effect.
Majority of patients:
81% have no first-degree relative with schizophrenia.
63% lack affected first- or second-degree relatives, highlighting complex, polygenic
inheritance.

22. 7. Neuroimaging Findings

Acute effects:
 Increased cerebral blood flow, particularly in frontal cortex, anterior cingulate, amygdala.

Long-term exposure:
 ↓ resting blood flow, possibly linked to amotivational syndrome.
 Mixed evidence for structural changes—some studies show:
o ↓ grey matter in memory/emotion regions (frontal cortex, amygdala).
o Ventricular enlargement, reduced prefrontal volume in those at risk.

Functional imaging:
 ↓ activity in anterior cingulate and amygdala in cannabis users during affective tasks.
 Suggests altered emotional regulation and impulsivity control.

High-risk individuals with cannabis/alcohol misuse show greater structural abnormalities, suggesting interaction
with genetic risk (e.g., schizophrenia family history).

23. Dopamine and Neuromelanin-MRI
The dopamine hypothesis suggests striatal hyperdopaminergia underlies positive
symptoms of schizophrenia.
Neuromelanin, a dopamine breakdown product, accumulates in SN/VTA and can be
measured using neuromelanin-sensitive MRI (nmMRI) as a proxy for long-term
dopamine function.
Elevated nmMRI signal in SN/VTA has been observed in:
Schizophrenia patients.
Individuals with cocaine use disorder.
Neuromelanin signal correlates with:
Dopamine synthesis and release capacity in striatum.
Severity of psychotic symptoms.

25. 8.Neurocognition and Cannabis Use
Cognitive impairments are consistently observed in cannabis users and are considered a potential
mediator of psychosis.
However, the relationship is complex and inconclusive:
Some studies show deterioration, others show no change, and a few report improvement in cognition.
Cannabis use beginning in early adolescence is more strongly associated with adverse cognitive effects.
Cognitive domains most affected include:
Working memory
Associative and spatial memory
Processing speed, attention, executive functions
Verbal fluency, learning, prospective memory, and object recognition
THC-induced cognitive dysfunction overlaps with endophenotypes associated with schizophrenia
vulnerability.

26. 9.Psychosocial Risk Factors and Cannabis
Cannabis use interacts with environmental stressors, particularly:
Childhood sexual abuse (CSA): Significantly associated with higher psychosis risk.
Urban upbringing (urbanicity): Associated with schizophrenia, possibly due to social fragmentation and
environmental stress.
These gene-environment interactions may sensitize the brain to cannabis effects, contributing to
psychotic outcomes.
Behavioral sensitization theory posits that cumulative stress exposure may prime individuals to
psychotic reactions from cannabis.
Cannabis is often used by psychosis patients for affect regulation and socialization, despite its
exacerbating effects.

27. Stress-Diathesis Model Applied to Cannabis and
Psychosis
Stress-Diathesis Model Applied to Cannabis and Psychosis
🔹 1. Diathesis = Underlying Vulnerability
This refers to genetic, neurodevelopmental, or psychological predisposition to psychosis. It may
be:
Genetic vulnerability: Family history of schizophrenia or other psychotic disorders.
Neurobiological factors: Altered dopamine signaling, abnormalities in brain structure/function
(e.g., hippocampus, prefrontal cortex).
Early life adversities: Childhood trauma, neglect, obstetric complications.
Trait-level vulnerabilities: Cognitive deficits, schizotypy, poor stress tolerance.
👉 These factors don’t cause psychosis alone, but increase susceptibility.

28. 2. Stress = Environmental Triggers
This includes external stressors such as:
Cannabis use, especially:
◦ High-potency THC
◦ Frequent use
◦ Use during adolescence
Social adversity: Urban living, migration, discrimination.
Psychosocial stressors: Family conflict, academic/employment stress, trauma.
Cannabis acts as a stressor that interacts with diathesis, tipping the balance toward psychosis in
vulnerable individuals.

29. Interaction: Diathesis + Stress → Psychosis Onset or
Exacerbation
Vulnerability
(Diathesis)
+
Stressor (Cannabis
Use)
→
Psychotic
Symptoms
COMT gene
polymorphism +
Adolescent
cannabis use →
Earlier
schizophrenia
onset
Familial risk of
psychosis
+ Daily THC use →
Transition to
psychosis
Subtle
cognitive/mood
symptoms
+
Chronic cannabis
use
→
Full-blown
psychosis
Example: Gene–Cannabis Interaction
•COMT gene: A polymorphism (Val158Met) affects dopamine metabolism.
• Adolescents with Val/Val genotype who use cannabis are at significantly higher risk of developing psychosis.
•This supports the idea that genetic vulnerability modifies the effect of cannabis as a stressor.

30. 10.Trajectory of Transition to Schizophrenia
oNeurobiological changes due to cannabis resemble those in schizophrenia:
o Abnormalities in dopamine, glutamate, GABA, serotonin, and cholinergic systems.
o Structural and functional imaging shows altered neuronal networks, though findings vary.
oDevelopmental models suggest:
o Either early (prenatal/perinatal) lesions with delayed emergence, or
o Late (adolescent) brain disturbances with shorter latency.
oTHC during adolescence may interfere with endocannabinoid modulation, altering late
neurodevelopmental processes critical to schizophrenia onset.

31. 11.Differential Effects of THC
oTHC produces transient exacerbations in psychotic and cognitive symptoms, more pronounced in
patients with schizophrenia.
oIndividuals with genetic vulnerability (e.g., COMT polymorphism) are more sensitive to
dopaminergic dysregulation caused by cannabis.
oAnimal and human studies show:
o Elevated dopamine in striatal and prefrontal areas post-THC exposure.
o Neurotransmitter disruption involving dopamine, GABA, and glutamate.

33. Impact on Prognosis in Schizophrenia
Cannabis use in schizophrenia is associated with:
◦ Earlier onset of psychotic illness
◦ Worsened prognosis
◦ Poor treatment adherence
◦ Increased relapses and hospitalizations
◦ However, abstinence significantly improves:
◦ Treatment response
◦ Prognosis
◦ Similar outcomes to non-users

34. Cannabis as a Contributing but Not Sufficient Cause
Cannabis is:
◦ Not necessary: Most schizophrenia patients have not used cannabis.
◦ Not sufficient: Most cannabis users do not develop schizophrenia.
However, it may influence:
◦ Age of onset
◦ Symptom severity
◦ Treatment outcomes
◦ Course and recurrence

35. Conclusion
The transition to psychosis due to cannabis remains uncertain, despite strong associative
evidence.
Cannabis-induced neurobiological changes share many features with schizophrenia but are
not causally conclusive.
A multi-factorial model—incorporating genetics, neurodevelopment, psychosocial adversity,
and cannabis exposure—is most plausible.

36. The endocannabinoid system remains a major area of focus for:
Understanding schizophrenia pathophysiology
Developing targeted treatments for cannabis-related disorders
There is a pressing need for longitudinal studies to map the timing, dose, genetic interactions, and
developmental stages critical in mediating cannabis-related psychosis risk.
The relationship between cannabis and psychosis is multifactorial and complex.
Cannabis use is best understood as a modifiable risk factor in a diathesis-stress framework, especially
for genetically predisposed individuals.
Preventive strategies and early treatment of cannabis misuse may have significant impact on reducing
the burden of psychotic disorders.

37. Future direction
Prevention of cannabis use, particularly in adolescents and genetically vulnerable individuals,
is a viable strategy to reduce psychosis risk.
Early intervention, abstinence promotion, and integrated treatment for CUD can:
Improve outcomes in FEP and schizophrenia.
Reduce long-term morbidity.

38. Reference
1. Saraiva, R., & Coentre, R. (2023). Cannabis and psychosis: An overview of the relationship / Cannabis e psicose: Uma visão geral da relação.
Revista da Sociedade Portuguesa de Psiquiatria e Saúde Mental (SPPSM), 9(3), 86–91. https://doi.org/10.51338/sppsm.2023.9.3.86
2. Ahrens J, Ford SD, Schaefer B, Reese D, Khan AR, Tibbo P, Rabin R, Cassidy CM, Palaniyappan L. Convergence of Cannabis and Psychosis on
the Dopamine System. JAMA Psychiatry. 2025 Jun 1;82(6):609-617. doi: 10.1001/jamapsychiatry.2025.0432. PMID: 40202728; PMCID:
PMC11983296.
3. Ganesh, S., & D’Souza, D. C. (2022). Cannabis and Psychosis: Recent Epidemiological Findings Continuing the “Causality Debate”. American
Journal of Psychiatry, 179(1), 8–10. https://doi.org/10.1176/appi.ajp.2021.21111126
4. Shrivastava A, Johnston M, Terpstra K, Bureau Y. Cannabis and psychosis: Neurobiology. Indian J Psychiatry. 2014 Jan;56(1):8-16. doi:
10.4103/0019-5545.124708. PMID: 24574553; PMCID: PMC3927252.
5. Kaplan & sadock’s comprehensive textbook of psychiatry volume i/ii tenth edition

39. Thank you