CBD is the only known cannabinoid so far that has been researched for schizophrenia that was found to help.

 

THC is known to increase the risk of psychosis in schizophrenia. (23G)

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Terpenes that could be a benefit: a-pinene, beta-caryophyllene, beta-caryophyllene oxide, and delta 3 carene.

 

Terpenes that could have side effects with schizophrenia: terpineol, linalool, thymol and carvacrol.

 

Terpenes that need to be researched: limonene, humulene, and a-bisabolol.

 

Terpenes that don't seem to help or harm: myrcene, fenchone, sabinene.

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Pathophysiology

 

 

Dopamine Dysregulation

 

 

Mesolimbic Pathway (Positive Symptoms)

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Excessive dopamine activity in this pathway is linked to hallucinations, delusions, and other positive symptoms. (9G)

 

D2 receptors in subcortical structures (e.g., ventral striatum) are often overactive. (9G)

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Mesocortical Pathway (Negative/Deficit Symptoms)

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Reduced dopamine in the prefrontal cortex contributes to anhedonia, apathy, social withdrawal, and other negative symptoms. (9G)

 

Impaired D1 and D2 signaling in frontal areas may underlie problems with executive function and cognition. (9G)

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Glutamate and the NMDA

 

Hypothesis NMDA Receptor Hypofunction

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     Some evidence suggests NMDA (a glutamate receptor) is underactive in schizophrenia, contributing to cognitive deficits and possibly fueling dopamine dysregulation. (10G)

 

Blocking NMDA channels (e.g., with ketamine, PCP) can mimic psychosis-like symptoms. (11G)

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Synaptic Pruning/Connectivity

 

     Hypoactive glutamate signaling may also impact how neurons form and maintain synaptic connections, relevant to both negative and positive symptoms. (12G)

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GABAergic and Serotonin Systems

 

GABA Interneurons

 

     Reduced GABA activity in specific cortical interneurons can disturb excitatory–inhibitory balance, affecting cognition and contributing to positive symptoms. (13G)

 

Interneurons in the dorsolateral prefrontal cortex frequently show gene expression changes tied to GABA. (14G)

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Serotonin (5-HT)

 

     5-HT2A receptors are often targeted by newer antipsychotics; blockade or modulation can help rebalance dopamine in certain pathways. (15G)

 

Abnormal serotonin–dopamine interactions may contribute to hallucinations and mood components. (16G)

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Brain Mapping and Structural Changes

 

 

Reduced Gray Matter

 

Studies show thinning of the prefrontal cortex, temporal lobe, and hippocampus, sometimes progressing over time. (17G)

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Functional Connectivity

 

     fMRI often reveals altered communication among cortical and subcortical regions, possibly influencing cognitive and emotional regulation. (18G)

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Nicotinic Receptors (nAChRs)

 

 

α7 nAChR: Reduced expression in brain regions (hippocampus, cingulate cortex) of patients; genetic variations at this receptor’s locus raise schizophrenia risk. (19G)

 

 

Self-Medication Hypothesis: High smoking rates among patients suggest nicotine from cigarettes (nAChR agonist) might temporarily improve attention and working memory, though its overall effect is diminished in schizophrenia. (19G)

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Muscarinic Receptors (mAChRs)

 

Muscarinic receptors are decreased in brain areas (prefrontal cortex, hippocampus). (19G)

 

     Antagonists (e.g., scopolamine) can produce psychosis-like symptoms, implying normal mAChR function helps maintain cognitive and emotional stability. (19G)

 

Xanomeline (an M1/M4 agonist) improved cognition in some trials, but side effects remain an obstacle. (19G)

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Cholinergic Impact on Cognition

 

 

     ACh modulates attention and working memory by enhancing thalamocortical inputs and reducing certain intra-cortical pathways,  increasing signal-to-noise in the cortex. (20G)

 

 

     In rodent and primate models, boosting cholinergic activity (via nAChRs or mAChRs) improves sensory processing and cue detection abilities often disrupted in schizophrenia. (21G)

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Cannabinoids and Terpenes

 

CBD clinical trial

 

     In that six-week, multi-center randomized controlled trial, participants with schizophrenia received 1,000 mg of CBD daily (500 mg twice a day). This was in an oral solution, The study concluded that CBD was well tolerated and showed moderate improvements in positive symptoms compared to placebo, though larger follow-up trials are still needed to confirm its efficacy. (22G)

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THC

 

Psychosis Exacerbation: THC can heighten dopamine activity in the mesolimbic pathway, which may worsen positive symptoms (hallucinations, delusions) or even trigger psychotic episodes. (23G)

 

Cognitive Impairment: THC might further diminish memory, attention, and executive function areas already affected in schizophrenia. (24G)

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Terpineol

 

     Terpineol is an anticholinergic. (11D) Increasing acetylcholine in schizophrenia could improve focus, attention, and working memory (19G) Some medications to treat schizophrenia produce extrapyramidal side-effects (EPS). Anticholinergic drugs are primarily used to treat EPS or prevent EPS induced by antipsychotics in the treatment of psychosis and schizophrenia. (25G) Terpineol might do the same with helping with EPS, but could make memory and attention worse from turning off the effects of acetylcholine.

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Thymol and Carvacrol

 

     Thymol and Carvacrol both inhibit α7 nicotinic acetylcholine receptors, (17E) and thymol is a GABA-A allosteric modulator. (23E) The α7 nicotinic inhibition from both terpenes could worsen attention and working memory. Thymol’s effect on GABA-A might reduce hyperactive neurons and reduce anxiety.

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Linalool

 

     Linalool inhibits acetylcholine release and is a NMDA receptor antagonist. (55C 12F) Inhibiting NMDA or acetylcholine can produce psychosis-like symptoms. (11G 19G)

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α-Bisabolol

 

     α-Bisabolol has neuroprotective benefits from preserving dopaminergic neurons by attenuating the downregulation of the anti-apoptotic protein Bcl-2, upregulation of the pro-apoptotic protein Bax, and the cleavage of caspases-3 and 9. (62D) This might help with negative symptoms from further dopaminergic neuron loss. It is also known as a relaxing Indica terpene so there is no research to show if there are side effects with memory or attention deficits with schizophrenia.

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Limonene

 

     Limonene directly binds to the adenosine A2A receptor. (89B) Limonene was also found to have anti-anxiety benefits, as it increases the amount of dopamine in the brain, and releases GABA. (90B) Limonene is a tough one to find out if this terpene will be a benefit or detriment to schizophrenia. The anti-anxiety benefits and its ability to increase GABA could help with the anxiety or tension aspects of schizophrenia, but the increase in dopamine could potentially worsen positive symptoms like hallucinations and delusions.

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Terpenes that are acetylcholinesterase inhibitors

 

     Terpenes that are acetylcholinesterase inhibitors are limonene, alpha-Pinene, beta-Caryophyllene, beta-Caryophyllene Oxide, humulene, and delta 3 Carene. (52C 37E)

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     α-Pinene, beta-caryophyllene, beta-caryophyllene oxide, and delta 3 carene would likely be the best choices so far out of all the terpenes since they increase acetylcholine. They do affect acetylcholine at different strengths. Some like caryophyllene do go to different receptors which could affect how much acetylcholinesterase (AchE) is being inhibited. As far as we know so far, a-pinene only affects the receptors on AchE, while caryophyllene also affects CB2.

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     Limonene and humulene needs to be researched for schizophrenia to see if that would cause side effects from an increase in dopamine from limonene. CB1 activation from humulene is not known if that would increase the risk of psychosis.

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Other terpenes, like myrcene, don't have much of an indication of good or bad interactions with schizophrenia.