What is regulated by cannabinoids

Since cannabinoids, unlike most neurotransmitters, act retrogradely (synthesis and release at the postsynapse, effect on receptors at the presynapse), they have a strong regulatory effect on other neurotransmitter systems.
The cannabinoid THC indirectly increases dopamine release and dopaminergic firing in the brain during acute consumption. Long-term use reduces dopaminergic levels.¹ THC does not act directly on dopamine neurons, but indirectly via cannabinoid receptors. These are found in many areas of the brain that have dopamine neurons.

Endocannabinoids are released from brain neurons when triggered by²

• depolarization-related increase in the intracellular Ca2+ concentration
• Activation of a group I metabotropic glutamate receptor (mGluR1, mGluR5)
  • e.g. in cortex, striatum, nucleus accumbens, hippocampus, VTA³

Endocannabinoids bind retrogradely to presynaptic cannabinoid receptors. They are then rapidly degraded.

Endocannabinoids also influence⁴⁵

• Brain development
• synaptic plasticity
• Reaction to endogenous and environmental stimuli.

• 1. Cannabinoids influence neurotransmitter systems
  • 1.1. Cannabinoids regulate dopamine
  • 1.2. Cannabinoids regulate acetylcholine (ACh) via dopamine
  • 1.3. Cannabinoids regulate noradrenaline
  • 1.4. Cannabinoids regulate serotonin
  • 1.5. Cannabinoids regulate GABA
  • 1.6. Cannabinoids regulate glutamate
  • 1.7. Cannabinoids influence opioid system (?)
  • 1.8. Biphasic dose-dependent effect of cannabinoids
• 2. Cannabinoids influence behavior
  • 2.1. Cannabinoids influence the energy balance of the brain
  • 2.2. Cannabinoids influence social behavior
  • 2.3. Cannabinoids regulate executive functions and cognitive flexibility
  • 2.4. Cannabinoids regulate depression
  • 2.5. Cannabinoids regulate anxiety
  • 2.6. Cannabinoids regulate compulsive behavior
  • 2.7. Cannabinoids regulate addiction
  • 2.8. Cannabinoids regulate appetite and food intake (also) via dopamine
  • 2.9. Cannabinoids modulate sleep
  • 2.10. Cannabinoids modulate stress
  • 2.11. Cannabinoids influence inflammation
  • 2.12. Cannabinoids influence pain
  • 2.13. Cannabinoids influence nausea
  • 2.14. Cannabinoids influence memory

1. Cannabinoids influence neurotransmitter systems¶

1.1. Cannabinoids regulate dopamine¶

See the articles Cannabinoids regulate dopamine And Cannabinoids also regulate appetite and food intake via dopamine

1.2. Cannabinoids regulate acetylcholine (ACh) via dopamine¶

Dopamine controls the release of acetylcholine in the hippocampus and PFC.³

• D2R agonists reduce ACh in the hippocampus⁶
• D1R agonists increase ACh in the hippocampus⁶⁷ and PFC⁸
• CB1 agonists⁹
  • low doses increase ACh in hippocampus and PFC¹⁰
    • possibly via D1R, which are located in the septum³¹¹
  • high doses reduce ACh in the hippocampus and PFC¹²
    • via hippocampal D2R³
• A CB1R antagonist increases ACh in hippocampus and PFC⁹

1.3. Cannabinoids regulate noradrenaline¶

Endocannabinoids influence the noradrenergic system.⁴¹³¹⁴

• CB1R agonists inhibit the noradrenaline system and interfere with attention processes.¹⁴
• Cannabinoids alter the release of noradrenaline in¹⁴
  • PFC
  • Locus coeruleus
  • Hippocampus
  • Hypothalamus
  • Cerebellum
• FAAH inhibitors increase noradrenergic firing in the nucleus coeruleus¹⁵
• CB1R is found in moderate amounts of mRNA in the noradrenergic nuclei locus coeruleus (66% somatodendritic, 22% in axon terminals, 12% in glia and small, non-myelinated axon-like structures) and NTS¹⁶
• The CB1R agonists WIN 55212-2, CP 55940 and THC increase the spontaneous firing rate of neurons in the locus coeruleus in a dose-dependent manner¹⁷¹⁸
  • Possibly due to the activation of CB1R in the prepositus hypoglossi and not to the activation of CB1R in the LC
• CB1R antagonists can increase the release of noradrenaline, e.g. in:¹⁴
  • PFC
  • Hypothalamus
• The CB1R antagonist rimonabant reduces the firing rate of noradrenergic neurons in the LC¹⁸
• Cannabinoids can reduce the phasic activity of locus coeruleus neurons via glutamate¹³
• Anandamide and the synthetic cannabinoid HU210 reduced the perivascular nerve stimulation (PNS)-induced norepinephrine release of the rat heart Langendorff preparation. 2-AG in the presence of DFP and indomethacin increased PNS-induced norepinephrine release, which was completely blocked by AM251.¹⁹

The endocannabinoid system regulates stress responses and emotional homeostasis by influencing noradrenergic circuits.²⁰

1.4. Cannabinoids regulate serotonin¶

Endocannabinoids influence the serotonergic system.⁴¹³ Endocannabinoids can regulate the efficiency of serotonergic neurotransmission not only by inhibiting serotonin release, but also (at least peripherally) by inhibiting serotonin reuptake.²¹

CB1Rs are also found on serotonergic neurons in the substantia nigra and the raphe nuclei.²²

• Serotonin increasing:

  • CB1R agonists
    • Inhibit serotonergic activity in dorsal raphe nuclei, CB1R antagonists increase it.²³
    • The CB1R agonist THC, given systemically, increases 5-HT levels in rats²⁴
  • CB1R antagonists increase serotonin release in the PFC¹⁴
  • WIN 55212-2 at low dose increases, at high dose decreases spontaneous firing of 5-HT neurons in the dorsal raphe nucleus (DRN)²⁵
  • CB1R agonists such as WIN 55212-2 and CP 55940 increase 5-HT efflux in the nucleus accumbens by inhibiting GABAergic interneurons in the DRN via CB1R; 5-HT in the DRN remained unchanged²⁶²⁷
  • A FAAH inhibitor promotes the activity of 5-HT neurons in the DRN¹⁵
  • FAAH-KO mice showed²⁸
    • Increased 5-HT firing in the dorsal raphe nuclei
    • Desensitized 5-HT(2A/2C) receptors in the PFC
    • Increased tone at the 5-HT(1A) heteroreceptors of the hippocampus

• Reducing serotonin

  • CB1R agonists inhibit the release of serotonin in the PFC¹⁴
  • CB1R agonists inhibit serotonergic activity in dorsal raphe nuclei, CB1R antagonists increase it.²³
  • THC reduces the 5-HT level in the ventral hippocampus²⁹
  • THC reduces 5-HT levels in the nucleus accumbens via activated glutamate neurons³⁰
  • WIN55212-2 and R-methanandamide reduced 5-HT release in the frontal cortex³¹
  • Show CB1R-KO mice³²
    • Increased basal extracellular 5-HT levels in the PFC
    • An attenuated fluoxetine-induced increase in extracellular 5-HT levels in the PFC
    • A significant reduction in the density of 5-HT transporter binding sites in the PFC and hippocampus
    • Altered 5-HT receptors:
      • Functional desensitization of the 5-HT(1A) autoreceptor
      • Reduced expression of the 5-HT(2C) receptor in dorsal raphe nuclei, nucleus accumbens and the paraventricular nucleus of the hypothalamus, all of which are associated with the control of emotional responses
      • Increased expression of the 5-HT(2C) receptor in the CA3 area of the ventral hippocampus

1.5. Cannabinoids regulate GABA¶

For the significant influence of cannabinoids on dopamine via the GABA pathway, see the article Cannabinoids regulate dopamine

• Endocannabinoids influence the GABAergic system.⁴
  • via CB1R actually inhibition of GABA neurons (significant inhibition of evoked and spontaneous GABA-mediated synaptic events³³.)
    • Consequences: less inhibition of dopamine neurons. As a result, cannabinoids indirectly increase dopamine levels.
    • However, the synthetic CB1R agonist HU210 caused a significant increase in GABA release³⁴
      • Either CB1Rs can promote the release of transmitters under certain circumstances, or HU210 mediates its effects via other pathways than CB1Rs

1.6. Cannabinoids regulate glutamate¶

For the significant influence of cannabinoids on dopamine via the glutamate pathway, see the article Cannabinoids regulate dopamine

CB1R mediates glutamatergic synaptic suppression in the hippocampus.³⁵
The CB1R agonist THC increased extracellular glutamate levels in the nucleus accumbens shell, VTA and mPFC.³⁶
Repeated administration of THC or synthetic cannabinoids reduced the expression of glutamate AMPA and NMDA receptors in the rat cerebellum.¹⁴

1.7. Cannabinoids influence opioid system (?)¶

The analgesic effects of CBR agonists are mediated by the release of endogenous opioids. CBR agonists triggered the release of the opioid dynorphin B in the spinal cord of rats. The CB1R antagonist AM251 reversed the analgesic effect of morphine. CBR agonists enhance the rewarding properties of opioids such as morphine and heroin.¹⁴

1.8. Biphasic dose-dependent effect of cannabinoids¶

Cannabinoid agonists often act differently in the forebrain in vivo depending on the dose.³
High doses are approx. one order of magnitude (one decimal place, ten times) higher than low doses.

• CB1R agonists on acetylcholine: (see above)⁹
  • low doses increase ACh in hippocampus and PFC
    • via septal D1R
  • high doses reduce ACh in hippocampus and PFC
    • via hippocampal D2R
  • with a constant amplitude of dopamine release³
  • with a constant increase in postsynaptic dopamine-dependent protein phosphorylation³
• 2-deoxyglycose utilization in the hippocampus³
  • low dose: stimulating
  • high dose: inhibitory
• cortically evoked potentials³
  • low dose: stimulating
  • high dose: inhibitory
• Locomotion³
  • low dose: stimulating
  • high dose: inhibitory
• CB1R agonists on glutamate in the PFC³⁷
  • low doses (0.1 and 1 mg/kg i.p.) increase glutamate
  • slightly higher dose (2 mg/kg) leaves glutamate unchanged
  • possibly because CB1Rs in presynapses of GABAergic interneurons (which control network activity) are more sensitive (and therefore respond at lower doses) than CB1Rs in pyramidal cortical neurons, which control net efflux towards reduced glutamate activity³

2. Cannabinoids influence behavior¶

2.1. Cannabinoids influence the energy balance of the brain¶

The Energy deficit hypothesis Explains ADHD with a lack of energy in the brain.

CB1Rs are also found on mitochondria.
Mitochondria regulate the energy balance in the brain via parvalbumin interneurons, among others. Brain regions rich in CB1Rs regulate excitatory/inhibitory activity and the balance between them.³⁸
Anandamide reduces calcium sensitivity and impairs membrane properties in mitochondria.³⁹

2.2. Cannabinoids influence social behavior¶

Social play increased AEA in the amygdala and nucleus accumbens, not in the PFC or hippocampus, and increased CB1R phosphorylation in the amygdala.⁴⁰

With regard to the effect of cannabinoids on social play and social behavior, a distinction must be made between endocannabinoids and externally supplied CB1R agonists.⁴¹

Externally administered CB1R agonists reduced social play:

• The CB1R agonist WIN55,212-2
  • reduced social play⁴², namely the request to play as well as the reaction to requests to play⁴³
  • during adolescence as in adulthood⁴⁴
  • reduces the time of social interaction in rats during adulthood
  • caused persistent deficits in social contacts, social behavior, social play, object recognition and self-care
• The CB1R agonist THC
  • Chronic gift reduced social play⁴⁵
  • chronic administration causes a reduction in social behavior, sexual behavior, nest-building behavior and litter size and increased non-social activity in mice⁴⁶
  • in childhood caused decreased social exploratory behavior and increased social play in adult rats⁴⁷
  • THC smoking in pregnant rat mothers caused less social exploratory behavior in adolescent male offspring and less exploratory behavior in adult offspring, and dose-dependently reduced behavioral flexibility⁴⁸
  • acute causes general sedation in mice⁴⁶
  • perinatal administration of THC causes⁴¹
    • in rats
      • impaired social interaction and play behavior in adulthood
    • only for girls, not for boys⁴⁹
      • reduced playing time in childhood
      • increased risk of aggressive behavior
      • increased attention problems
  • prenatally, the CBR agonist WIN55,212-2 reduced isolation-induced ultrasonic sounds and increased locomotor activity in males only. Administration of the positive allosteric modulator of the mGlu5 receptor CDPPB to the pups corrected this. Prepubertal and pubertal social play behavior, anxiety and temporal order memory of the rats remained unchanged by WIN55,212-2.

An externally administered CB1R antagonist reduced social play:

• The CB1R antagonist rimonabant reduced social play⁵⁰

Reinforcement of endocannabinoids predominantly increases social play.

• The FAAH inhibitor URB597 and the reuptake inhibitor VDM11 increased AEA in the amygdala, but not in the nucleus accumbens, and increased social play⁴⁰ via opioid and dopamine receptors⁴²
• The FAAH inhibitor URB597 increased social play depending on the social activity of the play partner⁴³
• The opioid agonist morphine increased social play independent of the social activity of the play partner⁴³, whereas the CB1R antagonist rimonabant suppressed this, independent of dopamine receptors.⁴² Pretreatment with the 2-AG depletion inhibitor JZL184 or the cannabinoid agonist WIN55,212-2 did not inhibit this.⁵¹
• A combination of URB597 and morphine doses, each of which was ineffective alone, increased social play.⁴²
• The 2-AG depletion inhibitor JZL184 promoted social play and increased CB1R activation in the nucleus accumbens and PFC, both of which were suppressed by pretreatment with the opioid receptor agonist morphine⁵¹
• The 2-AG degradation inhibitor MJN110 influenced aggressive grooming in socially isolated rats⁵²
• The selective AEA reuptake inhibitor VDM11 increased social play, which was prevented by the CB1R antagonist rimonabant, the opioid receptor antagonist naloxone and the dopamine receptor antagonist alpha-flupenthixol.⁵³
• The AEA and 2-AG depletion inhibitor JZL195 (0.1 mg/kg) increased social play behavior, the most characteristic social activity of adolescent rats, and increased social interaction in adult animals. The CB1R antagonist rimonabant inhibited this and led to increased 2-AG and unchanged AEA in the brain⁵⁴
• JZL195 (1 mg/kg) increased general social exploration in adolescent rats without affecting social play and induced anxiety-like effects in both adolescent and adult animals in the elevated plus maze test via CB1R. This correlated with elevated brain AEA and 2-AG in adolescent rats and only elevated 2-AG in adult animals.⁵⁴
• However, the less selective AEA reuptake inhibitor AM404 reduced social play without the CB1R antagonist rimonabant, the CB2R antagonist SR144528 or the TRPV1 antagonist capsazepine preventing it.⁵³
• The FAAH inhibitor URB597⁵⁵
  • increased social play behavior in adolescent Wistar rats under all experimental conditions
  • did not affect play and social behavior in Sprague-Dawley rats under any experimental condition
  • elevated 50 kHz USVs during social interaction in juvenile Wistar and adult Sprague-Dawley rats
  • AEA modulates social play in juvenile rats in a load-dependent but not a context-dependent manner. AEA modulation of social behavior and 50 kHz ultrasonic sounds in adults is load- and context-dependent.

Juvenile and adult Sprague-Dawley rats show more social behavior and 50 kHz ultrasonic sounds than Wistar rats. This could explain contradictory results on the effects of cannabinoid drugs on emotionality in different rodent strains.⁵⁵

In juvenile rats, encounters with unfamiliar rats increased AEA levels in the striatum. AEA remained unchanged in other brain regions, 2-AG and FAAH remained unchanged overall,⁵⁶

Pathway of action of reduced social behavior due to external CB1R agonists or CB1R overexpression in mPFC appears to be a disorder of cognitive function (e.g., behavioral flexibility) and emotional reactivity, which may be caused by endocannabinoid-induced alteration of dopaminergic, cholinergic, and serotonergic transmission in PFC⁵⁷⁵⁸ , both of which are required for appropriate social interactions⁵⁹

The positive effects of indirect CB1R agonists on social play appear to be mediated via dopamine and endoopioids, as they can be blocked by dopamine or μ-opioid receptor antagonists. Conversely, the game-promoting effects of opioid agonists can be attenuated by either opioid receptor or CB1R antagonists.⁴³⁴¹ Dopamine is involved in the facilitative effects of indirect cannabinoid agonists on social play.⁴³ In contrast, dopamine is not involved in the play–stimulating effects of morphine.⁴³
Endocannabinoids activate mesolimbic dopamine transmission, which is significantly involved in the modulation of social play.^60616263

In humans, CB1R gene variants influence the recognition of happy faces, social reward sensitivity through reward-related forebrain areas and thus social behavior.⁶⁴

Methylphenidate and atomoxetine reduce social play in rats.⁶⁵ This occurred when MPH was administered in the ACC, infralimbic cortex, basolateral amygdala or habenula, but not in the prelimbic, medial/ventral orbitofrontal or ventrolateral orbitofrontal cortex, mediodorsal thalamus or nucleus accumbens. The cause appears to be noradrenergic mechanisms in the PFC.⁶⁶⁶⁷
We hypothesize that this may provide a neurophysiological explanation for the reported “zombie” effects of methylphenidate (usually when the dosage is too high or rarely when the person with ADHD is hypersensitive).

2.3. Cannabinoids regulate executive functions and cognitive flexibility¶

In n = 157 women were found:⁶⁸

• AEA correlates positively with cognitive flexibility and decision-making ability
• 2-AG correlated negatively with cognitive flexibility
• Neither AEA nor 2-AG correlated with impulse inhibition

2.4. Cannabinoids regulate depression¶

Endocannabinoids are reduced in depression.⁶⁹⁷⁰⁷¹
- 2-AG is reduced in severe depression⁷²⁷³
- 2-AG tends to be elevated in mild depression⁷²
- MAGL inhibitors (which inhibit 2-AG degradation) have an antidepressant effect⁷⁴

The CB2R agonist β-caryophyllene improved all symptoms of depression induced by the Novelty Suppressed Feeding Test, the Tail Suspension Test and the Forced Swim Test in adult mice. Prior administration of the CB2R antagonist AM630 completely abolished the antidepressant effect⁷⁵

Chronic administration of the synthetic CB2R agonist HU210 showed an antidepressant effect.⁷⁶ The antidepressant effect was as strong as that of desimipramine.⁷⁷

Systemic administration of CB1R agonists and FAAH inhibitors has been shown to have an antidepressant effect. Local enhancement of CB1R signaling in the dorsal hippocampus triggers an antidepressant effect⁷⁸

2.5. Cannabinoids regulate anxiety¶

Endocannabinoids are reduced in anxiety disorders.⁷⁹
- AEA is reduced⁷³

The CB2R agonist β-caryophyllene improved anxiety behavior in adult mice time spent in the center of the arena without altering general motor activity in the OF test, which can be evaluated as a reduction of anxiety symptoms. Prior administration of the CB2R antagonist AM630 completely abolished the anxiolytic effect.⁷⁵⁸⁰ β-Caryophyllene has a calming effect.⁸¹

2.6. Cannabinoids regulate compulsive behavior¶

The CB2R agonist β-caryophyllene (beta-caryophyllene) improved the number of buried marbles and time spent digging in adult mice , suggesting an antigang effect.⁷⁵

2.7. Cannabinoids regulate addiction¶

β-Caryophyllene (beta-caryophyllene) inhibited cocaine-dependent behavior not via CB1R, CB2R or GPR55, but by activating PPARα and PPARγ.⁸²⁸³ β-Caryophyllene (beta-caryophyllene) also inhibited methamphetamine addiction⁸⁴, heroin addiction⁸⁵ nicotine addiction⁸⁶ and alcohol addiction¹⁴ via CB2R¹⁴⁸⁷ .
β-Caryophyllene (beta-caryophyllene) is an FDA-approved dietary supplement.⁸⁸

2.8. Cannabinoids regulate appetite and food intake (also) via dopamine¶

See the article Cannabinoids also regulate appetite and food intake via dopamine

2.9. Cannabinoids modulate sleep¶

Endocannabinoids are involved in the regulation of sleep.⁸⁹

2.10. Cannabinoids modulate stress¶

FAAH inhibitors (which inhibit the breakdown of AEA) and MAGL inhibitors (which inhibit the breakdown of 2-AG) influence the HPA axis and lead to reduced cortisol.⁷³

2.11. Cannabinoids influence inflammation¶

2-AG has a strong influence on the immune system. MAGL inhibitors therefore have an anti-inflammatory effect.⁷⁴

• CT-3 (ajulemic acid, lenabasum), a synthetic THC analog and CB2R agonist, did not prove helpful in a phase III study against diffuse cutaneous systemic sclerosis.⁹⁰

2.12. Cannabinoids influence pain¶

CB1R-KO mice⁹¹

• have a reduced sensitivity to pain
• show reduced pain relief due to cannabinoids
• nevertheless develop neuropathic pain

CB1R are highly regulated⁹¹

• for nerve injuries
• in many rat models of neuropathic pain

CB1 agonists have a pain-relieving effect on neuropathic pain.⁹¹⁹²

• THC (3 to 6 mg/kg) and CP 55,940 (0.05 to 0.025 mg/kg) relieved neuropathic pain in animal models more effectively than morphine (8 to 16 mg/kg) and gabapentin (50 mg/kg), both intraperitoneally. The analgesic effect appears to occur via CB1R.⁹¹
• CP 55,940, WIN 55,212-2 and HU-210 all produced complete reversal of mechanical hyperalgesia in the partial sciatic nerve ligation model of neuropathic pain.⁹¹

The selective CB2R agonist CT-3 (ajulemic acid, lenabasum, AJA, IP-751, JBT-101, anabasum)⁹⁰ is a synthetic THC analog that has shown good efficacy in neuropathic pain in rodents and humans and has no psychotropic effects.⁹³ At supratherapeutic doses, however, it increases the drug liking of THC taken in parallel⁹⁴

A combination of FAAH inhibitor and MAGL partial inhibitor relieves neuropathic and inflammation-related pain.⁹⁵

2.13. Cannabinoids influence nausea¶

Oral THC (Marinol®) has been approved by the FDA since 1985 to treat nausea associated with chemotherapy⁹¹
The synthetic THC analog nabilone (Cesamet®) was approved by the FDA in 1985 to treat nausea and vomiting associated with chemotherapy.⁹¹
The oral THC-CBD spray nabiximols (Sativex®) was first approved in the UK in 2010 for multiple sclerosis-related spasticity. It is also available in Spain, the Czech Republic, Germany, Denmark, Sweden, Italy, Austria, Poland, France and Canada (here also for neuropathic pain in multiple sclerosis or cancer). it was not yet approved in the USA in 2022, but approval is being pursued.

2.14. Cannabinoids influence memory¶

Glucocorticoids appear to recruit endocannabinoids from the amygdala to consolidate memory and store memory content.⁹⁶⁹⁷⁹⁸