Cannabis exerts its psychoactive effects primarily through Δ⁹-tetrahydrocannabinol (THC), the main psychoactive compound in the plant. THC interacts with the endocannabinoid system (ECS), particularly the CB₁ receptors, which are abundantly present in the central nervous system. The activation of these receptors influences dopamine release and other neurotransmitter systems, affecting cognition, mood, and perception.

1. Endocannabinoid System (ECS) and its Role in Dopamine Regulation

The endocannabinoid system consists of:

• Cannabinoid receptors (CB₁ and CB₂)
• Endocannabinoids (Anandamide and 2-AG)
• Enzymes (FAAH and MAGL) that degrade endocannabinoids

CB₁ Receptor Activation by THC

• The CB₁ receptor is highly expressed in the basal ganglia, hippocampus, amygdala, and prefrontal cortex—areas involved in movement, memory, emotions, and executive functions.
• Endocannabinoids (such as Anandamide) normally bind to CB₁ receptors, acting as a retrograde neurotransmitter, meaning they are released from postsynaptic neurons and travel backward to inhibit neurotransmitter release from presynaptic neurons.

When THC binds to CB₁ receptors, it mimics the action of endocannabinoids but with much stronger and longer-lasting effects, leading to widespread changes in neurotransmission.

2. THC and Dopamine Release

THC does not directly bind to dopamine receptors or dopamine transporters. Instead, it modulates dopamine release indirectly by acting on GABAergic interneurons.

Steps in THC-induced Dopamine Release:

1. THC binds to CB₁ receptors on GABAergic interneurons (which normally inhibit dopamine release).
2. Inhibition of GABAergic activity leads to reduced GABA release.
3. Less GABA means reduced inhibition of dopamine neurons in the ventral tegmental area (VTA).
4. Increased dopamine release in the nucleus accumbens (NAc), a key brain region involved in reward and reinforcement.
5. This results in euphoria, relaxation, altered perception of time, and reinforcement of cannabis use.

Summary: THC disinhibits dopamine neurons in the VTA by blocking GABAergic inhibition, causing dopamine levels to rise, leading to the characteristic psychoactive effects of cannabis.

3. Acute vs. Chronic Effects on Dopamine

Acute Effects (Short-term Use)

• Increased dopamine release in the mesolimbic reward pathway, leading to:

  • Euphoria
  • Relaxation
  • Enhanced sensory perception
  • Altered time perception
  • Motivation and reinforcement of drug-seeking behavior

• This dopamine surge is similar to what occurs with other drugs of abuse like nicotine and opioids, but weaker than stimulants like cocaine or amphetamines.

Chronic Effects (Long-term Use)

• Downregulation of dopamine receptors (D₂ receptors) in the striatum, leading to:

  • Blunted dopamine response (decreased reward sensitivity)
  • Reduced motivation (Amotivational Syndrome)
  • Cognitive impairments (working memory deficits)
  • Higher risk for psychiatric disorders (e.g., schizophrenia, depression, psychosis)

• Prolonged CB₁ receptor activation also reduces natural dopamine production, contributing to cannabis dependence and withdrawal symptoms.

4. Interaction with Other Neurotransmitter Systems

THC affects multiple neurotransmitters apart from dopamine:

A. Glutamate System

• THC inhibits glutamate release, impairing:
  • Memory formation (hippocampal dysfunction)
  • Executive function (prefrontal cortex dysfunction)
  • Learning and cognitive flexibility

B. Serotonin System

• THC increases serotonin release, contributing to:
  • Mood elevation (similar to antidepressants)
  • Anxiolytic effects at low doses
  • Paranoia and anxiety at high doses due to overstimulation

C. Norepinephrine System

• THC modulates norepinephrine release, leading to:
  • Increased heart rate
  • Heightened alertness
  • Sympathetic nervous system activation (fight-or-flight response)

D. Endorphin System

• THC enhances β-endorphins, which contributes to:
  • Pain relief (analgesic effect)
  • Relaxation
  • Mood enhancement

5. Clinical Implications of Dopamine Dysregulation in Cannabis Users

• Short-term dopamine increase leads to euphoria, but chronic use leads to dopamine depletion, reducing motivation and pleasure.
• Cannabis-induced dopamine dysregulation has been implicated in:
  • Schizophrenia (THC use in genetically predisposed individuals increases risk)
  • Depression and Anxiety (long-term users often report mood disturbances)
  • Cognitive Decline (memory and attention deficits)
  • Addiction Vulnerability (increased likelihood of developing substance use disorders)

6. Conclusion

THC affects the dopamine system indirectly, primarily by disinhibiting dopamine neurons via GABAergic modulation. This leads to short-term euphoria but long-term dopamine depletion, contributing to cannabis dependence, cognitive deficits, and mental health risks. Understanding this mechanism is crucial for developing targeted treatments for cannabis use disorder and managing its neuropsychiatric consequences.