Cannabis II: PharmD & Long-Term Effects

CB-Receptors: Locations in Body & Brain

• CB1 & CB2

  • CB1 → most common in brain & other organs (brain & CNS)

  • CB2 → more in the immune system (peripheral organs & I.S.)

Endogenous Cannabinoids (Endocannabinoids)

• Cannabinoids Receptors (CB) → are presynaptic receptors, & respond to body’s own “cannabis-like” substances 

  • like autoreceptors

  • G-protein coupled receptor

• Anandamide (AEA): (N-arachidonoyl-ethanol-amine) 1st endocannabinoid discovered

  • AEA synthesized “on demand” & metabolized very quickly @ synapses

• 2-AG: (2-arahidonoylglycerol)

  • more potent than AEA @ receptors

  • higher concentrations in NS than AEA

Cannabis PharmD

• post-synaptic is releasing to interact w/ presynaptic (retrograde messaging)

  • feedback system

• A-9-THC: some discrepancies in research, but considered either full or partial agonist @ CB₁ receptors

• CBD: variable, modulator w/ either PAM or NAM activity @ both CB₁ & CB₂ receptors

• stimulant & depressant

Endogenous Regulare Synaptic Transmission

• AEA & 2-AG → are released from post-synaptic neurons as retrograde messangers, where they bind to pre-synaptic CB₁ receptors (CB₁s are the most abundant GPCRs in the CNS

• Endocannabinoids inhibit the release of other NTs from other neurons, esp. glutamate & GABA, by inhibiting release from their terminals

Distribution of Human Brain Cannabinoid Receptors

• high to moderate # of receptors:

  • Cerebral cortex: prefrontal, cingulate

  • Mesolimbic System: hippocampus, amygdala, VTA

  • Mesostriatal: basal ganglia, substantia nigra

  • Other: cerebellum, hypothalamus (“4-Fs”, PAG (analgesia)

Cannabis Effects on Brain Function

• Emotion/mood: anxiolysis, euphoria, laughing fits (but panic reactions, paranoia can occur)

  • B.A./S.: amygdala, cingulate cortex

• Motivation: DA surge while high, but apathy, “a motivational syndrome” w/ chronic use

  • B.A./S.: Mesolimbic System (VTA → NAc)

• Movement: slowed (incl. speech), lethargy

  • B.A./S.: Mesostriatal System (SN → Basal Ganglia)

• Coordination: impaired coordination

  • B.A./S.: Cerebellum

• Perception: sensory distortion (auditory, CEVs, tactile)

  • B.A./S.: PFC, hippocampus

• Cognition: impaired EF (attention, WM, impulse control)

  • B.A./S.: PFC, hippocampus  

• Analgesia: reduced responses to pain

  • B.A./S.: Periqueductal Gray (PAG), spinal cord

• Appetite: smell & taste stimulated, increased responses to food (esp.; sugar, fat)

  • B.A./S.: hypothalamus 

Cannabis Use: Effects of Heavy or Long-Term Use

• In studies of low freq. “recreational” users → verbal fluency, attention, & concentration appear to be normal

• Heavy, regular, or daily/near daily (D/ND) use associated w/:

  • decreased cognition: memory, impulsivity, decision making, verbal fluency

  • increased stress reactivity 

  • amotivational syndrome: controversial, mixed evidence

    • ex: long-term use predicts low self-efficacy

      • results: nonusers = stayed the same,  user = dropped significantly [initiative; persistance = dropped both, but more users

  • increased risk of MDD psychosis

  • symptoms → esp. if introduced in teen yrs => potential for low IQ

• risk of adverse effects increase dramatically if cannabis used before age 17 

Long-Term Effects of Cannabis on the Brain? (study)

• “frequent” users (D/ND), reduced brain volumes in:

  • orbitofrontal cortex: emotional regulation

  • hippocampus: memory & cognition 

Cannabis Use & Elevated Risk of Psychosis

• observational studies → show increased risk

• Genetic SNPs → show increased risk

• COMT → enzyme that breaks down catecholamines

  • a predisposition component → can exacerbate w/ specific genetic variation 

Cannabis Tolerance, Withdrawal, & Dependence

• Dependence

  • 10-30% of users may have some degree of Cannabis Use Disorder (CUD)

  • compared to adults → use before age 18 elevates risk (4-7X) of CUD

  • CB₁ stimulation increases mesolimbic DA release indirectly by alternating Glu & GABA regulation of VTA

• Tolerance → does occur, but typically requires high dose, chronic use

  • likely due to PharmD (not metabolic) tolerance

• Withdrawal → 50% of regular users have mild to moderate symptoms

  • cravings, anxiety, irritability, depression, “fuzzy” cognition, insomnia, reduced appetite 

Cannabis Use Disorder: Treatment Role for CB Antagonist

• CB Antagonists: potential promise for CUD

  • potentially anti-craving/relapse drug for all types of drug addiction; modulates mesolimbic system

  • uncertain future, but scientists & drug companies actively investifating as therapeutic agents

• Rimonabant → (originally anti-obesity drug) showed some success in Europe, Mexico

  • but pulled from market in 2008 due to psychiatirc side-effects (depression, anxiety)

  • never FDA approved in the US 

Cannabis Use Disorder: Treatments (most off-label)

• Withdrawal treatments: symptom specific → insomnia (e.g., zolpidem/Ambien), anxiety/depression (e.g., quetiapine/Seroquel)

• substitution treatments: CB1R agonists (synthetics, e.g., dronabinol, nabilone)

• promising relapse treatments: naltrexone, N-acetylcysteine (NAC)

  • NAC: antioxidant thought to restore Glu homeostasis, may reduce cravings, increase odds of abstinence (w/ behavioral therapy)