Psychopharm Marijuana

Phytocannabinoids

120 unique compounds found in the cannabis sativa hemp plant—two are THC, and CBD

THC

Delta-9 tetrahydrocannabinol. The addictive compound in marijuana.

Hashish

very concentrated resin can be eaten or smoked--popular in Middle east

Dabbing

extraction of cannabis with butane through evaporation, leads to high concentration. Vaporized and inhaled

Half-life of marijuana

20-30 hrs

Significant marijuana metabolites

TCH-COOH, 11-hydroxy-THC

Cannabinoid receptor locations

basal ganglia, (including globus pallidus, putamen, caudate nucleus, substantia nigra, cingulate gyrus)

cerebellum

hippocampus

cerebral cortex

also in endocrine and immune systems, heart, liver, GI tract, bone, fat, lungs, and gonads

CB1 receptors

in the central nervous system

CB2 receptors

in the immune system and rest of body—and some in DA neurons in VTA. Largely responsible for behavioral effects of TCH

CB receptor action

Metabotropic—acts on Gi and Go protein-coupled receptors which inhibit cAMP and thus voltage-gated Ca2+ channels stay closed, K+ channels open——→ hyperpolarization (inhibition)

Cannabinoid changes in gene expression

THC activates MAP kinase which causes epigenetic changes in future gene expression for plasticity, learning, memory, and future THC use

Selective CB1 antagonists

Rimonabant is a selective CB1 antagonist that is used in research and has therapeutic potential in obesity and substance use disorders.

AM251 very similar.

THC behavioral effects

-reduced locomotor activity

-hypothermia

-catalepsy (muscle rigidity, mobility loss)

-hypoalgesia

-Biphasic effect on anxiety (anxiolysis in low doses, anxiogenesis at high doses)

-Disrupted memory retrieval

THC’s mechanism of anxiolysis

occurs at low doses: activates CB1 receptors on Glutamatergic neurons, inhibiting its release

THC’s mechanism of anxiogenesis

occurs at higher doses: CB1 activation on GABAergic receptors, inhibiting it’s release

THC’s mechanism of disrupting memory

activation of CB1 receptors in hippocampus results in inhibition of LTP in the dorsal hippocampus by reducing oscillatory gamma and theta electrical activity

CB2 receptors effect on immune system

when activated, they inhibit cytokines (immune cell signalers) that alter the way cells move to an area of inflammation

CBD possible neurochemical function

—allosteric modulator of the CB1 receptor, binding to a site on the receptor and antagonizing the positive effects of CB agonists when they bind

—inhibits breakdown of endogenous cannabinoids, enhancing their activity

—activates serotonergic receptors, contributing to anxiolytic effects

—Allosteric enhancement of glycine receptor activity

—Adenosine reuptake inhibitor

Endocannabinoids

endogenous cannabinoid-like lipids that bind to and activate CB1 receptors:

1) Anandamide (AEA)

2) 2- Arachidonoylglycerol (2-AG)

Synthesis & release of endocannabinoids

triggered by Ca2+ levels as a result of Ca2+ channels or NMDA channels opening, or activation of intracellular Ca2+ sites because of a 2nd messenger system

Metabolism of endocannabinoids

just for Anandamide: FAAH

just for 2-AG: MAGL

metabolizes both: COX-2

Retrograde signaling

a messenger molecule (in this case 2-AG) travelling in reverse from post-synaptic cell to pre-synaptic and inhibiting neurotransmitter release. occurs in hippocampus, striatum, and cerebellum

Peak intoxication

occurs when THC levels are already declining in the blood, indicating that THC brain vs plasma concentrations are not equal at the time of high

Acute adverse effects of THC

mostly occur with non-regular users or at high doses:

-anxiety

-psychotic symptoms (depersonalization, derealization, paranoia, etc)

-insomnia

-depression

-tachycardia

-GI issues

Reason for low reward-reinforcement

THC is only a partial agonist of the CB1 receptor,

Cognitive deficits from acute use

-illogical/ disordered thinking\

-fragmented speech

-concentration/focus issues

-learning and memory impairments

-reduced reaction time

-reduced ability to divide attention

-gaps in critical tracking

Learning & memory under THC

deficits most implicated in chronic use, from excessive GLU release—> NMDA overactivation. It can be prevented with CBD pretreatment before THC

Energy effects of THC

increased energy

THC & reward

less rewarding than some psychoactive drugs because it is only a partial agonist of the CB1 receptor—however, still activates the mesolimbic DA pathway and causes DA firing in VTA and NAcc

Marijuana use statistics

5-10% of those who try develop persistent use.

Most users start in adolescence and use peaks in young adulthood. Those who have not tried marijuana by mid-20s will likely never start

Characteristics of adolescents who use THC

-low behavioral control

-sensation seeking/ impulsiveness

-high autonomy

-low academic motivation

-rebel against authority & conduct issues

Later in life, achieve lower academic level, and occupational prestige/income

Risk factors for CUD

1) starting before 16

2) frequency of use

3) co-use w/tobacco

4) Gender (men more likely to have, women experience worse symptoms and quicker progression)

5) Legal status of cannabis

6) Genetics (50-60%)

7) Major life stressors/ comorbid disorders

THC tolerance

decreasing sensitivity to these effects:

-acute intoxicating/euphoric effects

--cognitive impairment

—anxiogenic effects

—physiological symptoms (e.g. tachycardia)

Effect of tolerance on receptors

chronic use (daily for 3 weeks) resulted in DOWNREGULATION of CB1 receptor density and desensitization of remaining receptors leading to reduced activation

Relationship between tolerance and withdrawal

intensity of withdrawal symptoms is negatively correlated with magnitude of receptor binding—so the more desensitized CB1 receptors have become, the worse withdrawal will be

Effect on other neurotransmitters

significantly reduced glutamine levels

reduced striatal DA synthesis and decreased DA response

Withdrawal symptoms

psychological:

-irritability/ aggression

-anxiety

-depressed mood’

-insomnia

-decreased appetite

Physical:

-abdominal pain

-tremors

-sweating/ fever/ chills

-headache

-cannabis craving

Reduced gray matter from THC

-orbitofrontal cortex

-Temporal lobe

-hippocampus

-amygdala

Increased gray matter from THC

in cerebellum

Chronic THC effects on dendrites

dendrites in PFC & NAcc significantly shortened

Negative health effects

chronic use—→ issues with cardiovascular, reproductive, and immune systems