cannabinoids, hallucinogens, and antidepressants

forms of Cannabinoid with highest THC levels

• hashish/kief - dried resin of flower tops of mature and unpollinated female plants

• charas - type of hashish in india/jamaica

forms of cannabinoid with mid THC levels

• ganja - dried buds on tops of female plants (mixture of bud and kief so less potent than straight kief

• sinsemilla - dried buds on tops of female plants that are denied fertilization → increased THCa levels = more THC than ganja

forms of cannabinoid with lowest THC levels

• marijuana - dried remainder of plant (no bud)

• bhang - food/drink infused with ground marijuana paste

synthetic cannabinoids

• dronabinol - THC pill to increase appetite and decrease nausea for cancer and AIDs pts → drawbacks bc of oral ingestion (vomit b4 pill works, 1st pass metab so can’t control dose, only has THC while real weed has 100s of compounds)

• K2/spice - synthetic THC sprayed onto dried plant matter

endocannabinoids

anandamide (AEA) and 2-AG

endocannabinoid mechanism of action

• not stored in vesicles bc too lipid soluble → produced on demand

• move retroactively - released from post synaptic terminal and bind to CB1 receptors onthe pre synaptic terminal of some NT to decrease further release of that NT

THC mechanism of action

partial agonist at CB1 and CB2 receptors → partial so not as big effect as real endocannabinoids

mechanism of action of CBD

• negative allosteric modulator of CB1 receptor DOES NOT BLOCK→ CBD bind at allosteric site on CB1 and decreases THC binding/signaling

• inhibits breakdown of endocannabinoids

• activates 5-HT1a receptors (serotonin 1a receptors)

• activates TRPV1 receptors, influences mu opiod receptors (it’s involvement in anti-inflammatatory has to do w this mechanism)

GENERAL hallucinogen mechanism of action

work within pyramidal cells in 5th layer of the prefrontal cortex

• directly activates 5-HT2A receptors in PFC

• indirectly activates PFC cells by releasing glutamate from pyramidal cells

types of hallucinogens with GENERAL MECHANISM

• mescaline (peyote) - top of cactus (button)

• NBOMES - very potent synthetic; on blotter papper/powder → usually sublingual/buccal

• psilocybin - mushrooms (psilocybin converted into psillocin)

• bufotenine (5-hydroxy-DMT) - venom from toad skin dried then smoked

• Ayahuasca/DMT - several diff. plants boiled → DMT present and HArmine is MAO inhibitor that allows oral ingestion

• DMT (businessman’s special) alone - same mix of stuff but no oral ingestion

• LSD - fungal alkaloids → oral

which hallucinogens have different mechanisms?

• MDMA (ecstasy)/ Molly

• Salvinorin A (salvia)

• Ibogaine

• Ketamine/PCP

MDMA Mechanism of action

synthetic! oral ingestion → Molly = pure crystal form

• increases serotonin, NE, and dopamine

  • blocks and reverses serotonin, NE, and dopamine transporters

  • inhibits monoamine transporter (VMAT)

Salvia mechanism of action

mexican sage plant leaves chewed, brewed, or smoked

• very selective kappa opiod receptor agonist

Ibogaine mechanism of action

west african iboga shrub; oral

• kappa opiod receptor agonist

• low affinity for 5-HT2A receptor (same as general but much less; not main mech)

Ketamine/PCP mechanism of action

PCP mostly smoked; Ketamine mostly inject, snort, or smoked but NO oral bc no psychedellic effect

• INHIBIT NMDA receptors (2nd block in addition to the Mg2+ block already there)

  • block open channel by binding site inside receptor

  • allows channel to open less by binding 2nd site outside receptor

MDMA therapeutic potential

reopens critical period → rat social personality switch paper

ibogaine therapeutic potential

possible treatment of opiod addiction

ketamine therapeutic potential

Esketamine - helps treatment-resistant major depressive disorder

BDNF theory of depression

childhood trauma is correlated with lower hippocampal volume and low hippocampal volume is correlated with depression

• when you’re stressed, there are high glucocorticoids present, which lowers BDNF in brain → decreases dendritic branches and spines in hippocampus

Monoamine hypothesis of depression

depression is caused by decreased monoamine function

• reserpine (hypertension drug) induced depression in patients → drug worked to block VMAT which lowers monoamines (can’t be packed into vesicles so break down)

why do antidepressants take long to work

antidepressants block reuptake and increase serotonin, but high serotonin triggers autoreceptors and decreases further synthesis and release of serotonin → autoreceptors must be desensitized over time for them to start working

monoamine oxidase inhibitors

block MAO which breaks down monoamines

Tricyclics (TCA)/ SNRIs

inhibit reuptake of 5-HT AND NE

SSRIs

inhibit 5-HT reuptake

3rd generation antidepressants

ketamine and lithium carbonate

lithium carbonate mechanism of action

used to treat bipolar disorder

• increases serotonin, tryptophan, and 5-HIAA to increase serotonin release

• decrease catecholamine activity by increasing reuptake and decreasing release