Marijuana and Cannabinoids

how is marijuana produced?

from the flowering hemp, Cannabis sativa

what was hemp historically used for?

major source of fiber for making fishing nets, rope, cloth, and paper

phytocannabinoids

compounds with a cannabinoid structure that are found in the cannabis plant

9-tetrahydrocannabinol (THC)

psychoactive chemical found in cannabis plants

Cannabidiol (CBD)

phytocannabinoid that lacks the intoxicating and dependence-producing effects of THC

desired effects of cannabis

• mild euphoria

• relaxation

• altered perceptions

• enhanced awareness

• creativity

side effects of cannabis

• bloodshot eyes

• dry mouth

• reduced memory

• sluggish motor coordination

• sluggish mental functioning

• anxiety, paranoia

compared to other drugs, how is cannabis compared in tolerance, dependence and fatality?

very low to moderate

the buzz

initial phase, feel lightheaded and the effects of the cannabis

the high

feeling of euphoria or exhilaration, disinhibition

stoned phase

chill, calm, relaxed or dream-like state, distortion perceptual sense such as in colors sounds or time

the come down

period where you come back to your baseline, depends on how much you consumed and individual factors such as metabolism

what are the three plants named in lecture that is often referred to as Cannabis?

• cannabis sativa

• cannabis indica

• cannabis ruderalis

marijuana

• derived from mexican word maraguanquo

  • usually a mix of dried leaves and flowering tops

how many phytocannabinoids does the cannabis plant have that can bind to cannabinoid receptors?

120

what type of properties does CBD have?

• antioxidant

• anticonvulsant

• anti-inflammatory

• antianxiety

• antipsychotic

• neuroprotective

how does the amount of THC vary?

• type of cannabis plant

• growing conditions of plant

• timing of harvest

• age of plant

• storage of dried leaves

which continent has the lowest cannabis use

Asia

which continents have the highest amount of cannabis usage?

North America and Australia

hashish

type of potent cannabis derivative that is smoked or eaten

most common form of administration of marijuana?

smoked or ingested

is THC water or fat soluble?

water-soluble and therefore cannot be injected

oral consumption of cannabis

prolonged but poor absorption of THC, resulting in low and variable plasma concentrations

where does THC travel through the blood and distributed to which areas of the body?

• deposited in fatty tissues and the brain

• accumulates in lungs, liver, kidney, spleen, adipose, and testes

metabolism of cannabinoids

• mostly occurs in the liver

• over 80 identified metabolites

  • some can inhibit CYP450 enzymes, resulting in possible cannabis-drug interactions

elimination of cannabis from the body

• metabolites excreted in the feces and urine

• THC has long half-lives - may remain in body for many days/weeks after use

where are endocannabinoid receptors found?

GABA neurons and glutamate neurons and glial cells

where are the highest density areas of CB1 in the brain?

high expression in basal ganglia, cerebellum, hpc, ctx

where are CB2 usually found?

immune system and brain (including microglia)

what does CB1 activation affect?

• anxiety

• anxiolysis at low doses

• anxiogenesis at higher doses

what does CB2 activation affect?

immune system causes cytokine release

are cannabinoid receptors ionotropic or metabotropic?

metabotropic, G-protein coupled receptors

where are CB1 receptors primarily located?

axon terminals as presynaptic receptors on GABA or glutamate neurons

what type of effect does presynaptic CB1 have on transmitter release?

inhibitory

what are the two main endocannabinoids?

• arachidonoyl ethanolamide (AEA) or anandamide

• 2-arachidonoylglycerol (2-AG)

anandaminide (AEA)

• discovered in 1992

• partial agonist at CB1

• in healthy subjects, AEA levels in the brain are very low

• has very short half-life (~2min) due to fast degradation by fatty acid amide hydroxylase (FAAH)

• the functional significance of AEA remains unclear

2-AG

• discovered in 1995

• full agonist at CB1 and CB2

• in healthy subjects, 2-AG levels are high in the brain

• degradation by and monoacylglycerol lipase (MAGL)

retrograde signaling

• the most common mechanism of eCB action

• presynaptic CB1 receptors activated by 2-AG; inhibit Ca2+ - mediated NT release of presynaptic cell

TRPV1 receptor

nonspecific cation channels that regulate pain processing, mood, motor function and learning/memory ‘

eCBs activate receptors on astrocytes do what?

causes glutamate release

THC is what type of agonist?

partial, and has a high affinity for CB1 receptors

CBD acts with which receptor

• only CB2

• on its own it isn’t an agonist,

• suggests that it is a negative allosteric modulator of the CB1 receptor, causing antagonistic effects

rimonabant

first selective anatagonist for CB1

how does rimonabant affect CB1 receptors in the hippocampus?

blocks the effects of a CB1 agonist, reducing memory impairments

eCBS normally stimulate what through CB1 receptors?

appetite, mood regulation, and reward signaling

• rimonabant has appetite suppression effects

what are some serious side effects for rimonabant?

• severe depression

• anxiety

• suicidal ideation

physiological effects if cannabis?

cardiovascular effects

• increased HR

• increased blood flow to skin, flushing

• bloodshot eyes

pulmonary effects

• brochodilation

• long-term use

dry mouth and throat

behavioral and cognitive effects?

• relaxation, mood life

• slowness - slowed cognitive processing, impaired memory, reduced ability to concentrate, fatigue, tiredness, confusion, slowed sense of time

• increase appetite

• less common:

  • increased awareness of sense

  • closed-eye visuals

  • anxiety/paranoia

  • inability to sleep

cognitive effects

• impaired learning and memory

• impaired attention and concentration

• impaired inhibitory control and other executive functions

• impaired psychomotor function

reinforcing effects are due to increase of what?

dopamine release

what percentage of individuals that use cannabis become dependent on it?

10%

factors contributing to development of cannabis use disorder:

• early onset of use

• genetic factors

• behavioral factors - e.g., coping strategies, concurrent use with tobacco

• psychological factors - e.g., comorbid psychiatric disorder such as ADHD

people who are more dependent and stronger withdrawal symptoms have how much receptors

not as many CB1 receptors

common withdrawal symptoms

• irritability

• depression

• insomnia

• weight changes

• flu-like symptoms

• anxiety

amotivational syndrome

• chronic state of apathy said to be seen in regular marihuana users even when not high

• symptoms: aimlessness, passivity, lack of communicativeness, lack of ambition, decreased productivity

effects of chronic cannabis use

• decreased functional activation

  • attention processing

  • decision-making, reward valuation

  • attentional processing

what systems are affected from repeated exposure to cannabinoids?

• glutamatergic

• GABAergic

• DAergic

effects on sex and reproduction

• animal studies have shown THC disrupts the menstrual cycle in females and causes reduced circulating testosterone in males

• chronic use is associated with negative effects on male fertility including decreased sperm count and decreased sperm motility

• THC can cross the placental barrier and can be found in breastmilk