3. Cannabis

Cannabis

plant (Cannabis sativa)

active ingredients called cannabinoids

tetrahydrocannabinol (THC) most common class

delta-9-THC (9THC) - most common

cannabinol (CBN) and cannabidiol (CBD)

oral, burning (CBD-> △9THC)

3 species which cannabis sativa (taller longer to mature, and higher in THC, lower in CBD) and cannabis india shorter, bushier, higher in CBD, more sedating 

Forms of Cannabis

-Marijuana

-Hashish

-Hash Oil

-Synthetic

marijuana

(dried leaves and flowers)

Smoked, baked into brownies or cookies

60s: 1.5% THC

80s: 3.0-3.5 % THC

90s: 5.4% THC

2008: 10% THC

most common form in north america. the content of thc has grown over the years.

Hashish

(dried resin from female plant)

Smoked, baked in candies or cookies

cannabinoids are highly soluable in ethanol. boil the hashish in alcohol

Hash oil

60% cannabinoids)

Boiling hashish in alcohol, filtering out

residue, evaporating alcohol Colour related to purity

Synthetic

Nabilone, Marinol

Used to treat chemotherapy-induced nausea

also used for anorexia because it stimulate the appetite. and weight loss because it can satate patients.

Cannabis Absorption

weak acid, pKa of 10.6 extremely lipid-soluble, (little water)

oral - absorbed slowly because of poor dispersion

peak effect after 1 to 3 hrs and may last 5

very little is ionized in the intestine therefore absorbed well

bcuz not much reaches the intestinal wall. you bake it in something that has a lot of oil to increased the dispersion. more likely to be absorbed in the intestine.

Inhalation of Cannabis

smoking, efficient, 10- 25% from joint

effect in a few minutes and peak 30-60 min.

vaporizer heats the plant to a point where cannabinoids reach boiling point and can inhale vapor.

-deep draws on the marijuana cigarette and hold the smoke in the lungs

-It appears that the depth of an inhalation is much

more important than the duration in determining THC

absorption

distribution of cannabis

the cannabinoids are distributed to all areas of the body according to blood flow but tend to become concentrated in the lungs, the kidneys, and the bile of the liver. Only about 1% of the administered dose at peak blood concentrations actually enters the brain.

Metabolism of cannabis

• △9THC -> 11-hydroxy-△9THC

• CBD blocks the metabolism of △9THC

• CBN speeds metabolism of △9THC

• CBD and CBN compete with THC for protein-binding in blood [increasing the amount of THC available for distribution to the brain]

• two phase removal: rapid (30 min half-life) then slow (20-30 hr half-life) [the rate of metabolism is limited by the rate at which the THC is released from body fat into the blood, which is quite slow.]

Traces may be detected in the body as long as 30 days later] turned into less lipid soluable metaboites which makes them easier to excrete

Delta-9-THC is converted primarily into 11-hydroxy-delta-9-THC

• △9THC -> 11-hydroxy-△9THC

• more active and gets into the brain (BBB) easily

• rapidly converted

-These substances are then rapidly converted into

more than 100 other metabolites, some of which may

have effects of their own

-Most of these metabolites are less lipid soluble and are more easily excreted

Neurophysiology of Cannabinoids

cannabinoid receptors

both activate cAMP response (2nd messenger) [metabotropic receptors that use camp as 2nd messenger]

found mostly on terminals (neuromodulators - enzymes to destroy in postsynaptic cell)

alter wide variety of neurotransmitters

receptors nucleus accumbens. activate mesolimbic dopamine system

endocannabinoids bind to CB1 and CB2

THC has a greater effect than the endocannabinoids

Function hypothesis: anandamide receptors involved in stress recovery -- "relax, eat, sleep, forget and protect"

cannabinoid receptors location

(CB1, CB2 )

cortex, hippocampus, cerebellum and basal ganglia (CB1); periphery (spleen, CB2)

CB2 receptors are found primarily in the spleen and the immune system. CB2 receptor is found in the brain as well

found mostly on terminals (neuromodulators - enzymes to destroy in postsynaptic cell)

depolarization -> postsynaptic release -> block arriving action potentials

when the membrane of the postsynaptic cell is depolarized, this triggers the release of an endocannabinoid that acts at the CB1 receptors on the presynaptic membrane, causing ion channels to open and consequently blocking the action potentials as they arrive.The result is that the presynaptic neuron is disabled. Thus, the postsynaptic neuron is able to shut down the presynaptic neuron. If the neurotransmitter released by the presynaptic neuron is inhibitory, the result is depolarization-induced suppression of inhibition (DSI). If the transmitter is excitatory, the result is depolarization-induced suppression of excitation (DSE)

endocannabinoids bind to CB1 and CB2

anandamide and 2-arachidonoylglycerol (2-AG) [plus others]

anandamide is present in chocolate and cocoa with two other similar chemicals that may act as cannabinoid mimics

Effects of Cannabis

 low to moderate doses:

 blood-shot eyes (dilation of blood vessels in the whites of the eye)

 dry mouth and compulsion to drink

 feeling of hunger that peaks 3 hrs after smoking (shows tolerance after 3 weeks of continuous use)

 increase in heart rate

 nausea and vomiting can develop if subject is moving

 high doses may cause headaches.

shipping chips to the border to help ppl with the munchies

Effects of Cannabis

sleep

low to moderate doses -> drowsiness and increase sleeping time.

high doses ↓ REM stage and ↑ stage 4

but higher doses can interfere with sleep,

causing restlessness and insomnia

effects of canabis

medicinal effects:

 treat Glaucoma

 antiemetic (stops nausea and vomiting)

 Movement and Spasticity Disorders

 multiple sclerosis, epilepsy, spinal cord injury

 Pain: CNS pain centres are less responsive to

pain after cannabinoid administration

cannabis treats glaucoma

a condition in which pressure in the eyes is too high, has been successfully treated with marijuana as THC reduces that pressure.

cannabis is an antiemetic (stops nausea and vomiting)

THC can act as an antiemetic (a drug that stops nausea and vomiting). Nabilone and Marinol are now frequently used to treat the nausea and sickness of people receiving chemotherapy for cancer.

cannabis treats movement disorders

THC has been shown to be effective in treating

movement disorders and spasticity. People with damaged spinal cords and people

suffering from diseases like multiple sclerosis often

experience uncontrollable muscle spasms, loss of mo-

tor control, and pain.

cannabis helps treat pain

CNS pain centres are less responsive to pain after cannabinoid administration

As effective as morphine at reducing pain responses in rats

Blocking CB1 spinal cord receptors increases sensitivity to pain

CNS neurons in pain centers become less responsive

to pain-inducing stimuli after administration of syn-

thetic cannabinoids (Martin et al., 1976). Also, blockade

of CB1 receptors in the spinal cord increases sensitiv-

ity to pain

Cannabis

Effects on Human Behaviour

euphoria to placid dreaminess

sensitive to the mood of others present

avoid effort (prefer tasks where they remain passive)

some control - behave normally if desired

no evidence enhances sensory experience or creativity

'temporal disintegration'; inability to retain and coordinate information for a purpose.

attention reduced

temporal disintegration

they lose the ability to retain and coordinate information for a purpose

for people under the influence of cannabis to start a sentence and then stop halfway through because they forgot what they started to say.

Some users have described this inability to hold things

in short-term storage

Cannabis

Effects on Non-Humans: non-conditioned behaviour

taming effect

decrease in food intake

does cause increased preference for sweet sugar solutions.

THC analgesic effects as potent as morphine, CBN as aspirin

The metabolites of THC are probably more potent than their parent compound.

Cannabis

Effects on Non-Humans: conditioned behaviour

interfere with tasks requiring short term memory or timing

poor on radial maze and matching-to- sample task

correlated with suppression of firing of hippocampal cells

Decreases avoidance at doses that do not alter escape.

No increase in punished responding

-common effect shared with the tranquilizers, anesthetics, and alcohol. One might expect that a drug that has both anxiolytic and analgesic effects would increase punished behavior, but neither delta-9-THC nor a similar cannabinoid, delta-8-THC, appears to increase behavior suppressed by punishment with electric shock

Cannabis

Dissociation

symmetrical dissociation

same with humans learning but prompting overcame problem

one study found evidence of asymmetrical dissociation

Both delta-9-THC and delta-8-THC cause dissociation in rats. Rats were unable to transfer to a nondrug state what they had learned in a drug state, and there was a symmetrical inability to transfer to the drug state what they had learned in the nondrug state Dissociation has also been demonstrated in humans using marijuana

Cannabis Dicrimination

rats can discriminate △9THC from placebo and generalize to △3THC and 11-hydroxy-△9THC , some to CBN but not to CBD

partial generalization to sedative drugs but not others, and only to high doses of anandamide

animals trained to discriminate THC generalized poorly to anandamide and then only when anandamide was given in high doses

Cannabis

Tolerance

disruption of operant behaviour of laboratory animals (within 5-6 days, lasts a month)

no tolerance to anorexia or discriminative stimulus effect

tolerance to lethal effects in pigeons

is not metabolic, but seems to be related to a reduction in number of CB receptors

no evidence of reverse tolerance

tolerance for subjective effects of THC after both high and low doses given 4 times a day over 4 consecutive days.

Cannabis

Withdrawal

no symptoms after chronic usage at low to moderate doses (1 marijuana cigarette per day for 28 days)

high doses can lead to withdrawal symptoms

- hot flashes, sweating and loss of appetite

Withdrawal symptoms have been seen after prolonged

administration of high doses in nonhumans. peaked between days 2 and 6. Withdrawal symptoms with the greatest severity generally included appetite change, restlessness,

Cannabis

Self-administration

Laboratory animals - Yes, but there are few demonstrations. Probably due to route of administration. Has been shown with WIN552-12 (water soluble synthetic)

humans will (steady amounts)

Cannabis

Harmful Effects

most studies, THC does not effect or lowers incidence of violence

large doses may cause adverse acute psychotic reaction or freakout [a panic that produces positive, negative, and cognitive symptoms.]

possibility that marijuana could precipitate schizophrenia in predisposed people.

Amotivational syndrome Data contradictory in studies with humans.

high levels reduce:sperm production and mobility, and testosterone (significant?)

marijuana use not associated with low birth weight or prematurity

reduces activity in the body's immune system. [reduce organ rejection and reduce arthritis which are both caused by overactive immune system]

Smoke contains higher % of cancerous material than tobacco smoke, but smoke less.

cannabidiol and THC are potent antioxidants

Cannabis harmful effects -Permanent Intellectual Impairment

and Brain Damage

long-term heavy use -> cannabis dementia

one study found shrinkage of the brain with the same loss of functions associated with chronic alcohol usage

monkeys (4-5 low to moderate joints/day for a year - 7 months after exposure - nothing

heavy use may cause subtle impairments of memory and higher mental functions - may be reversible.

no detectable difference in behaviour and brain anatomy

found that, although heavy cannabis users scored significantly below controls on cognitive tests on days 0, 1, and 7 of cannabis abstinence, by day 28 there were virtually no differences between the two groups on any cognitive tests.

amotivational syndrome

(monkeys) lowered breaking points on

a progressive ratio for food.

stepping stone hypothesis

gateway drug

e.g. virtually all heroin users had used marijuana before they adopted heroin do not prove causality

progression hypothesis

need "harder" drugs

but continue to use marijuana as well

two social factors may explain

correlation

1. provides the social setting

2. personality trait of curiosity is cause

if you smoke marajuana you are more curious about drugs. more interested in trying