Short overview of some more studied plant cannabinoids. THC and CBN have similar effects with CBN requiring ~20 times higher dose for same effects although as only difference CBN molecule has 2 extra double bonds in carbon circle.
(cannabigerol) is more common in legal (very low THC%) hemp strains but CBG strongly activates adrenaline receptors by 50% at 0,2 nM concentration (THC concentrations can reach to hundreds of times higher concentrations in recreational users) while weakly blocking CB1 receptors.
Cannabidiol (CBD) is more of a antagonist to cannabinoid receptors having opposite effects to THC.
CBD and THC are almost identical molecules but in CBD one of the THC rings seems broken open with 1 extra double bond and that reduces CBD's binding capacity by ~5000 times compared to THC while also giving it reverse effect when compared to THC.
is almost identical to THC and as the main difference the carbon tail to the right is shorter by 2 carbon atoms. It seems to be antagonist to CB1 receptors although in high doses it may agonist to CB1 and CB2.
Cannabinol is one THC degradation product which is needs higher dose for effects similar with THC. Tetrahydrocannabivarin
THCV is an strong CB1 antagonist. Around 60-75 nanomolar concentration of THCV was enough to bind with half of CB1 receptors.
Summary of cannabinoid effects.
THC proportion tends to be higher in sativa strains and CBD is more common in indica strains (Image source
CB1 antagonist rimonabant
reduces the effects of cannabis. When volunteer cannabis users took
rimonabant 40-90 mg per day for 8 days then they reported up to 40%
weaker cannabis effects although the longer they took rimonabant the
less it influenced cannabis. Taking rimonabant for 15 days in row didn't
seem to cause weaker maximum effects when compared to placebo group.
Similarly CB1 and CB2 antagonist CBD seems to reduce the effects of THC
increases release of GABA unlike THC that slows the release of GABA. As
GABA can inhibit unneeded activity CBD is studied as potential
Study about gateway theory
using the testimonies of 9282 people. Mostly people had very similar
choices in the sequence of drug experiments and only 5,2% had different
order. Most start with tobacco/ethanol, then try cannabis as first
illegal substance and after cannabis other illegal stuff.
of people tried something else beside cannabis as their first illegal drug.
cannabis users had not tried tobacco or ethanol.
tried other illegal substances before tobacco and ethanol.
THC in concentration ~1,5 mg/L reduces
excitotoxicity caused by NMDA by about half. Excitotoxicity was
measured indirectly by measuring damage caused by oxygen radicals.
is needed for sensory signals to reach brain and it works by letting
calcium into the cell although too much calcium can kill cell by making
it commit suicide (plus calcium influences cell replication and other
basic vital functions). THC can defend against this effect by blocking
calcium influx into cells
In general activating cannabinoid receptors reduces calcium influx
into cells and with less calcium neurons are less likely to activate or
release neurotransmitters. THC can reduce calcium influx by about 75%
in first 10 seconds and CBD can reduce it by same amount within 2
current could be reduced by ~75% with 100 nanomolar concentrations
but THC levels in human blood could reach 750 nM and CBD concentration
in brain can reach 3000 nM.
THC (10 mg) and CBD (600 mg) have opposite effects to brains blood oxygen use and memory according to a fMRI study
. THC caused psychosis like symptoms like anxiety and difficulty concentrating while CBD worked more like anti-psychotic.
and CBD changed blood use in opposite areas and areas influenced were
entire brain cortex, hippocampus, amygdala, cerebellum and basal
ganglia. THC usually caused smaller oxygen use in these areas compared
to placebo group and CBD increased oxygen use in these areas compared to
CB1 agonists and also antagonists like CBD block dopamine
reuptake to neurons causing more free dopamine around neurons.
to cannabis starts to be apparent within 1-2 days considering how much
it effects pulse and blood pressure. Long term use reduces pulse and
is a inhibitory neurotransmitter that is released more during evening
than in morning. THC and CBD can both slow its re-uptake by half with
realistic doses. Adenosine uptake is slowed 50% with 120 nM CBD or 270
nM. Considering previously mentioned studies recreational users may get
over 10 times higher dose in brain than the dose needed for 50% uptake
inhibition. Adenosine can also block activity of immune system cells.
In practice this should make THC and CBD users sleepy or drowsy to some extent
CDB activates 5-HT1
(intense activation may cause emotions, bright colors or fractal patterns) receptors and
less so 5-HT2 (intense activation may cause LSD type melting and flowing of
objects) receptors. THC didn't seem to bind with 5-HT1.
Effects of THC and CBD on human sleep
15 mg THC eaten didn't affect sleep considering brain waves although
next morning (mental state was checked at 8.30 AM on everyone) they seemed
sleepier and had weaker memory. CBD and THC together (5 mg each or 15 mg
of each) reduced proportion of deep sleep and higher doses usually
reduced time asleep. CBD seems to disturb sleep more than THC.
Pharmacokinetics (study of how drugs spread and get metabolized in body).
Human Cannabinoid Pharmacokinetics
2-56% of THC reaches blood. This % depends on how much was inhaled and how long it's held down. Example
of THC bloods levels that varied several times probably due to
different times holding the smoke in lungs, inhalation depth or smoking
Standard joints mentioned in this study had 3,5% THC (~34 mg per joint).
of blood THC levels during smoking. THC levels increase fast within first minute.
After smoking is stopped THC blood levels fall by half every ~10 minutes.
Within a hour THC levels could decrease ~100 times.
causes slower rise in blood THC with lower maximum concentration. About 10-20% of eaten THC reaches blood.
If volunteers were given 20 mg THC (15 mg for women) in sesame oil they got maximum THC levels in blood 4-6 hours later.
THC is relatively soluble in lipids, it tends to accumulate in fatty
tissue like under skin, lungs or brain itself. That's partially the
reason why THC levels fall so fast in blood.
In general less
than 1% of THC reaches brain. If THC is injected in rat muscle then at
most 0,06% of it reach brain. Therefore if joint has 20 mg THC with
10-25% (2-5 mg) reaching bloodstream and from that ~1% (10-50
micrograms) reaching brain.
When measuring 12 dead cannabis
users the THC levels in blood were 0,2-11ng/ml and in brain 0,9-29 ng/ml. Blood
THC levels were always lower than brain THC levels and in 3 of them
blood didn't have enough THC for detection.
Although THC is quickly removed from blood it may take 5 days to get rid of 80-90% of THC in body.
If volunteers got to use cannabis strains with high THC (6-17% THC)
or high CBD content (up to 5% CBD), then they described more pleasure
with high THC strains
than with high CBD strains. Volunteers took cannabis with themselves
and it was tested for composition. CBD/THC ratios varied at least 35
times (mass of CBD was 1-35% of THC mass). All cannabis types gave user
saliva similar THC concentration (15-21 ng/L) but CBD amounts varied ~20
times (0,14-2,48 ng/L).
As one major difference 3,5 grams was on
average smoked within 11 days if it had high THC % but with high CBD strains that 3,5 g
lasted on average 25 days.
Adult mice were feeded food mixed with THC or CBD. Later their hippocampi were checked for new neurons
CBD didn't disturb learning and it doubled the amount of new (colored)
neurons. THC disturbed learning but didn't change the amount of new
Lack of CB1 receptors (usually present through entire
hippocampus) sped up division of neuronal stem cells but slowed the
differentiation speed to neurons.
is a more recently found cannabinoid receptor that was found in 1999
compared to CB1 and CB2 which got discovered around 10 years earlier.
of cannabinoid binding to GPR55, CB1 and CB2 as activators (agonists). Examples
of antagonists to GPR55, CB1 and CB2. Some shown synthetic cannabinoids
(HU210, O1602, CP55940 and WIN55,212-2) have been sold as spice mixes.
is concentration that is needed to make receptor work at 50% of maximum
speed. Emax% shows how many % this substance could increase receptor
activity. For antagonists IC50 shows what concentration is needed to
slow receptor activity by 50%.
THC activates GPR55 and CB1 with
similar EC50 (6-8 nM). 1 nM of THC is 310 nanograms of THC per litre (1
mg of THC should give 12 micrograms of THC per liter for a 80 kg human).
THC activates CB2 to same extent with about 10 times lower concentration.
required at least 5000 times higher dose to activate CB1 and CB2 to
same extent. CBD is mostly strong at blocking GPR5 activity, CB1 and
CB2 need about 1000 times higher CBD doses to slow by half. IC50 for CBD
at GPR55 is 445 nanomoles per liter but humans may use so much CBD that
their brain CBD level reach 3 micromoles per liter.
CB2 receptors on bones
outside nervous system have mostly CB2 receptors which are also on bone
cells. Bone cells also produce cannabinoids. Mutant mice lacking CB2
seems to have faster bone density loss with aging. CB2 agonist stimulate
bone cells and such substances can preserve bone density. Removal of
ovaries causes faster bone density loss but CB2 agonists can slow this
loss to some extent (25% loss instead of 40% loss).
In bones osteoblasts
build bones and osteoclasts
bone tissue. CB2 agonist speed up osteoblast division and activity
while the same substances slow osteoclast multiplication and activity.
Cannabinoid receptor concentrations
in rats. In general cannabinoid receptors are all over nervous system
but concentrations can vary ~10 times. Highest cannabinoid binding was
in basal ganglia and dopamin source substantia nigra (~6 picomoles of
cannabinoid bound with milligram of tissue protein). Other high
concentration areas were cerebellum, olfactory areas and hippocampal
areas (~4 picomoles per mg protein). Brainstem, white matter and spinal
cord tend to be with lowest cannabinoid receptor density (~0,6-2
Time for CB1 receptor binding restoration (data from mice)
were given long acting CB1 agonists including THC and their receptor
binding was measured by removing parts of brain and measuring it after
death (reason why this data wasn't and could not be legally gathered
shows how strongly does
something bind with receptor and how small dose would be needed for
receptor filling. This binding falls with excessive receptor activation with almost any receptor and that's partially reason why withdrawal effects start. To measure it THC or other binding molecules might get
radioactive isotopes so they would have some measurable radiation.
Unbound molecules get washed off and molecules bound with receptors create light signal to show in what part of tissue they remained.
Mice got their dose 2
times per day for 15 days starting from 10 mg/kg THC (humans usually
dose around 10 mg for their entire body). Dose for mice was doubled
every 3 days up to 160 mg/ per kg body weight.
Animals were killed
1, 7 or 14 days after last dose. Those tested 1 day after last dose had
binding that was 50% of normal level in striatum and in hippocampus
its receptor binding was 25% of normal level. Animals that were tested
14 days after last dose seemed to have almost normal receptor binding.
about this binding restoration. Bmax shows the amount of substance to
saturate receptors. Emax shows how many % (maximum) can receptor
activity increase above baseline with given substance.
If human receptors restore with same speed then humans may need 14 days to restore their cannabinoid receptors and cannabis sensitivity
Cannabinoids on immune system
Because cannabinoids mildly suppress immune system
, it has been tried for suppressing inflammatory diseases.
receptors are mostly on neurons but CB2 receptors are mostly on other
cell types like on white blood cells. CB2 activation with agonists can
suppress immune system by inducing cell suicide (apoptosis) and by
reducing release of signal molecules that white blood vessels use for
guidance and acitivity.
Highest CB2 density is on B cells that
work as memory cells for immune system. THC concentration below 1
micromoles per litre increase B cell division in tonsils and 1-100
micromolar concentrations reduce B cell division.
Small amount of THC can stimulate human T cells grown on
dish but higher THC doses reduced T cell reactions to substances on
Anandamide which is produced by humans could be used to slow T and B cell division and it caused some apoptosis.
CB2 antagonists can reduce apoptosis caused by THC.
Humans may get 1 micromolar concentration of THC while smoking but that may be long way from damaging dose
10 micromolar concentration was enough to cause some apoptosis for white
blood cells in spleen but 20 micromolar concentration was needed for obvious apoptosis and necrosis.
In one study volunteers smoked cannabis for 64 days
and their immune system was studied. In the beginning their T cell
seemed to reduce by half but by the end of study cell numbers had
Because CB2 agonists (including THC) can cause apoptosis of
immune system cells, it was studied as possibly help against immune
system cancers like lymphoma and leukemia
Study on mouse didn't show much help (illustration
of results). THC group got 3-5 mg THC per body kg every day for 14 days. Both groups (8 mice in each group) were injected with lymphoma cells. THC group had 25% survival rate compared to 0% survival in control group. Deaths started about day later in THC group.
THC works on cells that have CB2 receptors and many tissues don't
have these much.
Breast cancer cells have almost no CB2 receptors and
these cells are more resistant to THC. On mice THC seemed to increase
the speed of breast cancer growth by inhibiting immune system.
Cannabis has been used to treat some symptoms of multiple sclerosis
Mainly against muscle spasms and pain. Doses used by humans should be
too low to seriously affect immune system and therefore may be too small
to block the inflammation that kills myelin cells around neurons.
Multiple sclerosis patients who used cannabis had weaker memory and attention
than nonsmokers. Their test scores were 5-50% lower than nonsmokers depending on sub-test.
Anxiety and depression levels were almost identical between smokers and
Long term health effects
In study with 18 frequent cannabis users
there didn't seem to be difference between their gray and white matter in comparison with nonusers.
Summary of 31 studies
about cannabis and brain size. In general chronic cannabis use showed no visible effect on brain sizes although some found small changes in one side of brain. One mentioned study studied 12 volunteers who on average used ~1,25 g cannabis per day for 6-20 years and no significant changes were found.
Even if one study found supposed shrinking in one side of brain then other investigators usually found changes in other areas. Authors of this summary were skeptical about changes found in only one side of brain as it may be normal deviation.
Summary of 2 large studies
. In first study 45 500 conscripts were questioned about cannabis use and 15 years later they were investigated again. In second study 65 000 15-49 year old male and female volunteers were questioned about cannabis use and rechecked 6 years later. Both studies were unable to find increased death rate among cannabis users.
Lung cancer usually starts around 20 years after starting smoking so these 2 studies might have been too short.
Also cannabis use tends to decrease with increasing age and cannabis users usually smoke around 1 cannabis cigarette per day unlike tobacco users who might use tens of cigarettes every day.
World Health Organization study
countries with 85 000 people. They mostly studied alcohol, tobacco, cannabis and cocaine use.
Unlike tobacco, cannabis wasn't associated with increased death rates. There didn't seem to be connection between cannabis use and harshness of local laws. Asia had low use rates as only 0,3% people questioned in China and 1,5% in Japan admitted using it.
Cannabis can cause psychosis
in some users so ~2% of cannabis users have schizophrenia while in general population this likelihood is 1%. Already diagnosed people with psychosis and cannabis use tend to have more symptoms but also with less mood disturbances and with less negative symptoms (negative symptom=something healthy have but unhealthy don't have or have less).
THC causes symptoms of psychosis (mood and attention disturbances) in healthy people which may be caused by reduced glutamate release. Other substances that block glutamate (PCP and ketamine) also cause psychotic behavior.
Mutations in comt gene
is one testable risk factor. COMT (catechol-O-methyl transferase) degrades dopamine, noradrenaline and adrenalin removing their activity (over activity by these substance can cause psychosis like amphetamine and cocaine users may show
People with normal COMT don't seem to have much extra psychosis (chart
). People who get less active form of COMT from both parents may have 10 times higher risk of getting diagnosed with psychosis after using cannabis (without cannabis ~1% and with cannabis ~13%).
Having less active COMT seems to increase chance of hearing voices.
Comparison of cannabinoid receptors
I made a BLAST search in NCBI website with cannabinoid receptors to see what other genes they are similar with.
sometimes duplicate themselves creating several copies that start to
evolve in different directions creating several new receptor proteins or
signal molecules that may have partially overlapping functions. Almost
every neurotransmitter receptor i ever compared was similar to some
other neurotransmitter receptor. With cannabinoid receptors these
similarities seem important because they could explain why cannabis
feels like it does. This comparison can also help find out what certain kind of protein does by checking what similar proteins more known proteins usually do.
One way to compare any receptor is to go to NCBI and search proteins
because every neurotransmitter receptor is a protein.
BLAST search with human GPR55
32% identity with lipid receptor (lysophospatidic acid receptor) that may influence calcium flow and cell division,
28% identity with bradykinin B1 receptor that widens blood vessels and lowers blood pressure,
26-27% max. identity with chemokine receptors that regulate white blood cells,
identity with CXCR4 and CCR4 receptors that are needed in immune
system. These 2 are also needed for HIV to enter white blood cells
(partially reason why cannabis is sometimes studied on HIV positive
26% identity with coagulation factor II (thrombin) receptor that is needed for blood coagulation.
25% identity with mu-opioid
receptor that binds morphin and is needed for the effects of morphine. That similarity might explain why cannabis can reduce morphine withdrawal and why many cannabis withdrawal symptoms (that wikipedia mentions and that i have personally experienced) feel similar to morphine withdrawal (runny nose, insomnia, cold/hot flashes, sweating, flu like feeling, possible headache, nausea, vomiting and diarrhea).
BLAST search of human CB1
45% identity with CB2 receptor.
31% identity with sphingosine receptor 1 that binds cells to each other within blood vessels.
29% identity with alpha adrenaline receptor.
identity with adenosine, ACTH and melanocortin receptors (adenosine
inhibits activity and other 2 are stress hormones). Same % with LPA
receptor that stimulates cell multiplication.
27% identity with serotonin 4 receptor (5-HT 4).
Most similarities were with stimulating receptors.
BLAST search for human CB2
(almost identical results to CB1 search):
45% identity with CB1,
28% identity with sphingosine receptor,
~25-28% identity with alpha/ beta adrenaline, LPA and melanocortin receptors.
I have had several experiences with cannabis.
first time with weed was with small dose of some relaxing strain. I
felt peaceful and happy with some memory problems. With that dose it was
not hard to pretend being sober.
Next try was completely
different. This time i had 0.5-1 gram and i decided to start with about
quarter of it. That strain seemed to be way more stimulating and
impossible to hide. I felt like on a roller coaster with intense
emotions and almost shaking body. It didn't feel like anything in movies
where someone keeps smoking and smiles calmly. Most later experiences
tended to have this stimulating, often panicky, feeling.
say cannabis doesn't work on them but that doesn't make much sense.
People have cannabinoid receptors and there don't seem to be
exceptions. I have personally seen such "immune to weed" people. They said
it doesn't work on them in first 15-30 minutes but they can look obviously
stiff. With cannabis spontaneous movements need constant concentration
and other times body gets frozen in some random position with arm
usually close to chest. Instead of being immune to cannabis some people
probably just have some serious case of poor self-awareness.
matter which strain i used (sativa or indica) they always caused
symptoms of low acetylcholine levels (weak memory, dry mouth, dry skin
and fast pulse), and more positive/negative emotions.
caused memory blackout. Memories of events are much fuzzier but more
notable events stay in memory. Movements tend to become stiffer and more
difficult to start. Tolerance develops fast and is usually obvious by
second day but even within the same day small loss of maximum effects
becomes noticeable .
Other common symptoms tended to be more strain dependent.
of panic inducing sensory overload is likely, especially when outside.
For example i was once biking next to a city street with heavy traffic
but several meters wide grassy zone to separate it from bikers road.
During that ride almost every car seemed to be somehow overwhelming and
main word that kept repeating in my head was that it was like a sensory
overload with awareness of passing cars capturing all the attention it
could while i was trying to concentrate on not hitting anyone or
I don't remember any hallucinations. Closest
thing to hallucinations is seen in periphery of vision. Everything looks
foggy in peripheral vision and if high those foggy things may be
mistaken for something else.
While watching TV shows:
almost never particularly liked scenes in movies or series with
cannabis jokes. Mostly these scenes just make me want to smoke again
when i'm not high making abstinence more difficult but they feel
unrealistic or over-glorifying weed when i'm high.
If the smoking went on for long time then this state becomes numb, emotionless feeling no matter how much extra i smoke.
Dopamine effects seem strong. Things may become interesting and foods may become tasty but with stressed high many foods can also look creepy if it can still remind the animal part it was made out of.
Emotions of day fade away fast. As more negative side effect good mood also tends to fade
away. Socializing becomes more difficult with that because moods
disappears fast and soon i kinda wake up and think how to end the
awkward silence. With enough dosage sentences devolve into single words (with muscle control to say only part of that word) without short term memory to add several words in row.
on sedative cannabis strains tended to cause increasing sleepiness with
slow and shallow breathing. Over-smoking on sativa strains caused
increasingly panicky feeling and everything becomes overwhelmingly
stressful. Often the only solution was to turn off sound on computer
because every noise became extremely emotional.
reason why i trust people with weed is that it probably makes them too
scared and stressed to take any additional risks. Even walking between
rooms or filling pipe can become complex.
I only noticed withdrawal when dosage got over 0,5 grams per day. Anxiety and hot/cold flashes become more common.
On next day calming strain caused anxiety, nausea and stressed feelings. If they created feeling of relaxed body then the aftereffects were among worst because next morning started with tensed unrelaxed muscles that wake me up hours earlier than i should. If weed didn't cause relaxed body then withdrawal was way more comfortable.
sativa causes emotionless calm physically more pleasant (mostly neutral)
aftereffects with stress resistance and bravery.
Some personal effects could be explained by 3 neurotransmitters.
THC can increase glutamate and dopamine levels while reducing concentration of GABA in prefrontal
cortex (place for concentration, emotionality and short term memory).
is common throughout nervous system being needed for having sensory
experiences, memory and consciousness in general. As one side effect
cannabis does work like sensory pathways and consciousness are working
with extra power (possible reason why THC can cause feelings of sensory
overload). Dopamine participates in staying mentally and physically
active. It might be seen with cannabis when thoughts keep going from one
thing to other for first couple of hours until brain becomes too tired
and no amount of weed can keep the train of thoughts going.
is the main inhibitor in brain. THC seems to reduce it's levels and it
might explain why THC can cause feelings of sensory overload. Part of
prefrontal cortex (part on top and sides of head but not between
hemispheres nor under prefrontal cortex) participates in remembering
recent events and items. If that part gets overactive due to lack of
GABA then it may start to notice and remember stuff way more easily but
because short term memory has very limited memory it also forgets stuff