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Monday, May 14, 2012

Cannabis


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.
CBG (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.

THCV 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.
CBD increases release of GABA unlike THC that slows the release of GABA. As GABA can inhibit unneeded activity CBD is studied as potential anti-epileptic. 

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. 
3,7% of people tried something else beside cannabis as their first illegal drug.
1,6% cannabis users had not tried tobacco or ethanol.
0,8% 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.
NMDA 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 minutes (illustration).
Calcium 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.
THC 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 placebo group.

CB1 agonists and also antagonists like CBD block dopamine reuptake to neurons causing more free dopamine around neurons.

Tolerance 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 blood pressure.

Adenosine 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.
With smoking 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 speed.
Standard joints mentioned in this study had 3,5% THC (~34 mg per joint).  
Image 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.
Eating THC 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.
Because 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 and appetite 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 neurons.  
Lack of CB1 receptors (usually present through entire hippocampus) sped up division of neuronal stem cells but slowed the differentiation speed to neurons.

GPR55 is a more recently found cannabinoid receptor that was found in 1999 compared to CB1 and CB2 which got discovered around 10 years earlier.
Examples 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.
EC50 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.
CBD 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.
Tissues 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 remove 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 picomoles -,,-). 

Time for CB1 receptor binding restoration (data from mice)

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 from humans).
Receptor binding 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.
Chart 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.
CB1 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 bacteria.  
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 normalized.  
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 nonsmokers.

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 in 17 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. 
Genes 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,
~26% 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 patients). 
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.
28% 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.

Personal notes

I have had several experiences with cannabis.

My 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.

Some 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.

Common effects:
no 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.
It never 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.

Feeling 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 anything.

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:
I 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.


Over-smoking 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. 

One 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.

Withdrawal:
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.
Paranoia causing 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).
Glutamate 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.
GABA 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 fast.

6 comments:

Anonymous said...

It was said that CBD didnt disturb learning and even doubled new cell growth. So when it comes to high CBD strains, are there still negative side-effects to smoking cannabis like memory loss? What should be the relation between THC and CBD, so that I could enjoy the effects of THC but have CBD counter it´s negative side effects?
That and the feeling of laziness are the 2 things that stop me from smoking as much as I would like. I´m trying to find out, if there is a strain, that would make you feel reaaaaally high but wouldn´t weaken one´s memory and learning ability.

Great reading though, time well spent..

Thank You!

Author said...

I get poor memory with all types although high CBD strains that make me sleepy seem to retain memory and ability to think somewhat better. Enthusiasm and motivation seem to come more from high THC strains that can make me very anxious.

I don`t know about THC and CBD % but i have often owned both types so if i get too tired i could get high THC strain and if i get too panicky i could take some high CBD strain.

Anonymous said...

Any information about the relation between cannabis use and amotivational syndrome? Quick search in google told me that its "scientifically not proven", but users reports claim it to be real. I´m also curious about the permanent changes in the brain after long-term use.

Thanks

Märt said...

Sorry for the delay. I didn't get notifications about new comments. I too feel more bored/apathetic about most stuff the day after smoking but i can still easily motivate myself to do anything i think is important. I don't know about any serious long term effect on brain. I haven't found pictures about brain shrinking due to that and if anti-cannabis activists would have found any such photo they would have had used those pictures for long time.

Harry said...

That chart with all the different cannabinoids is super interesting! I never really realized there were so many different ones with all sorts of different effects.

HerbTool said...

Harry, that's part of the reason why prohibition is so stupid. I mean, it should be entirely legal period, but if you were REALLY against people getting high (oh the horror) you could at least concede that there are some types that don't even get you high but have medical uses.