Cannabinoids and Cannabis

15 03 2011

Sigh. No matter how strict a disclaimer I put here, the hatemail and death threats keep trickling in and clogging my spam folder. Might as well get rid of it. Just try to think before sending me an idiotic e-mail littered with bad grammar and spelling, please. Some of us have work to do. Thanks.

Cannabinoid Chemistry

Chemically, cannabinoids are derivatives of 2,4-dihydroxy-3-(3′,7′-dimethyl-octa-2′,6′-dienyl)-6-alkyl-benzoic acid and its decarboxylation products.

Over 60 cannabinoids are known. Most of the time, the alkyl group is an amyl, but variants with a methyl, propyl or butyl exist. The latter variants are designated either with a prefix (e.g. propyl-Δ9-THC) or a Cn suffix (e.g. Δ9-THC-C3). The amyl cannabinoids are by far the most common in cannabinoid mixes; some chemotypes can contain relatively high propyl-cannabinoids, while the methyl and butyl cannabinoids have only been detected in trace concentrations.

There is no need to go into the structural details of the cannabinoids, so let’s skip right to what we’re interested in: the active ingredient, Δ9-THC, first isolated in 1942 (Wollner et al., 1942) and its structure elucidated in 1964 (Gaoni & Mechoulam, 1964). It’s a lipophilic, non-crystallising substance which, in the presence of heat and light, reacts with oxygen and gets dehydrated to cannabinol.

When smoked, some Δ9-THC gets inhaled into the lungs while the rest is lost through pyrolisis into inactive products. This loss is somewhat lessened by the decarboxylation of tetrahydrocannabinols into Δ9-THC when heated.

I will not summarise the biogenesis of cannabinoids. Consult Turner et al. (1980) and Kajima & Piraux (1982) for summaries of that.

Botanical Overview

Cannabinoids have only been found in Cannabis sativa L. (Rosales: Cannabaceae), commonly called hemp. C. sativa is a 0.3 m to 3.5 m weed with instantly-recognisable leaves. The perianth is at best reduced, in most cases absent. Male flowers have 5 stamens; female flowers have a fruit enveloped by a gland-rich hairy bract.

The systematics of the plant is somewhat problematic. Some treat Cannabis as a monotypical genus, i.e. with only one species (C. sativa). Others identify C. sativa asthe cultivated variant and C. ruderalis Janisch as the wild counterpart. Some even split C. indica Lam. as a separate species from C. sativa. See Mechoulam et al. (1976) & Turner et al. (1980) for reviews.

Biogeographically, hemp is endemic to the steppes of Asia and is cultivated in temperate and tropical regions on both hemispheres as a source of fiber.

The cannabinoids are concentrated in resin-like secretions around the flower, and are also present in the protoplasm and the sap. As the leaves grow larger, the cannabinoid concentration in them decreases; the stem contains negligible amounts and the roots and seeds none at all. See Turner et al. (1980) and Furr & Mahlberg (1981) for overviews.

These concentrations are determined genetically, with environmental effects being minimal (Turner et al., 1979). Through artificial selection, several cultivars have been obtained that vary starkly in their properties (Meijer et al., 1992):

  • Drug variants have > 1% Δ9-THC and a Δ9-THC:CBD (cannabidiol) ratio of > 1; they are grown in warmer climates (e.g. South Africa, Mexico, India); the propyl-Δ9-THC variants I mentioned at the start are the South African drug cultivars.
  • Intermediate forms have> 0.5% Δ9-THC and a Δ9-THC:CBD ratio of = 1; they are grown in the Mediterranean (e.g. Morocco, Lebanon).
  • Fiber hemp has < 0.25% Δ9-THC and a Δ9-THC:CBD ratio of < 1; it is grown in temperate regions for fiber.

Drug cultivars are also grown in colder climates, where they also deliver high concentrations of Δ9-THC, however the amount of time this can continue for is under debate, as the non-drug variants are better suited to the climate.

The produced drugs can contain up to 11% Δ9-THC and ~5% CBD. Depending on the age of the plant and preparation type, other cannabinoids can find their way into the drug, including tetrahydrocannabinolic acid A and B (up to 8%), cannabidiolic acid (up to 3%), cannabichromes (up to 1.5%), cannabinol (up to 1%), tetrahydrocannabivarol (i.e. propyl-Δ9-THC; up to 0.8%) and propyl-cannabinol (up to 0.4%). See Turner et al. (1979) and Hemphill et al. (1980) for overviews. Besides cannabinoids, around 400 secondary products have been found in Cannabis sativa.

Pharmacology

Cannabinoid absoprtion is particularly easy through the respiratory tract, hence why the drug is often smoked. The psychomimetic effect of Δ9-THC is almost immediate. The effects start seconds to a few minutes after inhalation and last between 2 and 4 hours. Peroral ingestion also allows for almost complete Δ9-THC absorption, however there is a 60 to 90 minute waiting time for any effect, and due to metabolism, only 5-10% of the original Δ9-THC amount is available.

Metabolism of Δ9-THC takes place mostly (95%) in the liver. The protein CYP2C9 transforms it first to 11-hydroxy-THC, a compound also pharmacologically active, and then oxidised to the inactive 11-nor-9-carboxy-THC (THC-COOH). Aprroximately 80% of it is excreted through urine and faeces. However, due to the lipophilic nature of cannabinoids, excretion takes place rather slowly and they accumulate in fatty tissues. They can be found in the blood plasma for up to 4 days after inhalation. Refer to Hollister (1971) and any pharmacology textbook for more information.

As one can tell by the names, in humans, cannabinoids affect the cannabinoid system, which plays roles in pain regulation, appetite control, the area postrema and immunomodulation. Cannabinoid receptors are G-protein-coupled receptors (we encountered them when looking at eyes!) and come in two types: the larger CB1-receptors comprise 472 amino acids and the smaller CB2-receptors comprise 360 amino acids. They’re coupled (through G-proteins, hence the name) to adenylate cyclase. The human body produces several chemicals, termed endocannabinoids, that serve as ligands of these receptors, including anandamide, 2-AG and 2-AGE. CB1-receptors are found in the CNS (except the brainstem) and in in various peripheral organs (e.g. gastrointestinal tract). CB2-receptors are almost unique to immune cells. Δ9-THC and other cannabinoids attack both these receptors. This causes a chain reaction: adenylate cyclase is blocked, causing a change in the modulation of ion conductivity, causing a blockage in neurotransmitter release in central and peripheral neurons. In other cells, various signal transduction pathways are also influenced, including those involved in apoptosis, differntiation and proliferation. Refer to Demuth & Molleman (2006), Fowler (2006) and any pharmacology textbook for more information.

Cannabinoids can damage chromosomes and are thus classified as embryo- and foetotoxic compounds. In mice and rats, cannabinol is more gametotoxic than Δ9-THC (Martin, 1986). Also of toxicological importance are the various effects cannabinoids have on endocrine systems, including lowering plasma testosterone levels (a direct effect of smoking a joint!) and disturbing menstruation cycles and spermatogenesis (Maykut, 1985).

Δ9-THC’s psychomimetic effect is highly-dependent on dosage. At low concentrations (50 µg/kg KG), smoked Δ9-THC induces mild euphoria. At higher concentrations (100 µg/kg), perceptions of space and time are affected. At 200 µg/kg KG, hallucinations come into the mix. At 300 µg/kg KG, cotton mouth, nausea, balance problems and even vomitting arise. Consciousness is never lost. As the dosage increases, speech and reaction time disturbances crop up. The risk of heart attack increases. Thinking ability gets impaired, as does navigation (blurry vision, slow readaptation to dark). It is recommended not to drive for 24 hours after ingesting high cannabis doses. The high ends with a long, deep sleep and a considerable hangover. Refer to any good book on drugs for this information.

Hemp Abuse

Cannabis sativa is one of the most commonly used psychotropic plants and has been so for 5000 years. The Ancient Egyptians, Indians and Chinese used it as a cure-all medicinal plant, including against regular pain, epilepsy and malaria. Herodotus wrote of how the Scythians smoked it as a recreational drug. Numerous archaeological finds from around the world, including seeds in a settlement and a smoking pipe, are testament to how popular hemp has been throughout the history of human culture. Refer to Jiang et al. (2006) and refs. therein, as well as any good book on drugs/marijuana.

At the start of the 20th century, cannabis increasingly gained popularity as a recreational drug in the USA, a habit that later spread to Europe. On average, people start consuming it as teenagers. Of those who try it, between 7 and 10% develop an addiction, a risk that increases the earlier the individual begins experimenting.

The part of the plant that is nowadays used as a drug is the dried shoot tip. This is what is referred to as marijuana, grass, pot, weed, kif or whatever fancy names it goes by these days. This tradition comes from South American countries (Columbia, Bolivia), southern USA states, Mexico, several African countries (Zambia, Ghana, Kenya, Sierra Leone) and Thailand. It is rolled into a joint, or in a pipe, most commonly mixed with tobacco and/or oregano, and smoked. What is referred to as hashish (hash, shit) is the resin of the plant. In Nepal and Cashmere, this is obtained by scraping it off the plant; in the Mediterranean area, the trichomes are separated from the rest of the plant. They can then be smoked like weed, or made into a tea, or made into cakes (hash brownies, space cakes). Out of India and Morocco came another form of drug in the 1960s, variably termed Hash-Oil, Red Oil or Indian Oil. This is merely a distilled Cannabis extract. Sources: any good cannabis book.

Toxicity

The LD50 of the cannabinoids is relatively low and relatively constant across all model organisms. Intravenously, it lies between 43-60 mg/kg KG; intraperitoneally, 170-450 mg/kg KG; perorally, 480-2000 mg/kg KG. For humans, it lies between 1 and 12 g. Children are most at risk and can suffer cannabis poisoning from if ingesting the rests of joints, bits of marijuana, hash tea or brownies. Refer to any good cannabis book for these details.

The symptoms of acute cannabinoid toxicity are numerous, and are exacerbated in children. They include paranoia, euphoria, vomitting, uncontrollable crying, shakiness and ‘feeling cold’. On the non-psychological side, extremities feel numb and the heart rate becomes erratic. If abnormally large doses are ingested, then collapse, respiratory arrest and a coma are the usual outcome. That said, death from cannabinoid toxicity are extremely rare. Refer to Ashton (1999) and Nelson et al. (1999) for more information.

Chronic Toxicity

Okay, this is the section which will most likely get me the most hatemail. Hopefully I make up for it in the next section, but it shouldn’t matter. Facts are facts, no matter if you like them or not :)

Consistent misuse of cannabis leads to reduced physical and mental activity, reduction in thinking abilities, in reaction times, motivation and interest, apathy and eventually to psychological breakdown (Foltin et al., 1990; Ashton, 1999; Pope Jr. et al., 2003; Messinis et al., 2006). The increasingly early ages that kids are starting to use marijuana is a large cause of worry, as it affects the development of their personality at its most critical time; there is an increased risk of schizophrenia (Jockers-Scherübl et al., 2003; Kalant, 2004).

Cannabis use also affects the female reproductive system. The fertilised egg’s trip down the Fallopian tubes is slower. More worrisome is the fact that cannabinoids can pass through the placental barrier and directly affect the development of the foetus. Besides lower than average birth weights, abnormal behavioural patterns are common in children born of cannabis-using mothers. The risk of premature birth increases. See Fried (1989) and Fried & Smith (2001) for reviews of these. Cannabinoids can also pass through to the baby through breast milk, and children that were breastfed with cannabinoid-enriched breastmilk show marked retardation in motor development (Astley & Little, 1990).

Another important aspect to keep in mind is the high number of carcinogens in joints. Just as with tobacco smoking, the risk of infalammation and cancer of the respiratory tracts increases starkly with cannabis use. In fact, smoking a joint is as damaging as smoking 7 cigarettes, as far as the lungs are concerned.Children are also at risk from the second-hand smoke. Refer to Martin (1986) and Kalant (2004) for overviews.

While there is no purely biological link to dependency on harder drugs, due to the close contact with the drug scene in general, it is often the case that harder drugs (LSD, heroin) will be attempted by cannabis users. This is a socio-cultural effect, not a biological one, and can easily be prevented.

Pharmaceutical Potential of Cannabinoids

With the bad stuff out of the way, let’s end this on a positive note. This may reflect my own bias as a cannabis smoker, but whatever. Cannabinoids could have interesting uses in therapy. A trans form of Δ9-THC, dronabinol, is commonly used as a painkiller for multiple sclerosis sufferers, spinal injuries, phantom pains in amputees, cancer patients, etc. It can also be used by cancer patients undergoing chemotherapy or AIDS patients, glaucoma sufferers, etc. as an appetite stimulant and to reduce the feelings of nausea. Refer to Ben Amar (2006) and Kalant (2004) for more information.

On the other hand, cannabinoid antagonists are being developed. These can’t pass the blood-brain barrier and thus can only affect the peripheral nociceptive nerves. These have been shown to have anti-artheroclerotic effects in mice (Steffens, 2005) as well as blocking dermatitis (Karsak et al., 2007), so they definitely have potential.

One such antagonist, a CB1 receptor antagonist called Rimobant was released in 2006 throughout Europe as a treatment for severe depression. Other such drugs have potential similar applications for psychiatric diseases, but also for nicotine addiction.

However, in just about every country in the world, owning, selling, cultivating and selling cannabis illegal. Some countries (e.g. Germany) now have a exemption for medicinal marijuana use, however any medicine containing Δ9-THC remains strictly a prescription drug. That said, hemp products made of the fiber cultivars (Δ9-THC < 0.2% in Germany) are, at least in Germany, allowed. These products (include food products, oil, cosmetics, etc.) have strict limits on how much Δ9-THC they can contain, limits which are strictly enforced. I do not know how the situation is In other countries though.

And that’s it for cannabis. This post is a summary of all I know about the topic; read the relevant papers cited before you even think of spamming my inbox. This goes for both the LEGALIZE EET brigade and the WEED IS HEROIN THINK OF THE CHILDREN troupe. Thanks.

Literature Cited:

Ashton, C. H. 1999. Adverse effects of cannabis and cannabinoids. British Journal of Anaesthesia 83, 637-649.

Astley, S. J. & Little, R. E. 1990. Maternal marijuana use during lactation and infant development at one year. Neurotoxicology and Teratology 12, 161-168.

Ben Amar, M. 2006. Cannabinoids in medicine: A review of their therapeutic potential. Journal of Ethnopharmacology 105, 1-25.

Demuth, D. G. & Molleman, A. 2006. Cannabinoid signalling. Life Sciences 78, 549-563.

Foltin, R. W., Fischman, M. W., Brady, J. V., Kelly, T. H., Bernstein, D. J. & Nellis, M. J. 1990. Marijuana and behavioral contingencies. Drug Development Research 20, 67-80.

Fowler, C. J. 2006. The cannabinoid system and its pharmacological manipulation – a review, with emphasis upon the uptake of and hydrolysis of anandamide. Fundamental & Clinical Pharmacology 20, 549-562.

Fried, P. A. 1989. Postnatal consequences of maternal marijuana use in humans. Annals of the New York Academy of Sciences 562, 123-132.

Fried, P. A. & Smith, A. M. 2001. A literature review of the consequences of prenatal marijuana exposure: An emerging theme of a deficiency in aspects of executive function. Neurotoxicology and Teratology 23, 1-11.

Furr, M. & Mahlberg, P. G. 1981. Histochemical analyses of lacticifers and glandular trichomes in Cannabis sativa. Journal of Natural Products 44, 153-159.

Gaoni, Y. & Mechoulam, R. 1964. Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish. Journal of the American Chemical Society 86, 1646-1647.

Hemphill, J. K., Turner, J. C. & Mahlberg, P. G. 1980. Cannabinoid content of individual plant organs from different geographical strains of Cannabis sativa L. Journal of Natural Products 43, 112-122.

Hollister, L. E. 1971. Marihuana in Man: Three years later. Science 172, 21-29.

Jiang, H.-E., Li, X., Zhao, Y.-X., Ferguson, D. K., Hueber, F., Bera, S., Wang, Y.-F., Zhao, L.-C., Liu, C.-J. & Li, C.-S. 2006. A new insight into Cannabis sativa (Cannabaceae) utilization from 2500-year-old Yanghai Tombs, Xinjiang, China. Journal of Ethnopharmacology 108, 414-422.

Jockers-Scherübl, M. C., Matthies, U., Danker-Hopfe, H., Lang, U. E., Mahlberg, R. & Hellweg, R. 2003. Chronic cannabis abuse raises nerve growth factor serum concentrations in drug-naive schizophrenic patients. Journal of Psychopharmacology 17, 439-445.

Kajima, M. & Piraux, M. 1982. The biogenesis of cannabinoids in Cannabis sativa. Phytochemistry 21, 67-69.

Kalant, H. 2004. Adverse effects of cannabis on health: an update of the literature since 1996. Progress in Neuro-Psychopharmacology and Biological Psychiatry 28, 849-863.

Karsak, M., Gaffal, E., Date, R., Wang-Eckhardt, L., Rehnelt, J., Petrosino, S., Starowicz, K., Steuder, R., Schlicker, E., Cravatt, B., Mechoulam, R., Buettner, R., Werner, S., di Marzo, V., Tüting, T. & Zimmer, A. 2007. Attenuation of allergic contact dermatitis through the endocannabinoid system. Science 316, 1494-1497.

Martin, B. R. 1986. Cellular effects of cannabinoids. Pharmacological Reviews 38, 45-74.

Maykut, M. O. 1985. Health consequences of acute and chronic marihuana use. Progress in Neuro-Psychopharmacology and Biological Psychiatry 9, 209-238.

Mechoulam. R., McCallum, N. K. & Burstein, S. 1976. Recent advances in the chemistry and biochemistry of cannabis. Chemical Reviews 76, 75-112.

Meijer, E. P. M., Kamp, H. J. & Euwijk, F. A. 1992. Characterisation of Cannabis accessions with regard to cannabinoid content in relation to other plant characters. Euphytica 62, 187-200.

Messinis, L., Kyprianidou, A., Malefaki, S. & Papathanasopoulos, P. 2006. Neuropsychological deficits in long-term frequent cannabis users. Neurology 66, 737-739.

Nelson, L. S., Holland, J. A. & Ravikumar, P. R. 1999. Dangerous form of marijuana. Annals of Emergency Medicine 34, 115-116.

Pope Jr., H. G., Gruber, A. J., Hudson, J. I., Cohane, G., Huestis, M. A. & Yurgelun-Todd, D. 2003. Early-onset cannabis use and cognitive deficits: what is the nature of the association? Drug and Alcohol Dependence 69, 303-310.

Steffens, S., Veillard, N. R., Arnaud, C., Pelli, G., Burger, F., Staub, C., Zimmer, A., Frossard, J.-L. & Mach, F. 2005. Low dose oral cannabinoid therapy reduces progression of artherosclerosis in mice. Nature 434, 782-786.

Turner, C. E., Cheng, P. C., Lewis, G. S., Russel, M. H. & Sharma, G. K. 1979. Constituents of Cannabis sativa XV: Botanical and chemical profile of Indian variants. Planta Medica 37, 217-225.

Turner, C. E., Elsohly, M. A. & Boeren, E. G. 1980. Constituents of Cannabis sativa L. XVII. A review of the natural constituents. Journal of Natural Products 43, 169-234.

Wollner, H. J., Matchett, J. R., Levine, J. & Loewe, S. 1942. Isolation of a Physiologically Active Tetrahydrocannabinol from Cannabis Sativa Resin. Journal of the American Chemical Society 64, 26-29.


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16 responses

24 03 2011
cherokeerj

some good information but the problem with your therories are 1st-you started with a false/corrupted base model. if you began your studies off of previouse studies than you can not come to any “FACTUAL” conclusions. 2nd lets say my first reason is false and the studies and tests you have done started with factual basis than your conclusions are still(even if based upon some fact) are an opinion science is rarely conclusive for every positive conclusion 2 negitives can be found by reputable scientest and vice versa. visit a court room sometime when opposing scientific views are asked to testify. i am not saying you are or are not a shill or out for your own agenda(i am), i will not attack you personnaly but some of your statements in your opening sounds like a watered down version of “reefer madness” like your warning that if you are trying for first time be sure to be with a friend or a doctor – please you state you are a scientist yet you are still trying to give the idea that some wild trip or some uncontrolable urge could happen that the person might freak out. then you made a statement regarding getting a headache(you made it sound typical/routine) if you smoked a half of a joint versus smoking a whole joint. well could the time you smoked a half a joint not been properly cultivated you know flushed in final stage of flowering etc… there could have been numerous reasons why you got a headache could have even been something esle you took or ate or stress for a scientist you draw some fuzzy connections leave an air of superiority and that since you are a “scientist” that what you are saying is “the ultimate facts” and beyond reproach. at one time the world leading scientist said the world was flat.

24 03 2011
Marc

Oh, I didn’t intend for any ‘reefer madness’ effect :) I’m just covering my ass, since this is a somewhat medical topic, not a zoological one as most of the other posts on here. No scaremongering intended. Same with consulting with a doctor and being with a friend. Of course marijuana is as benign in its effects as drugs come, but you are still taking in a substance that will alter your psychological state. Not doing so under supervision, at least for the first time, is stupid tbh.

I stated that the headache is my personal reaction as an example of an idiosyncracy: it’s not a typical thing, it’s just a personal quirk. No generalisation intended.

Sorry for those misunderstandings – the three paragraphs at the beginning are disclaimers, nothing more. I didn’t mean to appeal to authority.

About ‘facts’ in science, I don’t like going into philosophical wankery, so I just used it as meaning “this is what the data points us to”. You have to understand that there are basically two classes: you have raw research results and you have models. Raw results are (for all intents and purposes) facts, you can’t argue with them (except to point out methodological errors, etc). Models are interpretations of lots of facts and of course they can be wrong. But the only way to prove that they’re wrong is by finding more facts (i.e. research results).

As for the whole world was flat gambit, that’s pretty much a myth: we’ve known the Earth was at least a sphere since the Ancient Egyptians, if not earlier. You might want to use alchemy or the left-right theory of sex determination next time :) But I get the meaning. The critical difference is that we now have a self-correcting scientific method (see previous paragraph). The way we dumped our old hypotheses was by finding results that opposed them. And if you’re not going to present results that go against anything I stated here, I’ll just have to say that the last sentence was pretty damn weird.

19 09 2011
Karl Rubin

Great article, thank you. And i absolutely agree with you, be with a friend the first time you do it. I really freaked out the first time i got high.

19 09 2011
Karl Rubin

There is one thing that´s bothering me though, you state that the high ends with deep sleep and a considerable hangover. I smoked cannabis almost daily for about 2 years and i can´t recall ever having a hangover. I have asked some friends about this and they say the same thing.

19 09 2011
Marc

You’re right, nobody I know has had that either. I don’t have the book where I stole that from anymore, but it might be that that’s the effect of pure THC injected straight into the bloodstream at a high dose, so it’s the proper pharmacological effect, not the lower doses of unpure THC you get by smoking, etc.

16 07 2012
Amabella Lush

What a load of bollocks!

20 07 2012
22 07 2012
22 07 2012
Anonymous

This is all horse shit hahahahhaahahha. Fuck I found this article because I was reading one about how cannabinoids ARE found in breast milk, but it is suppose to happen, and has nothing to do with smoking marijuana. This is suuuuuuuch bull.

23 07 2012
killerbabies

I think smoking weed is fun. But it should be 21+ so you don’t mess up those developing teen brains! But, let us adults have our fun,

23 07 2012
23 07 2012
Marijuana in Breast Milk?!!! « BIO-SIL SOUTH AFRICA Blog

[...] http://bioteaching.wordpress.com/2011/03/15/cannabinoids-and-cannabis/ Share this:TwitterEmailPrintFacebookDiggRedditStumbleUponLike this:LikeBe the first to like this. [...]

24 07 2012
Cannabinoide in der Muttermilch gefunden – Substanzen wie im Marihuana

[...] Bioteaching: Cannabinoids and Cananbis [...]

20 09 2012
Anonymous

One thing is that “medicine” isnt produced untill extracted at a low temp. The healig process takes energy from the body to restore things there by makeing you sleepy not hung over. Hemp oil made right will cure anything but everyone will need diff amounts to cude diff things. I speak from exp. iv made the oil manny times useig it for thigs that you so called doc and scientests need permission to test it on. Trust me it works for everything.
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11 11 2012
Interesting Papers of the Past 2 Weeks « Teaching Biology

[...] wrote an introduction to cannabis, mentioning endocannabinoids and their medical relevance. This special issue’s got tons more [...]

9 11 2013
2013 Holiday Shopping: Top 5 Popular Botany Books | Teaching Biology

[…] to rely on this plant and adapts it to suit our needs.My comment: Over two years later, and my Cannabis post still brings in hate mail and death threats. If only its wonderful mellowing effects can switch off […]

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