Strain- and species-dependent effects of cannabis — Placebo or Real?

[TheWhisper]

Source: 420Microbiologist on /r/explainlikeimfive

This comment was posted in reply to the question — What are the differences between cannabis sativa and indica in terms of scientifically observable effects on the body/mind?

Edit: people want a tl;dr - strains don't have different effects on people. Continue reading as people get upset with me for disproving their beliefs with science

No way, this is pretty awesome because I am researcher in the Cannabis field. If you want a genuine scientific answer, I can go much much much more in-depth.

The current scientific theory is that different strains of weed either a) don't genuinely produce different effects or b) the different effects felt by the user are due to minute differences in Cannabinoids. I can quickly talk about both.

I'm going to go unconventional and start with b. The long standing belief in smoking circles is that different strains of weed have different amounts of cannabinoids and terpenes. Both are non-essential products made by Cannabis sativa. Different strains, due to genetics and environmental conditions, will produce different ratios of these compounds. This theory is largely supported by MD Ethan Russo who published the 2011 article Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects.

But there are problems with this hypothesis

Primarily that the real life numbers don't support Dr. Russo's claims. The quantities of terpenes found in cannabis plants isn't enough to feel an effect. An example is Myrcene, one of the most produced terpenes in Cannabis, is present at 10-12mg/gdw (1% of the dry weight of the female flower). The active dose of Myrcene is 10mg/kg (*edit, fixed the values*) body weight. That means you would need to smoke 10g of Cannabis to feel any effect of Myrcene. If you weighed 1 kilo (2.2 pounds). Similarly the notion of isomers of THC (the primary psychoactive compound) can cause different effects is enticing. We see this with vaping or in edibles, where the constant low heat produces more 10-hydroxy-THC vs. d-9 THC that is produced from combustion. But again in Cannabis plants, d-1 or d-9 THCa (the precursor to THC) is around 99% THC isomers found. The remaining 1% is split between up to 8 other THC isomers, so their values aren't enough to induce effect.

So that leaves us with theory a). Do different strains produce different effects in people? Probably not. Now I want to say that strains that have varied THC quantities do have different intensities of highs. But with that said, its important to note the two structures at play when smoking happens. The plant and the person. Cannabis as a plant is actually remarkably homogenous (genetically identical). In fact there is no such thing as Cannabis indica. There is only one species! Cannabis sativa. Indica, if it exists, is so similar that it would be a subspecies at best. Cannabis sativa sub. indica. So the biochemical pathways to produce cannabinoids come from the genetics, and the genetics are nearly identical.

Now lets look at people. We have an endocannabinoid system, including a CB1 receptor that binds THC and CB2 which binds CBD. CB1 is neurologically active, which is why THC gives the high sensation. CB2 is an immune receptor which is why CBD has anti-inflammatory effects. CB1 is activated by THC. It's a special type of receptor (GPCR) that is involved in signaling. The ability to study this signaling has shown that it has a role in hunger (PMOC disruption), a role in happiness (5HT activity) and many other things. The fact that these things are altered when consuming THC makes sense because it alters perception.

And perception is most likely the reason why people experience differences between strains. Your mood and environment when you smoke has much larger role on your state of mind when stoned. Smoking a strain at your house vs. smoking somewhere else may induce minorly different effects, even though its the same strain. Similarly smoking different strains in the same spot may result in the exact same sensation. Examples may include smoking after running vs smoking after being inactive, or smoking in the morning after fasting vs smoking after a meal. Smoking in the middle of the day vs. smoking at night.

In fact, this is true of other psychoactive hallucinogenic compounds like LSD and psilocybin and psilocin, though they have much greater effect on perception.

Some choice lines that I think will create some interesting discussion:

"The quantities of terpenes found in cannabis plants isn't enough to feel an effect. An example is Myrcene, one of the most produced terpenes in Cannabis, is present at 10-12mg/gdw (1% of the dry weight of the female flower). The active dose of Myrcene is 10mg/kg (edit, fixed the values) body weight."

"Do different strains produce different effects in people? Probably not."

"Cannabis as a plant is actually remarkably homogenous (genetically identical). In fact there is no such thing as Cannabis indica. There is only one species! Cannabis sativa. Indica, if it exists, is so similar that it would be a subspecies at best."

What do people think? I don't feel like the poster adequately addresses the conclusions of the paper they reference in the beginning, and they don't include any of their own references or citations. This puts their accuracy into question. Additionally, they make no reference to the myriad cannabinoids in cannabis, aside from just CBD.

EDIT:

In another comment, they also address the synergistic effects of terpenes, or lack thereof:

What you're talking about is a potential affect, but whenever experiments set out to measure what you're talking about, they always come back with results that disprove what you're saying. There is no evidence of a synergystic effect between terpenes and cannabinoid signaling.

I'm sorry I can't explain your anecdotal evidence, and maybe one day science will catch up to these phenomena.

EDIT2:

When asked about why some strains produce a clear-headed body high and others produce a cloudy head high with no body high, they responded:

The best explanation for this, so far, would be the presence of minor psychoactive compounds in cannabis like CBN or 10-OH-THC. CBN is what happens when THC oxidizes (usually a long period of time). Like THC, CBN is also binds to CB1, the neurological receptor, but has about 10% the affinity (binding capacity/attraction to the receptor). So you feel a minor effect.

This compound is also found in higher presence in edibles and during vaping, along with the other THC isomer, which leads to the "body high" sensation.

The problem is that it still doesn't hold up to scientific scrutiny.

 

[TastyClouds]

The biggest flaw I see in the posters argument is the fact that he/she is asserting that because the concentrations of ONE particular chemical or terpene found in Cannabis isn't high enough to feel an affect that you cannot feel different effects from the combination of multiple terpenes and in different quantities, which is something that was never touched on and frankly there isn't enough research on at this point in time to make a conclusive statement about.

I have used enough Cannabis to know that there are certainly different effects you will feel with different strains that to me are clearly not a placebo if you want to call it that. I think the claims that the terpenes naturally found in Cannabis don't produce an effect are premature simply due to the fact there hasn't been any in depth studies that actually give insight into how humans react to terpenes.

 

[Baron23]

"Do different strains produce different effects in people? Probably not."

So, is this guy a researcher only because if he/she has used cannabis they would never make such a patently false statement.

He/she may not know why there is a difference, science may not be able to attribute characteristics of the effect to specific chemicals and/or their ratios, but to anybody who has actually consumed cannabis the truth is self-evident.

I don't care what you want to call them, Sativa, Indica, hybrids of various descriptions, but some cannabis gives me significant anxiety, some does not, some gets me up, most put me on the couch. Vape some Lemon Haze then on a different day vape some Bubba Kush and the difference is apparent, not a placebo effect, and not a matter of what kind of day I'm having.

I write this based on long years of first hand direct experience.

 

[TheWhisper]

They're a microbiologist living in a legal state, and they do partake.

 

[lwien]

The only way to solve this debate is to do some blind testing, eh? In my opinion, unless the test is blind, there is no way to rule out the possibility of a placebo effect.

 

[HighSeasSailor]

I see a few problems.

First, why bring up phylogenetics? Almost everything on the market now is a hybrid and cannabis for consumption is plainly a domesticated crop. This is a distraction from the issue, the natural history of Cannabis as a genus is fascinating but irrelevant.

Second, I think even a blind test would produce potentially useless results, or would prove something else entirely. Consider wine. It's a common pop culture experiment to present cheap blended wine as expensive vintage and watch the clueless marks nod sagely in approval of the obviously fine wine. While this could be taken as evidence that the average person cannot distinguish good wine from bad, it would be completely incorrect to conclude that cheap or expensive, all wine is the same - sommeliers and critics regularly demonstrate the ability to consistently distinguish wines, as do critics of vodka and most other spirits.

Third, I question the language of both premise and conclusion. What is a strain? Anything that a dispensary gives a name to? That hardly seems like scientific rigor. He already admits that some strains have different effects based on THC and CBD content, as well. His claim is bold enough to imply that he's accounted for every single chemical found in cannabis, individually, as an aggregate, via interactions, and via chemical transformation during consumption or metabolism. That sounds more like the wheelhouse of a biochemist if you ask me, and I don't think anyone alive claims to have done all that.

 

[psychonaut]

I'll give my story here. I know a few younger adults who don't really feel any difference between sativa, hybrid and indica. They also claim that vaporizing doesn't get them as high. They also think that dabbing off a nail that's probably still 900 degrees is the best way to dab because you actually get stoned. Oh and edibles are hard to feel. I explained that this is due in part to edibles converting the THC through the liver, so the head high is almost non-existent. Either way, they felt it wasn't "working".

This has all led me to think that the problem is probably more in their level of consumption than anything else. Smoking or vaporizing past the point of being able to recognize anything other than just a feeling of finally being "stoned".

For me, I can vaporize at a nice steady temp of about 400-410F and feel a difference between a sativa and an indica. The hybrids, I can usually tell if it's a 60/40 sativa because of the euphoria generated by the strain seems to dominate the relaxation that I normally feel from the indica.

Now on to my experience story. Apparently cannabis can suppress the appetite. I had never heard of such a thing, it's either gave me the munchies or didn't. I had never ran into a strain that destroys the appetite. Well, I got my hands on some good white widow flower and concentrates. I noticed something weird after my session. I lost my appetite completely. Food didn't smell as appetizing and certainly I wasn't ready to eat when I normally would be. I didn't really think anything of it, so low and behold a couple of days later, I had the same exact experience. I looked around my research sites, and apparently white widow is known for appetite suppression. I believe it has something to do with the terpenes. Humulene is pretty prevalent in white widow, so my conclusion is that the humulene is contributing to my lack of appetite.

https://www.leafly.com/news/cannabi...ene-and-trans-nerolidol-what-are-the-benefits

I try to judge the effects objectively, most often waiting to read the laefly or breeders description of effects after my session to compare.

 

[Squiby]

Humulene is pretty prevalent in white widow, so my conclusion is that the

THCV is supposed to suppress appetite. It is mostly found in Landraces. I love them for their clear energetic high and they never give me the munchies. Durban Poison is my favourite.

One of White Widow' s parents is a Landrace.

 

[CarolKing]

Strains definitely have different effects. Also take into consideration different growing conditions and the way the cannabis was treated during the curing phase. The cannabis needs to be grown by people that know what they are doing every phase along the way. Excellent cannabis is grown by excellent farmers.

Air, heat and light takes its toll on cannabis. So it needs to be in an air tight container in a dark cool place. It can lose its effectiveness if not treated and stored under the right condition. The medical canabinoids can disintegrate over time if the cannabis isn't stored properly.

Two exact strains grown by 2 different farmers can be different in vapor taste and quality.

 

[archangelz001]

This statement:
"Cannabis as a plant is actually remarkably homogenous (genetically identical). In fact there is no such thing as Cannabis indica. There is only one species! Cannabis sativa. Indica, if it exists, is so similar that it would be a subspecies at best."
is just his opinion. He may be a microbiologist, but he's not a geneticist. Neither am I, but I've read enough about the naming convention common in the US that was prevalent long before the advent of dispensaries anywhere. When I first started smoking cannabis in the 60's it was all called cannabis sativa - the narrow leafleted variety available from tropical countries south of the US border. But the naming of cannabis sativa occurred 200 years earlier and all the fiber hemp produced in Europe over the centuries was also called cannabis sativa. Then we found out about cannabis from Afghanistan and Pakistan that was short, bushy and had broad leaves. I highly recommend a book by Michael Backes called Cannabis Pharmacy. On page 52 he discusses the Sativa vs. Indica myth.

"Over 10 years ago Karl Hillig was working on his doctoral degree at Indiana University. Part of Hilleg's dissertation was to examine the differences in the genetics between varieties from around the world and he made an interesting discovery. All drug strains of cannabis shared a relatively narrow range of genes. And all fiber strains of cannabis, the ones we call hemp, shared another small set of genes. And theres was not much crossover between them as might be expected. So, Hillig decided to clean up the nomenclature. He decided that all fiber varieties, hemp, should be classified as Cannabis Sativa, but noted some crucial distinctions. He divided drug Indica cannabis into broad-leafleted drug (BLD) and narrow-leafleted drug (NLD) varities. Most of today's drug cannabis varieties are a hybrid of these two biotypes, leaning toward the BLD side in appearance, but possessing characteristics from both cultivars. Most NLD-dominant hybrids are somewhat stimulating and cerebral compared to pure BLDs such as Bubba Kush."

Now this won't stop the popular references to Indicas, Indica-dom hybrids, Sativas and Sativa-dom hybrids that have been in use for many years, but it's clear that from a geneticist's point of view they are incorrect. But I can tell you that I won't be able to go to sleep for 90 minutes after vaping some Jack Herer, but GDP or Bubba Kush will put me out within 30 minutes.

 

[CarolKing]

I have certain strains that I use for day and strains that I use for night time and for pain. I use a hybrid during the day and I save my Indica for night. I don't usually use straight Sativa strains - prefer a Sativa Hybrid.

I like to read up about different strains. FC had been a god spend for me. I have learned so much regarding our fav medicine and flower. Sometime you wasn't straight info. With FC it cuts through a lot of the other stuff and gets to the point with its various thread topics.

 

[Serious]

Even though I've been enjoying cannabis for fifty years plus, because my state legislature is populated by knuckle-dragging morons, medical-quality weed is not available to me. Because of that, I have always been a little cynical about the subject brought forth by the OP myself.
One session with ACDC has convinced me. Wonderfully stoned and incredibly clear-headed is the holy grail I've been looking for; I have to find a source for this stuff.

 

[looney2nz]

seriously gob-smacked at the stupidity of this whole hypothesis

did this person even consult with a botanist? How many compounds are they tracking? (out of >400)

LOVE to see data on interactions between compounds... oh that's right, they were just talkin' out their ass

Don't believe in the entourage effect? If they're in CA, have a legal rec, I'll wager I can change their mind in under an hour.

 

[MoltenTiger]

Anecdotally speaking, I really think there is a missing chunk of information existing on this topic.

Because experience definitely shows different effect from different types of plant, even from the same seed (genotype) grown in different areas. The difference is minor, but noticeable.

The ECS is prone to interaction from a very wide spectrum of molecules, and so there is a massive range of cannabinoids not identified in any given type of flower.

It's pretty bloody hard to identify a cannabinoid, I assume they mostly use spectroscopy to find concentration - meaning they are only identifying from a known list.
I doubt this list is substantial enough to make any verifiable claims on the variance of effect due to identifiable chemicals in vapour or smoke.

The chemicals on this list show that d9THC has the strongest agonising interaction with CB1, CB2 receptors compared to the others. But it certainly shows, too, that other chemicals also have varying levels of agonising tendencies.

Branching into terpenoids and other various chemicals is interesting by itself, but is limited by the same existing research orienting around isolating them (however much less so, with only 2 unique-to-cannabis chemicals found, in my readings).
And the biggest unkown with these types of chemicals is their synergistic nature when amongst cannabinoids. It's perfectly valid to say that X chemical needs to be taken at Y threshold to induce effect, but this study seems to entirely neglect the fact that when taken in conjunction with a synergistic chemical, the threshold tolerance is negligible as the action is fundamentally altered/enhanced.

Like, eat some Grapefruit that has an MAOI effect, and then eat some magic mushrooms. This is dangerous (so don't actually try this at home) because you are gambling with your systems ability to process things, MAOIs have an effect on the efficacy of psilocin (or any tryptamine).

This is what they say about terpenes and other constituents of cannabis, and I think that sounds pretty reasonable. Especially when considering the anecdotal evidence, which at this point is the most substantial evidence IMO.

The difference is there, unarguably, and the science to define why is a decade away, or so.

 

[looney2nz]

Anecdotally speaking, I really think there is a missing chunk of information existing on this topic.

Because experience definitely shows different effect from different types of plant, even from the same seed (genotype) grown in different areas. The difference is minor, but noticeable.

The ECS is prone to interaction from a very wide spectrum of molecules, and so there is a massive range of cannabinoids not identified in any given type of flower.

It's pretty bloody hard to identify a cannabinoid, I assume they mostly use spectroscopy to find concentration - meaning they are only identifying from a known list.
I doubt this list is substantial enough to make any verifiable claims on the variance of effect due to identifiable chemicals in vapour or smoke.

The chemicals on this list show that d9THC has the strongest agonising interaction with CB1, CB2 receptors compared to the others. But it certainly shows, too, that other chemicals also have varying levels of agonising tendencies.

Branching into terpenoids and other various chemicals is interesting by itself, but is limited by the same existing research orienting around isolating them (however much less so, with only 2 unique-to-cannabis chemicals found, in my readings).
And the biggest unkown with these types of chemicals is their synergistic nature when amongst cannabinoids. It's perfectly valid to say that X chemical needs to be taken at Y threshold to induce effect, but this study seems to entirely neglect the fact that when taken in conjunction with a synergistic chemical, the threshold tolerance is negligible as the action is fundamentally altered/enhanced.

Like, eat some Grapefruit that has an MAOI effect, and then eat some magic mushrooms. This is dangerous (so don't actually try this at home) because you are gambling with your systems ability to process things, MAOIs have an effect on the efficacy of psilocin (or any tryptamine).

This is what they say about terpenes and other constituents of cannabis, and I think that sounds pretty reasonable. Especially when considering the anecdotal evidence, which at this point is the most substantial evidence IMO.

The difference is there, unarguably, and the science to define why is a decade away, or so.

I think a lot of the testing is using HPLC these days, but I know they add other specific tests. GCMS is still used, and some flame ionization tests that I've utterly brainfarted on

I'm hoping that we start expanding our view of even the 85 compounds that are commonly referenced. Need to know more about CBC, CBG, any acidic forms or rare forms like THCv. So, it's off to the races... except academic research is still stalled by Federal Policy (so BigPharma gets a jump, and BigCanna is right behind it). Hopefully they will pull their collective heads out of their asses far enough to Reschedule or DEschedule cannabis... but the reality is, they will probably drop it to Schedule II (cocaine, methamphetamine). Farcical, truly

Sadly in CA, you rarely see anyone testing for contaminants, for some reason it always has an 'NA'
next to those checkboxes That REALLY pisses me off
At one point my friend Eric and I started looking into environmentally friendly contact tests (like they wipe you down with if they think you're a terrorist) which are pretty cheap (affordable) and you could test for fungicides & pesticides, and heavy metals pretty easily.
Testing for dangerous bacteria could possibly be more involved, but by no means impossible.

Now that all the growers hair is collectively on fire...

Look, it is MORE than possible to grow/manufacture product in an environmentally friendly as well as PATIENT friendly manner. HMS did it in Arcata until Eric's death, and they gave 50-55% of their product away free to indigent patients. Clean high quality organic product (ironic/sick for the DEA to go after them).

Was it Chris Conrad that has the 'Clean Green' certification program? Nope!, it's Chris Van Hook - http://www.cleangreencert.org/about-us/. Chris Conrad (www.chrisconrad.com) is a top notch expert witness (for some reason I always brainfart between the 2 of them!) both of them were also friends of Eric.
Any state that isn't paying attention to this is missing the mark and endangering patients and special event stoners alike.

THAT said, at the risk of suggesting something challenging to folks who are now viewing these budding industries revenue streams... the best science comes out of collaboration, sharing information.
Cognitive Dissonance much? But REALLY, think of it, if all the labs in all the states were working together, they'd not only be helping each other, they'd probably be raising the QoS metric significantly as well as dropping the price by more efficient processes. Very likely educating a lot of people long the way, if not at least highlighting where they are deficient and need to develop.

We could then expand basic tests to include far more than THC, CBD and CBN (you're lucky if they do THCa or CBDa). Then we can start comparing notes on stuff like CBC or CBG, not to mention the MANY interactions possible from the terpenes and decide where to focus and do actual studies.

That said, when I first started this battle for lab testing (8 years ago on/in ASA), you'd have thought the town was out with torches and pickaxes... the fact that it's finally here, even to a limited degree right now, is a beginning.

wait, what was I saying? what was the question?

 

[MoltenTiger]

A good way to research this is by studying the varying effect of synthetic cannabinoids. The difficulty being you can't actually use human test subjects.
However there's plenty of anecdotal evidence showing a vast array of effects of chemical isomers.

This is a common range found within various "K2" smoking blends.

Bottom Line:Since even subtle structural differences can lead to differential metabolism, formation of novel, biologically active metabolites may be responsible for the distinct effects associated with K2 use.These molecules also stimulated G-proteins with equal or greater efficacy relative to Δ(9)-THC, a CB1R partial agonist.
...
We report that several hydroxylated derivatives of JWH-018 not only retain nanomolar binding affinity for CB1Rs, but also exhibit a range of intrinsic activities from partial to full agonism. This new information is critical for understanding the pharmacological significance of JWH-018 metabolites produced in humans.

So whether you're dealing with a partial or a full agonist, you get drastically different effects - but you get consistent results per chemical or even with mixtures. Dosage and tolerance levels can fluctuate response, but the action remains the same.
So I figure, if a particular plant has a particular isomer of THC or the likes, then it will have a signature to its effect, akin to various "K2" blends with the same base-structure active chemical.
Furthermore, the anti-inflammatory agents and whatever else is in cannabis vapour/smoke is also unique to the plant in relative concentrations. So it's different every time, but most similar with the same product or genotype.

I suppose the limitation is human testing and the inability to define dank. But I am lead to believe that a slight change in partial agonist strength has a potentially drastic affect on the sensation of a particular drug-type. I think studies on LSD and various tryptamines expose this too.

Here is a great study looking at "Cannabis and Cannabis Extracts: Greater Than the Sum of Their Parts?"
http://www.cannabis-med.org/data/pdf/2001-03-04-7.pdf

 

[Winegums]

No difference between sativa and indica? The guy is talking out his ass. Take some green crack in the morning and you'll be more awake than if you had coffee. Take some bubba kush in the evening and you'll be locked to the couch struggling to get up. The difference in effects is drastic and should be obvious.

 

[Bad Ocelot]

I'm sure effects vary by the chemical contents of the plant, but as plants aren't standardized, there is going to be some variability within members of the same species, strain, etc based on growing conditions, age, time of harvest, and then after harvest things like curing & storage could well affect the active substituents before it reaches the end user.

 

[Tranquility]

Placebo or real? I have no idea. But, there's a chance it ain't what you think it is.

https://www.biorxiv.org/content/biorxiv/early/2018/05/28/332320.full.pdf

Cannabis sativa is listed as a Schedule I substance by the United States Drug Enforcement Agency and has been federally illegal in the United States since 1937. However, the majority of states in the United States, as well as several countries, now have various levels of legal Cannabis. Products are labeled with identifying strain names but there is no official mechanism to register Cannabis strains, therefore the potential exists for incorrect identification or labeling. This study uses genetic analyses to investigate strain reliability from the consumer point of view. Ten microsatellite regions were used to examine samples from strains obtained from dispensaries in three states. Samples were examined for genetic similarity within strains, and also a possible genetic distinction between Sativa, Indica, or Hybrid types. The analyses revealed genetic inconsistencies within strains. Additionally, although there was strong statistical support dividing the samples into two genetic groups, the groups did not correspond to commonly reported Sativa/Hybrid/Indica types. Genetic differences have the potential to lead to phenotypic differences and unexpected effects, which could be surprising for the recreational user, but have more serious implications for patients relying on strains that alleviate specific medical symptoms.​

 

[archangelz001]

@OldNewbie that's why an "indica" with the same terpene profile as a "sativa" will have the same effect. It's all in the terpene entourage effect...