CB1 agonism & Hippocampal neurogenesis

[any major dude]

Don't know if this has come up here before, but I didn't see a thread regarding it right off.

I had thought the use of cannabis as an anti-depressant was more of a legal strategy/way for large numbers of people to obtain prescriptions, but it appears there may be at least some legitimacy to it. Apparently agonism @ CB1 (in this study by the synthetic cannabinoid HU210 and the endogenous cannabinoid anandamide, THC wasn't used in this study, but since it is more selective for CB1 than CB2, I would imagine these results could be extrapolated to it as well) promotes embryonic hippocampal neural stem/progenator cell proliferation.

Now I'm no fan of SSRI anti-depressants, especially given their lack of efficacy as compared to placebo in most populations. However there is some research that has found they prevent hippocampal shrinkage in extremely depressed women (also this is the only demographic I'm aware of in which SSRIs are more effective than placebo, this may be the case for extremely depressed men as well, I just haven't seen any research on it) and this is now what some researchers (and the drug companies that make SSRIs) are claiming causes the anti-depressant effect.

If the hippocampal neurogenesis hypothesis regarding anti-depressants is true, then there's no need to take pills that cause erectile dysfunction, night-sweats, nausea, weight gain, the feeling of mild electric shocks at the base of your skull, vaginal dryness, gross amounts of apathy, general disinterest in sex, dizzyness, etc, because you can have all the benefits of SSRIs from just smoking a crap ton of reefer. Though the amount you'd have to smoke would probably still cause weight gain. I was going to say apathy too, but I'd differentiate between pothead laziness & SSRI induced apathy, as I've experienced both. The latter really makes me not give a shit about anything, whereas with the former, I'm interested in things, I just want to learn about them from my couch or computer chair.

Here's a link to the full text of the study. And an article with an accurate summary in New Scientist, if you're pressed for time

Again, its with rats, so it may not translate to humans, but rats are where the discovery of SSRI induced neurogenesis happened as well.

Also, don't you like that they used the phrase "chronic...treatment" in the abstract? And "Chronic High Doses" in the article title...

 

[stormyweathers]

what is the distinction between a low and high dose?

 

[/navarone/]

All weed has done for me is making me dumber.

I have read some papers that i cant find stating brain developmentl disorders (in the hyppocampus i think)
By teens smoking regilarly snoking cannabis, same goes for other drugs like amphetamines.

Anyway the choice is yours so do as you wish.

 

[any major dude]

SSRIs and such are actually quite useful for alleviating negative affect but do little to nothing for positive affect (often actually making it worse) and of course have loads of side effects. Hence, a lot of people don't respond to them and/or can't tolerate them. In any case though, I agree and I think they suck too. An ideal antidepressant would have far fewer side effects and would work for both positive and negative affect. Opioids sound like they could fill that role perfectly in my opinion.

As for cannabinoids for depression.. this is a tricky subject for a few reasons. First off, in some ways the side effects of cannabinoids can be worse than current antidepressants.. there's the psychedelic aspect of course, then "munchies"/weight gain, "amotivational syndrome", paranoia/anxiety, and short-term memory loss. Also neurotoxicity was shown for THC under specific circumstances recently (see here and here).

For the subjective side effects, it depends on how the person in question responds to the drug. I for instance experience strong psychedelic effects and anxiety/mild panic attacks even from low doses of weed. It wasn't like this when I first started but now it is and pot is much more depressive-like than antidepressant for me. This is the case with a lot of people.

Also.. I've read that low dose THC is antidepressant/anxiolytic while high dose is depressive/anxiogenic (according to rodent assays using the FST/TST and such). Apparently at low doses CB1 activation enhances signaling of 5-HT1A and mu/delta-opioid systems, whereas at high doses the 5-HT1A enhancement is dramatically reversed and kappa-opioid transmission is enhanced, or something along those lines. Simultaneous exposure to THC and a stressor (such as depression itself) can potentially turn a positive THC dose into an unpleasant experience.

Another thing.. there is evidence that THC shrinks the amygdala and hippocampus with long-term, chronic use. The latter of course would run completely contradictorily to your intention that CB1 activation would increase BDNF release and augment hippocampal neurogenesis.

So I'd say the evidence is mixed right now.

The reference to using THC on a very wide scale for depression was a bit of tongue in cheek humor, though I do think it would be less destructive than prescribing SSRIs to anyone who happens to feel sad on occasion. I was just amazed that there was actually any legitimacy to the "marijuana for anxiety/depression" theory.

If one wanted to translate this, and the studies that have replicated the results, into a treatment that was largely side effect free, they would probably stick with the endogenous cannabinoid used in the study. However, pharmaceutical companies won't produce anything that already exists in nature, because you can't patent it, which would hurt their profit margin. Seems silly i know, but that's capitalism for you.

And in reference to the neurotoxicity you mentioned, the studies you linked to were regarding single, very low (0.001mg/kg) doses of THC in mice. The cannabinoid induced neurogenesis as reported by the study i originally linked to requires repeated high doses.

I couldn't really find any info on amygdalar & hippocampal shrinkage induced by cannabinoids. The only thing i saw that might infer something was a study, with far too small an n, that inferred some differences in basolateral amygdalar function in heavy cannabis users as compared to non-smokers by viewing masked faces whilst participants had an fMRI strapped on their noggin... Certainly interesting, but i'm unsure as to the validity.

 

[kken]

All weed has done for me is making me dumber.

I have read some papers that i cant find stating brain developmentl disorders (in the hyppocampus i think)
By teens smoking regilarly snoking cannabis, same goes for other drugs like amphetamines.

Anyway the choice is yours so do as you wish.

would be nice to see those sources when you have time to find em (related to cannabis) not interested about amphetamines.


heres my subjective experience:

synthetic cb1/cb2 agonist worked wonders for my depression. way better than ssris ever did. It seemed to activate me more (energy and motivation) and not just feeling sleepy all day long (note: i used large dose of cb1 agonist before going sleep. None during the day). It took about 10 days of use for noticeable relief at day time. night time was always blissful. After day 4 the same large dose started working as anxiety relief but only at nights when i used it. 4 weeks or so and it started to work as anxiety relief at day time (no need for benzos or beta blockers anymore!). Cannot say if this is permanent or if it will reverse after stopping usage, since im still on the same regimen but hopefully it stays permanent

compared to ssris (tried few) only gave me side-effects and some energy but no motivation. It took about 2 months for them to start giving noticeable relief. Symptoms came back very fast after stopping ssri medication

cant say if it made me "dumber" like you say. I can sense that my short term memory isnt what it was before i started. But i guess memory problems will reverse after stopping usage

 

[seep]

If one wanted to translate this, and the studies that have replicated the results, into a treatment that was largely side effect free, they would probably stick with the endogenous cannabinoid used in the study. However, pharmaceutical companies won't produce anything that already exists in nature, because you can't patent it.

Generally this is true, but they can engineer a strain that synthesizes a novel and more efficacious alkaloid, and the patent for that would not expire. I'd be surprised if someone isn't already working on this.

Out-of-control neurogenesis in the dentate gyrus is a suspected cause of some disease processes, most notably Alzheimer's. Lithium has been proposed as a way of treating this (lithium, now there's a pharmacological entity that can't be patented).

 

[Advaneuro]

I very much enjoy cannabis i believe it helps me lead a forfilling life however i dont believe a CB1 agonist is an approiate antidepressent.

. One theory of learning/Thinking would support that by our teens the accumlative effects of learning to that point, often lost and redundant information inhibts our ability to process and store new material.CB1 agonism cause "long term depression" between synapes, this enhances learning by allowing new connections to be formed as and were needed. This may explain the freedom of mind experienced by cannabis users.

Long term depression maybe caused by many biological pathways, but with CB1 it is affected through Metabotropic glutamate receptor 5 which has the charateristic of only allowing repotention of synaptic connections at the theta rythm(4-8hz). When the body activates this receptor it has the ability to control the localisation to a high degree and hence achieve aims,but by dumping a chemical accross the whole body you effect most neurons. The result is that the brains signal transduction is severly compromised because of the reduced information load that maybe transmited. Schizophrenia and Autism are both conditions were the central control is operating at the theta rythm.

CB2 also shows a strong neurogenic effect, combined with NMDA antagonist effects, has anyone tried HU211(not210)?

I hope this helps to explain the side effects of CB1 agonists and why i advise against daily use

 

[kken]

erm sources would always be nice. you sound like you are throwing random stuff together. Are you saying CB1 agonist also activates mGluR5 ?

even if that would be true. i highly doubt that mGluR5 activation is behind cannabinoid mediated plasticity at any brain region.

HU211 seems interesting indeed

 

[Advaneuro]

Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens
exert
mGlu5 is predominantly located in postsynaptic elements (35) and because our BAPTA experiments show that eCB-LTD requires postsynaptic Ca2+ elevation, we hypothesized that prolonged stimulation of cortical glutamatergic afferents could activate postsynaptic mGlu5, whose role might be to translate the glutamate signal into eCB signaling. Indeed, Fig. 4 B shows that eCB-LTD is completely abolished by the broad-spectrum mGlu antagonist LY341495 and more importantly by the specific mGlu5 antagonist 2-methyl-6-(phenylethynyl) pyridine (MPEP) (36). In accord with a role of mGlu5, it was found that direct stimulation with the specific group 1 mGluR agonist (S)-DHPG (100 μM, 10 min) also causes LTD. Moreover, whereas direct pharmacological stimulation of mGlu5 with (S)-DHPG is sufficient to induce LTD in wild-type mice (Fig. 4 C, black dots), the long-term effects of the specific mGlu5 agonist were absent in CB1−/− mice (Fig. 4 C, white dots). Accordingly, the CB1 antagonist SR141716A (1 μM) eliminated mGlu5-LTD

 

[qwe]

i really hope society's emotional reaction to drugs simmers down a bit. these drugs have so much potential to help so many people. not to mention the radical (good) changes in society if psychedelics were widely used (hehe, that'd lower addictions too, irony)

it appears to me that cannabis is usually a self-medicating thing (in addition to the social thing). thanks for the study

 

[/navarone/]

But smoking cannabis is the most hardmul ROA out of all of em. Many good cannabinoids deteriorate with smoking.
I would propose cannabis as a herbal pill or as a food ingredient.
Plus hemp fiber is very resistent and would be a good dietary fiber alternative.

 

[qwe]

or vaporizer, if you want a faster buzz

 

[any major dude]

I recently read a study that blocked neurogenesis (in rats on SSRI's IIRC) via the rather interesting method of..., well i'll just quote it as its stated as simply as possible in the abstract " developing a transgenic mouse line to reversibly ablate adult neural stem cells and suppress neurogenesis. The nestin-tk mouse expresses herpes simplex virus thymidine kinase (tk) under the control of the nestin 2nd intronic enhancer, which drives expression in neural progenitors. Administration of ganciclovir (GCV) kills actively dividing cells expressing this transgene." The "andtidepressant" effect still occurred, sans neurogenesis. Don't know if this has been or will be repeated, but definitely a potential blow to the neurogenesis theory of depression. This research seems to show that that the antidepressant effect may be due to "re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex."

There is evidence to the contrary, but I think the more recent research is largely leaning this direction.

Also, I think the withdrawl of Rimonabant (CB1 antagonist) from the market due to it causing depression could support the CB1 agonist anti-depressant theory. There is a fair amount of research that is very recent or still ongoing into this area. I was going to post a link to a study, but honestly just search pubmed.gov for cannabinoid antidepressant, there's new stuff coming out all the time. The entire first page is all from late 2009-March 2010.

Anyone have access to, or even just the abstract from this study on WIN-55,212-2?

EDIT: added appropriate links & edited errors.

 

[melange]

maybe cb1 agonism prevents hippocampal dendritic atrophy

 

[any major dude]

I think i've read something to that effect before. Believe it was in relation to certain neuroprotective qualities of some cannabinoids and the potential utility in treating things like Alzheimer's, dementia, and just general effects of ageing.