34 replies to this topic

[Flex]

Found this paper recently and it made me wonder that the effects arent well researched and that the effects of Cannabis might have chronic consequences even to those who havent smoked in the adolescence:

 

Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity

We found that marijuana abusers display attenuated dopamine (DA) responses to MP, including reduced decreases in striatal distribution volumes. These deficits cannot be unambiguously ascribed to reduced DA release (because decreases in nondisplaceable binding potential were not blunted) but could reflect a downstream postsynaptic effect that in the ventral striatum (brain reward region) might contribute to marijuana’s negative emotionality and addictive behaviors.

http://www.pnas.org/...1/30/E3149.full

 

MP = Methylphenidate

 

I will try to find some targets and corresponding supplements that might (sigh) reverse something

and post it + I will report the results.

 

There are several papers that have to be read regarding:

- the cause of the  decrease of tyrosine hydroxylase

- the reason of decreased dopamine activation/response, release and synthesis in the Striatum.

-> according to one paper, it could be a downstream problem and I believe to read something about fos antigenes

- any other related problem like, altered plasticity.

 

Dont get me wrong, I´m aware that I´m just an amateur but a desperate one..

my problems are: affect i.e. mutism and avolition in social interactions, introverty, cognition, memory retrieval & a few others.

So You might allready assume that my social life was, is and will be bad, means no wife no childern & etc. if this goes on.

So I need a solution !

Lets see how far this goes. Perhaps some questions cant be answered even by the scientists up to this date.

 

I´m happy for any thoughts and inputs

Edited by Flex, 24 May 2015 - 01:39 AM.

[fntms]

You could try a course of sulbutiamine, up to 600mg per day. It helps with introversion.

[Flex]

Thanks will try it

Btw: Carnosine had some similair effects, hard to describe: kind of emancipation/self-assertion but not exactly what I wanted.

[OneScrewLoose]

First thing I would do is try CBD. It works as an inverse agonist at CB2, essentially having the opposite effect of THC. It does not make you high and is 100% legal. I recommend this ejuice:
http://www.ehookahbr...h-vapor-flavors

 

And getting and Ego-C Twist for $15 on eBay to start off with.

 

If you want to explore the effects of increased DA in a short time, try over the counter L-Dopa, which must be combined wit EGCG for it to get the brain. If that helps, then there are approaches that can be taken to help repair the dopamine system.

[Flex]

Thanks but I believe that something which acts on the CB1 receptor would be more suitable.

I will of course nevertheless try CBD and the L-Dopa + EGCG combo.

Edited by Flex, 26 May 2015 - 02:40 PM.

[gamesguru]

Flex, it sounds like the PMAS study does not evaluate effects in abstinent former abusers (ie. one who vaped 5 lbs in 5 years during the end of high school and beginning of college).

It would be necessary to look at abstinent users to evaluate long-term damages, if any are detectable.  You need to give the body time to heal itself, to re-equalize and restore homeostasis.

Only from there should we consider restorative strategies....but I am convinced the first step is to stop using the herb every day.  Try to keep its use to after 5pm, eventually to two days weekly, with the goal of finally cutting it out.  I don't think THC has much of a role to play in a successful and fulfilling life.  I mean you could vape the pure CBD strains, those should be at least pro-cognitive, pro-emotive, but trust me, you're not gonna find any pleasure or enjoyment or addiction in that.

[Flex]

Yes its afaik not know whether those alteration will relieve to a great extend. This sentences sounds concerning:

Structural and Functional Imaging Studies in Chronic Cannabis Users: A Systematic Review of Adolescent and Adult Findings

However, overall the results suggest that long-term cannabis use may result in persistent alterations in brain function and morphology that would extend beyond the period of intoxication [28], [31], and that earlier onset of use may be associated with greater detrimental effects [32], [33].

http://www.ncbi.nlm....les/PMC3563634/

 

I´m still affected and havesome doubts on the body owns healing capacity

because I´ve smoked from the age of 15 to 22, had 2 Years a break because of Risperdal (which was a "bright idea" from my psychiatrist)

and kept on from 24 untill 26. I had since then, here and there, some sessions but rather random and I havent smoked pot from Sept 2013 untill recently

As You see, I had long breaks but no big improvements in terms of affect.

Those problems are actually exact the same as the negative symptoms of Schizophrenia, exept the lack of emotion

 

A short summary of a list of negative symptoms are:

    lack of emotion - the inability to enjoy regular activities (visiting with friends, etc.) as much as before
    Low energy - the person tends to sit around and sleep much more than normal
    lack of interest in life, low motivation
    Affective flattening - a blank, blunted facial expression or less lively facial movements, flat voice (lack of normal intonations and variance) or physical movements.
    Alogia (difficulty or inability to speak)
    Inappropriate social skills or lack of interest or ability to socialize with other people
    Inability to make friends or keep friends, or not caring to have friends
    Social isolation - person spends most of the day alone or only with close family

http://www.schizophr...diag.php#common

 

The long break did improve the emotions and the interrest in socializing but not the ability (funny huh?).

And everything other stayed more or less the same, unless when taken something like EGCG & etc.

 

I have to add that I´ve experimented 2 years ago with Ethyphenidate + various stuff like Amisulpride and L-dpoa

and this fried my brain which resulted into Depressions and somewhat lower emotions and decrease of libido and euphoria,

but I dont believe that it affected my skills too much.

 

Admittely my affect was not that great before but ok and a near relative who smoked randomly, dont have those problems as I.

Edited by Flex, 26 May 2015 - 08:14 PM.

[Flex]

From my experience, the responses arent that big so I gonna post nevertheless as a kind of a blog with questions and possible ways to takle this.

 

Again a clue that points out the negative (and possible longterm effects) of cannabis:

The link between dopamine function and apathy in cannabis users: an [18F]-DOPA PET imaging study

Cannabis is the most widely used illicit drug in the world, and regular use has been associated with reduced motivation, i.e. apathy. Regular long-term cannabis use has been associated with reduced dopamine synthesis capacity. The mesolimbic dopaminergic system mediates the processing of incentive stimuli by modifying their motivational value, which in turn is modulated by endocannabinoid signalling. Thus, it has been proposed that dopaminergic dysfunction underlies the apathy associated with chronic cannabis use.

http://link.springer...0213-014-3523-4

 

Heres one of the underlying mechanisms:

Cannabinoid Action Depends on Phosphorylation of Dopamine- and cAMP-Regulated Phosphoprotein of 32 kDa at the Protein Kinase A Site in Striatal Projection Neurons

Herbal cannabis, smoked in the form of marihuana or hashish, is the most common illicit drug consumed in the Western world. In the brain, cannabinoids interact with neuronal CB1 receptors, thereby producing a marked reduction of motor activity. Here, we report that the motor depressant effect produced by the cannabinoid receptor agonist (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]trans-4-(3-hydroxypropyl)cyclohexanol (CP55,940) is attenuated by genetic inactivation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32),

http://www.jneurosci...pe2=tf_ipsecsha

 

--> reduced motor activity is afaik either caused by reduced dopamine D2 activation and/or by reduced dopamine production and is related to the Striatum which is also implicated into mood, affect and motivation and perhaps cognition( since theres a crosstalk between e.g. the PFC)

 

- I´ve read allready a bit into DARPP-32 because its also impicated into the effects of cocaine ( a desperate attempt to improve my situation 2 years ago..)

See my post#2 in my:

Cocaine News + reversal thread

http://www.longecity...ad/#entry653765

 

This looks also interresting:

Concomitant activation of adenylyl cyclase suppresses the opposite influences of CB(1) cannabinoid receptor agonists on tyrosine hydroxylase expression.

http://www.ncbi.nlm....pubmed/18992715

 

--> The reason might be:

Reciprocal influences of CB1 cannabinoid receptor agonists on ERK and JNK signalling in N1E-115 cells.

Using a luciferase reporter assay, we observed that the MAP/ERK kinase (MEK1/2) inhibitors, U0126 (5 μM) and PD98059 (25 μM) reduced basal activity of the TH gene promoter while SP600125 (10 μM), an inhibitor of JNK, significantly increased this basal activity.

http://www.sciencedi...014579308008399

 

This author (Bosier B) has done further seemingly, helpful investigations into this topic. Admittely, his statement seem to me sometimes contradictory e.g. in regards of TH expression.

Anyway, Forskolin seems to further decrease the TH expression:

 

Concomitant activation of adenylyl cyclase suppresses the opposite influences of CB(1) cannabinoid receptor agonists on tyrosine hydroxylase expression.

Therefore, we studied the consequences of manipulating adenylyl cyclase activity with forskolin on the regulation of TH gene transcription in neuroblastoma cells (N1E-115). Reporter gene experiments performed with the luciferase sequence cloned under the control of modified fragments of the TH gene promoter revealed that the AP-1 consensus sequence is essential for cannabinoid-mediated regulation of TH expression. Consistently, inhibition of PKC totally blocked the responses mediated by both HU 210 and CP 55,940. In addition, forskolin which boosts adenylyl cyclase activity remarkably modified the responses to the cannabinoid agonists. Thus, in these conditions, both agonists efficiently reduced TH gene promoter activity, a response requiring functional PKA/CRE-dependent signallings. Finally, the modulations of the promoter were inhibited in pertussis toxin treated cells, suggesting that responses to both agonists are mediated through G(i/o)-dependent mechanisms. Emphasising on the importance of functional selectivity at GPCRs, these data demonstrate that the concomitant activation of adenylyl cyclase by forskolin strongly influences the biochemical responses triggered by distinct cannabinoid agonists.

http://www.ncbi.nlm....pubmed/18992715

 

 

As expected for cannabinoid agonists, the exposure to either Δ(9)-THC, HU 210 or CP 55,940 induced both catalepsy and hypolocomotion. Supporting a possible long-lasting control on dopaminergic activity..

- so here comes the ? -

we noticed a significant HU 210-mediated increase in TH expression in the striatum that was concomitant with an increase in striatal dopamine content. Surprisingly, while a similar trend was reported with Δ(9)-THC, CP 55,940 completely failed to modulate TH expression or dopamine content. Nevertheless, the access of CP 55,940 to brain structures was validated by determinations of drug concentrations in the tissue and by ex vivo binding experiments. Furthermore, confirming the central activity of CP 55,940, the analysis of dopamine metabolites revealed a reduction in striatal DOPAC concentrations. Consistent with the involvement of the CB(1) cannabinoid receptor in these different responses, both HU 210- and CP 55,940-mediated effects were prevented by SR 141716A. Therefore, the present data suggest that both HU 210 and CP 55,940 cause a delayed/persistent regulation of the dopamine neurotransmission system.

 

SR 141716A = a CB1 antagonist prevents the effects on TH expression

 

 

EDIT :

 

Found a full-text of

Differential modulations of striatal tyrosine hydroxylase and dopamine metabolism by cannabinoid agonists as evidence for functional selectivity in vivo.

 

http://www.uclouvain...acology2012.pdf

Its beeing confirmed that adenyl cyclase is responsible for the decrease of TH. Interrestingly, HU-210 shares similair effects to THC but THC seem to not affect TH that much.

 

I´m currently thinkng of HU-210 sour4ces but have to look more into it.

TH-expression might be good on the first look but its also implicated into Alzheimer and PArkinson so a balanced increas would be wise (if possible)

Edited by Flex, 26 May 2015 - 10:32 PM.

[OneScrewLoose]

Flex, it sounds like the PMAS study does not evaluate effects in abstinent former abusers (ie. one who vaped 5 lbs in 5 years during the end of high school and beginning of college).
It would be necessary to look at abstinent users to evaluate long-term damages, if any are detectable. You need to give the body time to heal itself, to re-equalize and restore homeostasis.
Only from there should we consider restorative strategies....but I am convinced the first step is to stop using the herb every day. Try to keep its use to after 5pm, eventually to two days weekly, with the goal of finally cutting it out. I don't think THC has much of a role to play in a successful and fulfilling life. I mean you could vape the pure CBD strains, those should be at least pro-cognitive, pro-emotive, but trust me, you're not gonna find any pleasure or enjoyment or addiction in that.

I've met people who get immmediate relaxation from CBD. And nothing in others. By being an inverse agonist at CB2, it releases GABA, where as THC reduces GABA release. This is what causes the increased depth of sensation when smoking weed, and why it makes some anxious. CBD is not habit forming in the least and does not cause any high.

I agree that he should quit completely. But why should he suffer as his body rebuilds when there are safe things out there that can ease the transition AND help repair?

Edited by OneScrewLoose, 26 May 2015 - 10:51 PM.

[gamesguru]

Yes its afaik not know whether those alteration will relieve to a great extend.

Tried unsuccessfully for 20 mins to pin down a citation, but I have read many places that upon cessation at least the behavioral/memory/cognitive deficits, measured of course by cognitive tests in a lab, reverse themselves to a degree they are not significant or measurable.  The emotional disruption, in my reading, is more permanent (maybe behavioral isn't the word).

 

 

I've met people who get immmediate relaxation from CBD. And nothing in others. By being an inverse agonist at CB2, it releases GABA, where as THC reduces GABA release. This is what causes the increased depth of sensation when smoking weed, and why it makes some anxious.

I agree that he should quit completely. But why should he suffer as his body rebuilds when there are safe things out there that can ease the transition AND help repair?

 

According to ScienceGuy then, CBD would be expected to down-regulate GABA receptors and promote anxiety, in the long term chronic user.  Had no idea about the connexion between GABA and depth perception.

 

 

As his body rebounds you mean?  He hasn't damaged cells per se, but he has tinkered with receptor densities and wiring patterns.  To return to near baseline, this will require abstinence and time.  Time heals all wounds, and this isn't even a wound.

Which things are recommended in the transition/withdrawal?  Falcarinol, fish oil, magnesium?  Please enlighten me.

[OneScrewLoose]

I've seen no evidence that chronic CBD use upregulates CB2 receptors or changes GABA receptor density. Not all substances cause as much of a homeostatic response (if at all), as others. For instance, it appears the melatonin does not downregulate melatonin receptors. It turns out amphetamines do not downregulate VMAT transporters while cocaine does. Nardil, the irreversible MAO-I has a paradoxical effect of lowering norepinephrine. A recently designed opiate, derived from salvia, agonizes mu receptors without causing downregulation at all. Theoretically however, this might kill you. The antipsychotic Amisulpride increase dopaminergic activity at doses below 400mg, and decreases it at doses above 400mg.

These things are often way more complicated than they seem. Given the complete lack of abuse potential of CBD, I would not worry about GABA downregulation.

Yes, rebound is what I meant. And taking certain things can help that rebounding, like CBD and L-Dopa.

Edited by OneScrewLoose, 27 May 2015 - 01:45 AM.

[VerdeGo]

How often during a day did you use cannabis? 

 

You may want to look into myrcene, found in lemongrass oil and cannabis, as there is some evidence it binds to cannibinoid receptor 1. 

 

http://www.ncbi.nlm....pubmed/20118579

 

Cannabis is full of terpenes and terpenoids, and so are essential oils. Some oils may negate some of the effects you are experiencing. I'd also consider rosemary oil for a 70% increase in memory, and other oils for specific issues. 

 

https://www.leafly.c...is-aromatherapy

 

http://herbs.mxf.yuk...cs#.VWU__09Viko

 

The effects of lemongrass oil are very unique, but definitely marijuana-ish. This is no doubt from the myrcene content. Myrcene is said to be a major player in the marijuana high of good quality marijuana.

In me, 3 drops taken in a capsule are felt within 10 minutes. It begins with a mild tingling sensation, some sedation, mostly of a mental nature similar to marijuana. It definitely makes me a little "stoned". It's not at all psychedelic though. It's just a mental "stoning" effect. It's actually quite pleasant. I can see it would go well with passionflower. I have not yet tried it with passionflower however.

Lemongrass oil should NOT be confused with lemon oil. Their effects are COMPLETELY DIFFERENT. Lemon oil is a stimulant/nootropic. Lemongrass is a marijuana-like sedative, with some pain relieving effects. The two do smell similar however because they both contain a ton of citral, but effects wise, they are worlds apart.

I like them both, but for different purposes.

I have yet to combine lemongrass oil with anything else. The myrcene content should help activate allylbenzenes and other oils. It is said to help many compounds cross the blood brain barrier.

Elemi oil actually contains some myrcene. Some contains quite a lot. I've had elemi oil before that had effects that were similar to lemongrass oil, but it was also psychedelic (because of the elemicin). I have the feeling myrcene will potentiate elemicin to a certain level. This is one thing I plan to try in the near future.

On it's own, lemongrass is quite pleasant. I don't normally like sedatives, but myrcene is a pleasant sedative. It doesn't make me feel withdrawn, which is the thing I usually hate about most other sedatives. Myrcene seems to be a sedative that's also an anti-depressant, and a pain reliever. It's nice for helping you sleep at night, that's for sure.

[OneScrewLoose]

How often during a day did you use cannabis? 

 

You may want to look into myrcene, found in lemongrass oil and cannabis, as there is some evidence it binds to cannibinoid receptor 1. 

 

http://www.ncbi.nlm....pubmed/20118579

 

Cannabis is full of terpenes and terpenoids, and so are essential oils. Some oils may negate some of the effects you are experiencing. I'd also consider rosemary oil for a 70% increase in memory, and other oils for specific issues. 

 

https://www.leafly.c...is-aromatherapy

 

http://herbs.mxf.yuk...cs#.VWU__09Viko

 

The effects of lemongrass oil are very unique, but definitely marijuana-ish. This is no doubt from the myrcene content. Myrcene is said to be a major player in the marijuana high of good quality marijuana.

In me, 3 drops taken in a capsule are felt within 10 minutes. It begins with a mild tingling sensation, some sedation, mostly of a mental nature similar to marijuana. It definitely makes me a little "stoned". It's not at all psychedelic though. It's just a mental "stoning" effect. It's actually quite pleasant. I can see it would go well with passionflower. I have not yet tried it with passionflower however.

Lemongrass oil should NOT be confused with lemon oil. Their effects are COMPLETELY DIFFERENT. Lemon oil is a stimulant/nootropic. Lemongrass is a marijuana-like sedative, with some pain relieving effects. The two do smell similar however because they both contain a ton of citral, but effects wise, they are worlds apart.

I like them both, but for different purposes.

I have yet to combine lemongrass oil with anything else. The myrcene content should help activate allylbenzenes and other oils. It is said to help many compounds cross the blood brain barrier.

Elemi oil actually contains some myrcene. Some contains quite a lot. I've had elemi oil before that had effects that were similar to lemongrass oil, but it was also psychedelic (because of the elemicin). I have the feeling myrcene will potentiate elemicin to a certain level. This is one thing I plan to try in the near future.

On it's own, lemongrass is quite pleasant. I don't normally like sedatives, but myrcene is a pleasant sedative. It doesn't make me feel withdrawn, which is the thing I usually hate about most other sedatives. Myrcene seems to be a sedative that's also an anti-depressant, and a pain reliever. It's nice for helping you sleep at night, that's for sure.

I have to raise some umbridge here, and I might come off as a dick, but it has to be said. There's no evidence for any effect from Lemongrass Oil. The last two links you used have no citations. The first one is from journal with an impact factor of only 1.38. Anything below 2 is to be taken with a huge grain of salt. Here is the full study from that link:

https://www.jstage.j...2/58_2_201/_pdf

Quantitative comparison of cannabis smoke and vapor shows that vaporizing cannabis with the Volcano® is a more reliable and safer administration form for the delivery of D9 - THC due to the lack of pyrolytic degradation and more effi- cient D9 -THC volatilization.

Sounds like an advertisement. They could have used any non-branded vaporizer. Additionally, all the terpenoids seem to come from cannabis in this case, and you can't simply extract that to terpenoids in other substances.

Essential oils are not a cure all, and on top of that, their evidence for efficacy seems scarce.

[Flex]

Ok after hours of recherche I´m quiet exhausted and I just want to post my findings.

So, I found out this:

 

The coactivation of CB1 and adenly cyclase/ and or other targets like the Dopamine D2 receptor leads to an activation of G protein coupled receptors, in this case G i/o (but perhaps Gq/11 as well)

Gi/o exert ist action by decreasing AP-1 translation (or something like that) which in turn decreaes the Tyrosin hydooxilase expression.

 

The effects of THC can not be reverted by a CB1 antagonist but by a gi/o inhibitor i.e. Pertussis toxin (PTx)

Sources for this are mainly:

http://www.ncbi.nlm....les/PMC2527844/

http://www.uclouvain...acology2012.pdf

and maybe other papers from Bosier

 

So I spend a good ammount  of the time finding a inhibitor like PTx and found Lithium (dont know whether there are more)

 

Lithium increases tyrosine hydroxylase levels both in vivo and in vitro.

http://www.ncbi.nlm..../pubmed/9523597

 

Lithium regulates PKC-mediated intracellular cross-talk and gene expression in the CNS in vivo.

http://www.ncbi.nlm....pubmed/11249800

 

You might think, this is an old hat and why didnt I looked for anything that increases TH expression ?

I believe that I have to tackle paticular this mechanism to be sure to reverse one of the "root causes"

because I was affraid that other compounds wont be able to reverse it and wouldnt work or couldnt have any enduring effects.

 

I dont know whether its mentioned in the posted papers but I´ve read that an impaired reactivity of the dopamine receptors in the Striatum is also responsible for the blunting/amotivational effects of weed.

This could be explained by altered G Protein signalling, incl, coupling and uncoupling like in the case of SSRIs

 

Differential regulation of 5-HT1A receptor-G protein interactions in brain following chronic antidepressant administration.

Thus, the desensitization of somatodendritic 5-HT(1A) autoreceptors in the dorsal and median raphe following chronic SSRI treatment appears to be due to a reduced capacity of the 5-HT(1A) receptor to activate G protein.

http://www.ncbi.nlm....pubmed/11927181

 

The list goes actually on e.g. altered NMDA/AMPA ration, impaired calcium signalling ( could be afaik reversed by Piracetam) and other ion channels but I would be happy if at least my affect gets better.

In regards of Cognitive (PFC) functions, I found this and I´m curious whether its responsible for the decrease of PFC function alá due to too much sedation(?):

 

Forebrain-specific inactivation of Gq/G11 family G proteins results in age-dependent epilepsy and impaired endocannabinoid formation.

We investigated the role of Gq/G11 family G proteins in the regulation of neuronal excitability in mice that selectively lack the alpha-subunits of Gq and G11, G alpha q and G alpha 11, respectively, in forebrain principal neurons. Surprisingly, mutant mice exhibited increased seizure susceptibility, and the activation of neuroprotective mechanisms was impaired

http://www.ncbi.nlm....pubmed/16847339

 

Found in:

http://www.420magazi...-dependent.html

 

 

Edit: have to add that inhibition of Gi/o can(?) decrease BDNF and GDNF and lead to cell death (apostosis)

 

The G-protein inhibitor, pertussis toxin, inhibits the secretion of brain-derived neurotrophic factor.

http://www.ncbi.nlm....pubmed/11098120

 

Tricyclic antidepressant amitriptyline-induced glial cell line-derived neurotrophic factor production involves pertussis toxin-sensitive Gαi/o activation in astroglial cells

http://www.jbc.org/c...jbc.M114.622415

Edited by Flex, 29 May 2015 - 02:25 AM.

[VerdeGo]

If lithium increases tyrosine levels, why not take tyrosine itself? Or DLPA for endorphins/dopamine? 

 

Here's a few other suggestions to look into. Since cannabis releases a lot of melatonin, supplementing with melatonin may help. L-glycine can help with a solid night's sleep, and is often used with melatonin. Cannabis also affects glycine receptors, so it may ease symptoms. Magnesium and taurine (or try magnesium taurate) help to regulate neurotransmitters. Liquid carnitine with B6 has helped me in past predicaments. I'm sure I'll be in your shoes at some point Flex, and I'd like to see a range of effective options that don't involve drugs that are prescription-only or have a long list of side effects. Perhaps taking certain nutrients, minerals, vitamins, aminos, etc., that target certain areas that cannabis does can cause a blanketing effect and reduce any discomfort. As far as restoring your brain for the long term, magnesium and taurine seem like suitable options. And if you want to increase your memory try things that are proven to work like rosemary oil or capsules. You can also go to your local vitamin store and sample a "tester" bottle of rosemary or lemongrass to see what effects you experience for free. No money wasted. 

 

http://news.discover...mory-130409.htm

 

A study presented at the British Psychological Society’s annual conference in Harrogate showed that the smell of the essential oil from the herb appears to enhance the ability to remember events and complex tasks.

 

I'd keep your options simple, and try the stuff with the best safety records first, and then branch out. I haven't heard of any reports of permanent brain damage from long term cannabis use, but then again I haven't really searched. I'm still confused as to how long you have used it and how long it's been since you last smoked, along with how much you were smoking/vaping each day (along with how often during the day). I'm sorry if I missed this from your previous posts. Since cannabis affects the brain in so many ways, a balanced and healthy approach should be crucial, along with proper diet and exercise. I wish you all the best, and please keep us informed of your progress.

[Flex]

Thank You, I appreciate Your help and Your suggestions.

I´ve segmented my post in several parts, so You dont have to read an entire block

 

- I´ve smoked arround 10 Years cannabis and this on average 3 Joints almost every day, so I would say ca. 0.6 grams/day. I´ve quit 2 Years ago but have reduced it almost completly 4 Years ago.

I was somehow addicted to it and a week without dope was totally unusual i.e. beeing sober was new for me ( dont want to overdo this, to put it in the right way: there was a drug-seeking behavior but more psychological)

 

- In regards of cannabis induced damage, I´ve read that it can promote apostosis (via decrease of mitochndrial respiration, increase of COX-2 signaling-> inflammation)

not only in cancer cells but afaik You would have to be a hardcore smoker and this over Years to be concerned, apparently overdoing anything is allways not good.

Cannabis is linked to a decrease of the brain volume and densities of receptors, which are, as far as I know, reversible.

However there is a difference of cannabis- or any other compound exposure in different developmental stages e.g. prenatal or, more commonly, adolescence which causes alterations that wouldnt affect an adult.

 

In the adolescence, Your brain reoganizes its receptors (e.g. pruning) and pathways via cannabinoid receptors (among other mechansms)

and in addition of e.g. those effects in the prevorious posts, Your brain growth and development is also altered even when exposed to cigarettes at that time.

Example: even when You arent genetically "destinated" to develop psychosis, You might have a 3 fold greater chance to it because of the changes.

--> A Psychiatrist has told me that my case can be considered as nerval anesthesia, means: fried brain.. but You never know whether anything ground-breaking comes out the next Years.

 

Btw: When asking a Doc about the end of adolescence, he would answer You that he doesnt knows^^

It has been just recently researched that the PFC(preforntal cortex) matures untill the age of 30.

Afaik this is the case in males, the adolescence in womens ends afaik at 22y

 

- comming back to the post above:

its not about Tyrosine but an enzyme that is called tyrosine hydrooxilase(TH). This converts in the brain tyrosine into dopamine.

So if You inhibit TH, You would develop transiently parkinson symptoms as well a cognitive impairments & etc.

Cannabis does this enduringly in a brain region via a certain mechanism , so I´ve looked for something that reverses its effects via the same way because I cant know whether a different route is blocked by this mechanism.

 

I´ve tried already many many substances, I guess arround 100 different medications and herbs  but the effects were mostly not perresistent

Btw: cerebrolysin had some good effects but it didnt work for everything.

 

- I´m aware that perscription drugs are problematic. Beside their adverse effects, they could change something like SSRI´s causes perresistent sexual dysfunctions.

In my view could actually every med have secondary mechanism that arent allways related to the primary and which is either good or bad.

Its just that uptill now I couldnt find anything that has the same effects like Lithium.

 

- I had allready some good effects with fresh rosemary and it did definetly something, thanks again for the suggestion.

Unfortunaetly is Germany not that service-oriented in regards of free samples.. I´m currently out of money but I will look into it when I´m liquid again.

Will of course keep You informed about the progress.

Edited by Flex, 29 May 2015 - 10:01 PM.

[VerdeGo]

Dopamine (or lack thereof) can play a role in addiction. Beyond that, I don't know the specifics. Have you looked into gastrodin with its ability to regenerate neurons? It sounds very promising, and also boosts GABA by 34%, but unfortunately it's not widely known, and there aren't many subjective reports about it. I still looks promising for neuroregeneration. 

 

You were taking the Risperdal for bipolar? Have you conidered the possibility it is schizophrenia? 

 

As far as rosemary, you received a positive benefit from the plant itself or the oil? If it was simply from inhaling the strong scent of a sprig of rosemary, then you just might greatly benefit from the essential oil, which would be far more powerful in effects. If this is the case, I'd save up some money and give it a try. 

 

Cannabis may or may not have long term effects on cognition 1-4 weeks after quitting (looks like it does), but chances are you simply need to correct something in the brain to regain your full cognition and return to a state of homeostasis. If I was in your shoes, I'd definitely give magnesium and/or taurine a try (as long as they don't interact with anything you're taking), and stick to rosemary or other things that have been proven to be effective for you. Both magnesium, taurine, and glycine are said to be very helpful to people experiencing those side effects, and references are easy to find online. 

 

Have you tried NSAIDs (anti inflammatory pain relievers?). Simply to test out whether brain inflammation is an issue. Take an ibuprofen and see if your cognition drastically improves. Such an approach is successfully treating depression and other issues in some patients, but it's only a temporary approach to see what the root cause is. Rosemary is also an anti-inflammatory, so I wonder if you're experiencing any inflammation that's affecting cognitive function? 

 

http://evolutionaryp...izophrenia.html

 

It seems that withdrawal and long term effects of other substances can be abated with similar-acting substances, but since cannabis is so complex and unique, it's hard to find a magic bullet to replace it or ease to ease its withdrawal. 

 

 

Edited by VerdeGo, 30 May 2015 - 05:13 AM.

[Flex]

X link to my findings of cannabinoid antagonists

 

Cannabinoid: cb1 antagonist cb2 agonists/antagonists and Gpr55 antagonists

http://www.longecity...55-antagonists/

[Mind_Paralysis]

Verdego: I'd recommend he tries out Tylenol/Paracetamol/Alvedon/Acetaminophen instead of an NSAID, if he wants to affect neural inflammation. It's actually been proven to have anxiolytic effects, and it does interact fairly directly with iLb - he should notice effects quicker on Paracetamol than on NSAID's.

 

Flex, have you considered trying one of the Racetams, while you're recouping? I'm thinking if you're more towards the Schizo-affective state, then Aniracetam might work wonders for you.

[gamesguru]

- so here comes the ? -

we noticed a significant HU 210-mediated increase in TH expression in the striatum that was concomitant with an increase in striatal dopamine content. Surprisingly, while a similar trend was reported with Δ(9)-THC, CP 55,940 completely failed to modulate TH expression or dopamine content. Nevertheless, the access of CP 55,940 to brain structures was validated by determinations of drug concentrations in the tissue and by ex vivo binding experiments. Furthermore, confirming the central activity of CP 55,940, the analysis of dopamine metabolites revealed a reduction in striatal DOPAC concentrations. Consistent with the involvement of the CB(1) cannabinoid receptor in these different responses, both HU 210- and CP 55,940-mediated effects were prevented by SR 141716A. Therefore, the present data suggest that both HU 210 and CP 55,940 cause a delayed/persistent regulation of the dopamine neurotransmission system.

 

SR 141716A = a CB1 antagonist prevents the effects on TH expression

 

 

EDIT :

 

Found a full-text of

Differential modulations of striatal tyrosine hydroxylase and dopamine metabolism by cannabinoid agonists as evidence for functional selectivity in vivo.

 

http://www.uclouvain...acology2012.pdf

Its beeing confirmed that adenyl cyclase is responsible for the decrease of TH. Interrestingly, HU-210 shares similair effects to THC but THC seem to not affect TH that much.

 

I´m currently thinkng of HU-210 sour4ces but have to look more into it.

TH-expression might be good on the first look but its also implicated into Alzheimer and PArkinson so a balanced increas would be wise (if possible)

 

Any word on effects of am2201?  Am curious.

 

Also this post reminds me of another by you: http://www.longecity...ds/#entry706163.

Might horny goat weed and it TH-regulation be of use in restoring persistent dopamine-excited states to baseline?
 

[gamesguru]

instead of an NSAID, if he wants to affect neural inflammation ...

ilb = incidental lewy body???

 

 

Ginger—An Herbal Medicinal Product with Broad Anti-Inflammatory Actions

http://online.lieber.../jmf.2005.8.125

 

Ginger Extract Inhibits β-Amyloid Peptide–Induced Cytokine and Chemokine Expression in Cultured THP-1 Monocyte

online.liebertpub.com/doi/abs/10.1089/acm.2004.10.1009

 

Interleukin-1bold beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain

http://www.nature.co...s/410471a0.html

 

Cyclooxygenase-2 inhibitors in ginger

http://www.sciencedi...367326X1000239X

------

 

Consumption of Grape Seed Extract Prevents Amyloid-β Deposition and Attenuates Inflammation in Brain

http://link.springer...2640-009-9000-x

 

Polyphenols and mitochondria: An update on their increasingly emerging ROS-scavenging independent actions

http://www.sciencedi...00398611400174X

 

Anthocyanins Attenuate Inflammatory Stress Signaling in Mouse Brain BV-2 Microglial Cells

http://pubs.acs.org/....1021/jf203989k

 

[Flex]

 

Any word on effects of am2201?  Am curious.

 

Also this post reminds me of another by you: http://www.longecity...ds/#entry706163.

Might horny goat weed and it TH-regulation be of use in restoring persistent dopamine-excited states to baseline?
 

 

 

no the Scientists used afaik only the 2 mentioned ligands and not AM2201

albeit they have some differences in regards of TH expression IIRC, I dont know what differences might AM2201 bear because I didnt found much about it.

Wouldnt touch any synthetic canabinoid anyway. I´m just for the pathways that are affected by THC.

 

tried Horny goat weed + topiramate(25mg) just recently.

had some good minor effects but I have to take this for a longer time to see whether its something substancial.

 

Pregabalin and topiramate regulate behavioural and brain gene transcription changes induced by spontaneous cannabinoid withdrawal in mice.

http://www.ncbi.nlm....pubmed/22017514

 

 

@Stinkorninjor & Verdego

 

Thanks for the suggestions but I have a few chinese meds that modulate COX-2 as well as other inflammation pathways

Paeonol exerts an anticancer effect on human colorectal cancer cells through inhibition of PGE₂ synthesis and COX-2 expression.

http://www.ncbi.nlm....pubmed/25322760

 

Anti-inflammatory effects of Scutellaria baicalensis extract via suppression of immune modulators and MAP kinase signaling molecules.
http://www.ncbi.nlm....pubmed/19699788

 

Effect of baicalin on toll-like receptor 4-mediated ischemia/reperfusion inflammatory responses in alcoholic fatty liver condition.

http://www.ncbi.nlm....pubmed/22019745

[gamesguru]

Many Americans, perhaps 100,000 used AM2201 on probation with the courts, to avoid positive drug tests, when it was in legal spice blends and urine tests had not been standardized.

But if there is no information in the literature about it, there is no use speculating on its potential permanent effects.

[Ron.Stone]

Hey Flex, 

 

what is the current state of your research? 

[gamesguru]

I'm thinking Flex has high functioning autism or aspergers.  He has an exceptional vocab and intelligence, but blunted affect and poor social skill.  He admits he had poor affect before Cannabis, and that his social impairment does not resolve despite extended periods of abstinence.  He thinks it is schizophrenia, but he reports no positive [delusions/hallucinations/thought alienation] or cognitive symptoms [well maybe a little disorganized thinking, but nothing too worrisome], only negative.  All things point to autism.

[Sleepdealer]

He sounds basically like me. I too sort of experience the same negative symptoms that are also included in schizophrenia. Actually I wonder. When there will be something that effectively treats the negative symptoms in schizophrenic patients, will it for for people like us who don't really have schizophrenia, but only most of the negative symptoms? I'm curious for what we will be writing about here on Longecity in 10-20 years.

[Mind_Paralysis]

He sounds basically like me. I too sort of experience the same negative symptoms that are also included in schizophrenia. Actually I wonder. When there will be something that effectively treats the negative symptoms in schizophrenic patients, will it for for people like us who don't really have schizophrenia, but only most of the negative symptoms? I'm curious for what we will be writing about here on Longecity in 10-20 years.

 

Possibly selective D4 dopamine agonists.

 

A-412,997 is the gift that just keeps on giving, but never gets anything back... from the drug-companies.

 

https://en.wikipedia.../wiki/A-412,997

 

Dopamine, cognitive function, and gamma oscillations: role of D4 receptors

http://www.ncbi.nlm....les/PMC3698457/

 

The negative symptoms of Schizophrenia wears some resemblance to predominantly inattentive ADHD, or to be more accurate, SCT - Sluggish Cognitive Tempo - and this perticular compound was created because research within ADHD had shown that the D4 -receptor sub-type appears to be substantially different from the other receptors, and primarily involved in cognition - hence it was (is?) being researched as a potential treatment for such cognitive disorders.

 

Someone later then figured out that since D4-selective agonists do not cause addiction, mania or any peripheral effects whatsoever, that perhaps they could then be used to treat negative symptoms, since it appears as if agonism on the D1, D2, D3, D5 receptors appear to be the ones that cause such effects - and lo and behold...

The answer is yes.

 

Much like Buprion and Effexor have been shown to be safe additions to the treatment of Bipolar disorder, when combined with mood-stabilisers, perhaps D4-agonists may prove to be a safe and efficient treatment-method of negative symptoms within Schizophrenia - when combined with antipsychotics, of course.

 

 

(not that it necessarily would be necessary, in order to prevent triggering positive symptoms, but mainly because the patients have to be on antipsychotics anyway)

[Sleepdealer]

The article seems relevant but won't a D4 agonist just downregulate the D4 receptors in the end? If there's a -/- mutation which already decreases novelty seeking behaviour and causes cognition problems, then that would be bad. Also, A-412,997 is insanely expensive and in very low quantities as far as I can see.

Edited by Sleepdealer, 01 November 2015 - 08:49 PM.

[basileuz]

Low-dose naltrexone (LDN).

There's a lot of FUD about it, but it really works for drug recovery. Your dopamine receptors become like new.

Take 5mg before going to sleep. Should be easy to obtain since it's unscheduled.

[Sleepdealer]

Okay, well it seems it's a prescription drug here in Sweden. But still, the price tag on A-412,997 is still well over a hundred bucks and that's only for a few milligrams, so it's not really viable, as of yet.