I was seriously laughing as I scrolled through your pics of open tabs, until I stopped scrolling!
SweetSue's Class Notes
- Thread starter SweetSue
- Start date
- Thread starter
- #742
Are you referring to the link to cannabis and depression? If so, not to worry. I was researching how the major cannabinoids affect mental states, and in particular depression.
I do a lot of research for other members. I live in a bubble of joy Shed. That statement is as true as it gets. That bubble keeps mental anguish and confusion at bay.
If that was the concern...... you’re a good friend to pick it up like that.
I'd love that to be true, and in an ideal world it would be (even if I noticed that specifically I would assume it was pure research!), but it was actually the one telling me to Try the "Pussy Pocket."
overlord
Well-Known Member
Since you mentioned it...
- Thread starter
- #745
Thanks Sue, on it 
.
.- Thread starter
- #747
Thanks Sue, on it
The correct search is “pussy pocket, Oprah”.
You’re all welcome.
Really?
- Thread starter
- #749
- Thread starter
- #750
Having that fisherman in my life has broadened my research horizons. 
Good old Oprah...
"You get an orgasm, you get an orgasm, you get an orgasm, you get an orgasm, you get an orgasm, you get an orgasm, you get an orgasm, you get an orgasm, you get an orgasm! Everybody gets an orgasm!"
"You get an orgasm, you get an orgasm, you get an orgasm, you get an orgasm, you get an orgasm, you get an orgasm, you get an orgasm, you get an orgasm, you get an orgasm! Everybody gets an orgasm!"
- Thread starter
- #752
walleye
Well-Known Member
June 18, 1979 2pm 24 years old. I had a day like Ralphy in Christmas Story fight scene. I was about to destroy the enemy, they had it coming and I was overwhelming more powerful. An angel intervened, physically fought me and struck me in the side with the absolute least damage possible in the heat of battle. For 40 days I was forbidden any strength in my body while my mind pondered and continued to witness the world passing by.
Who here has ever experienced 'blue balls'? I have. I can say with authority that orgasms are a human necessity even holy men and priests can not deny!
My first day allowed to walk again ( this has happened more than once) I sat on a park bench for 5 minutes amongst a crowd, watching a baseball game, leaning into my cane, and was promptly removed by police for loitering in the park on a Saturday afternoon! The problem having 6 older brothers in a small town! Son of a bitch, the lesson continues!
Let no man scoff at or deny their human needs nor divine interventions, or they are only lying to themselves...and walk kinda funny!!
Who here has ever experienced 'blue balls'? I have. I can say with authority that orgasms are a human necessity even holy men and priests can not deny!
My first day allowed to walk again ( this has happened more than once) I sat on a park bench for 5 minutes amongst a crowd, watching a baseball game, leaning into my cane, and was promptly removed by police for loitering in the park on a Saturday afternoon! The problem having 6 older brothers in a small town! Son of a bitch, the lesson continues!
Let no man scoff at or deny their human needs nor divine interventions, or they are only lying to themselves...and walk kinda funny!!
- Thread starter
- #754
Ezra Parzybok - ezrahelps.com
Why cannabis stops working or has the opposite effect for some users.
- explaining biphasic, or paradoxical effects of cannabis
Sometimes cannabis products give different peopleopposite effects;
- stimulating vs invigorating
- amplifying pain response vs pain relief
The #1 reason people choose cannabis is to relieve anxiety, and
The #1 reason people stop using cannabis is because they feel it increases their anxiety.
1:29 These are called biphasic or paradoxical effects. Cannabis can create opposite effects.
- it’s not uncommon in medicine
- Ritalin is a good ex., used to calm hyperactive young children and as an alerting drug by college students because it gives them energy
2:33 The ECS is an endogenous cell feedback system of communication
- ECS produces endocannabinoids (eCBs) for signaling
- cannabis produces phytocannabinoids that activate the same receptors our eCBs do
2:52 It’s important to remember that the ECS is our largest cellular communication system, presenting receptors on almost all of our cells, throughout the body.
- Pharmaceuticals trigger certain aspects of our body.
- Phytocannabinoids can access the ECS
Everyone has a unique ECS expression and will react in their own way to cannabis.
- One person may try cannabis and have a positive experience, and find symptom relief.
- Another person can use cannabis and feel horrible.
I’m sorry, I gotta throw my hand up in the air. So far I’m reading these responses as potential dosing problems that simply mean we haven’t found the correct dose. This last point I’d start by looking at things like set and setting, expectations, fears about cannabis......I’m not hearing what I expected about biphasic effects. My, my, I’m an impatient woman, aren’t I?
3:33 Each cannabis plant has a diversified profile of dozens and dozens of cannabinoids
- some are active, some inactive
- the vast majority of cannabinoids found in cannabis are unknown, in trace amounts
- their combined action is called the “entourage effect” We left out terpenes and flavonoids
- they enter the body and have different effects
4:15 You’ll get different effects depending on
- where they enter the body
- how they enter the body
4:25 You can take a sedating strain into the body as an edible and get a calming effect
- smoke the same dose and you get the rapid rush to the brain and you may feel anxious, paranoid
Or not.
stimulated There ya go.
- different ingestion methods can give vastly different results
4:49 The same strain, grown in different mediums, different locations, using identical genetics yield significantly different oils, based on the thousands of little decisions that go into growing cannabis.
- Factoring in all the variables of medium and nutrient choice, lighting, location, harvest scheduling, drying and curing variables you’ll likely get very different effects from plants.
- Different phenotypes give you the same challenge.
Every patient is a new start. Every new batch of flower or oil is a new start. That‘s the standard for setting a regimen. As a recreational user it’s smart to do the same until you know the tolerances.
Social obligations call.
- Thread starter
- #755
Ezra Parzybok - ezrahelps.com
Why cannabis stops working or has the opposite effect for some users.
- explaining biphasic, or paradoxical effects of cannabis
Sometimes cannabis products give different peopleopposite effects;
- stimulating vs invigorating
- amplifying pain response vs pain relief
The #1 reason people choose cannabis is to relieve anxiety, and
The #1 reason people stop using cannabis is because they feel it increases their anxiety.
1:29 These are called biphasic or paradoxical effects. Cannabis can create opposite effects.
- it’s not uncommon in medicine
- Ritalin is a good ex., used to calm hyperactive young children and as an alerting drug by college students because it gives them energy
2:33 The ECS is an endogenous cell feedback system of communication
- ECS produces endocannabinoids (eCBs) for signaling
- cannabis produces phytocannabinoids that activate the same receptors our eCBs do
2:52 It’s important to remember that the ECS is our largest cellular communication system, presenting receptors on almost all of our cells, throughout the body.
- Pharmaceuticals trigger certain aspects of our body.
- Phytocannabinoids can access the ECS
Everyone has a unique ECS expression and will react in their own way to cannabis.
- One person may try cannabis and have a positive experience, and find symptom relief.
- Another person can use cannabis and feel horrible.
I’m sorry, I gotta throw my hand up in the air. So far I’m reading these responses as potential dosing problems that simply mean we haven’t found the correct dose. This last point I’d start by looking at things like set and setting, expectations, fears about cannabis......I’m not hearing what I expected about biphasic effects. My, my, I’m an impatient woman, aren’t I?
3:33 Each cannabis plant has a diversified profile of dozens and dozens of cannabinoids
- some are active, some inactive
- the vast majority of cannabinoids found in cannabis are unknown, in trace amounts
- their combined action is called the “entourage effect” We left out terpenes and flavonoids
- they enter the body and have different effects
4:15 You’ll get different effects depending on
- where they enter the body
- how they enter the body
4:25 You can take a sedating strain into the body as an edible and get a calming effect
- smoke the same dose and you get the rapid rush to the brain and you may feel anxious, paranoid
Or not.
stimulated There ya go.
- different ingestion methods can give vastly different results from the same strain; ingested it might be sedative, where smoked it might be energetic
4:49 The same strain, grown in different mediums, different locations, using identical genetics yield significantly different oils, based on the thousands of little decisions that go into growing cannabis.
- Factoring in all the variables of medium and nutrient choice, lighting, temperature, location, harvest scheduling, drying and curing variables you’ll likely get very different effects from plants.
- Different phenotypes give you the same challenge.
- two flower tops from identical genetics but different plants can have biphasic effects - one energizing, the other more narcotic.
- there are a myriad of ways to grow, formulate, and administer cannabis
Every patient is a new start. Every new batch of flower or oil is a new start. That‘s the standard for setting a regimen. As a recreational user it’s smart to do the same until you know the tolerances.
6:00 - He uses the analogy of THC being like calling the fire department. You need response, and you need it now!
- THC comes in loud and powerful. We feel it in the body, and we know it’s there.
CBD is like calling the therapist. They’ll talk to you, and it’s gonna be a positive or neutral experience, much more subtle than THC.
7:20 His story goes like this:
You call the fire department (THC) and they come to the rescue. A big, loud and brightly flashing truck roars across your lawn, chewing up the grass in advance of the firemen breaking down the door and breaking windows to put out your fire (pain), disturbing the neighbors as they go.
Maybe they put the fire out, but they create a lot of mess and racket doing so, and your body remembers that.
After a while your body says, “ Whoa! I can’t take any more fire department! Even though it’s taking my pain away I can’t handle fire trucks and firemen going through my house and breaking up my things.“
As you can guess, I’m having serious problems with this analogy. Made me wonder if the man has ever used cannabis with enough THC to experience being high. It’s scary sometimes how many people are out there talking about using cannabis properly who have no experience with cannabis-induced euphoria.
Benefit of a doubt Susan. Benefit of a doubt.
He goes on to claim that over time some patients begin to feel more intense and stimulated with THC-dominant strains, and then he goes on to say, “[…] and will not have the effects they want.”
Is he talking about someone using the strain for relaxation but developing a response of stimulating instead?
7:35 He calls this the “self-regulating properties of cannabis.” In our neighborhoods we don’t want the fire department called for every little thing, and our bodies don’t want THC to be the response for every single ailment.
7:48 Humans want to treat cannabis like a pharmaceutical, but it’s really designed to regulate the system.
I don’t think cannabis was designed with us in mind.
8:12 Too much THC in the system will create an imbalance. Too much of the same strain or too often with the same administrative method and the body says, “Enough. Don’t want this one anymore.”
No.........It’s simple cellular biology. Run the system too hot and receptors go into temporary hiding. Cool things down and the system adjusts. That’s the pure and simple about tolerance, if you ignore the contribution of terpenes.
You know, it might be the terpenes we build the tolerance to, or the effects the terpenes create. That would explain why switching chemovars would keep tolerance at bay.
All we’re really doing is bringing in reserve troops for a temporary fill. A responsible regimen checks periodically to see how strong the ECS has grown while you’ve been assisting. I’m not sure where this guy’s going, but it’s only four more minutes.
8:24 You have to learn to develop a little intuition, to listen to your body, or have a specialist like him to guide you through the process.
8:43 CBD can have similar issues, though more subtly expressed.
- Back to his analogies:
CBD is like going to a therapist. Some days are better than others. Sometimes after going for years you don’t seem to be progressing and the visits become more stressful than the problem you’re trying to solve.
The body does the same thing. The body will begin to tell you that if you take in any more CND it’ll begin to make you more anxious, more fatigued, like it’s not treating symptoms as effectively as it used to.
9:40 He claims that some of his hyper-sensitive patients get more hyper and anxious and have reactions opposite from those desired from both THC and CBD, or a combination.
10:05 - Cannabis alters our consciousness, and when we perception of the world is altered it leaves us vulnerable REALLY? Vulnerable?
We have so many stereotypes about cannabis in our society.
- If a senior who smoked cannabis in college and had a bad experience at that time now wants to use cannabis to improve her life we have to acknowledge that her context with cannabis is one of anxiety.
- She’s scared that she might get high. She’s scared that something might happen.
- If she lacks guidance as to cannabinoid and terpene profiles and modes of consumption she might well repeat that bad experience and avoid future use.
Budtenders can help by having empathy and listening to the stories of the customers for clues on how to guide them.
- They might need a little hand-holding.
He recommends you find a qualified practitioner As do I
The biphasic nature of cannabis won’t go away. You’ll never be able to package cannabis in a neat white pill and say, “So many mg, so many times a day“ and expect to have the same results across the board.
Ezra helps people understand cannabis.
[/QUOTE]- Thread starter
- #756
That definitely wasn’t what I expected, and I don’t think I learned what I wanted to about the biphasic effects of cannabis. I did, however pick up a couple interesting ideas.
On to more study. I’ll check out Dr. Sulak next, since that’s where I was headed when Ezra distracted me.
On to more study. I’ll check out Dr. Sulak next, since that’s where I was headed when Ezra distracted me.
- Thread starter
- #757
Interesting article, so badly formatted I had to bring it back and make it easier to read. Forgive me Melissa.
Source: Labroots.com
JUL 06, 2018 12:10 PM PDT
How the Biphasic Effect of Cannabinoids Controls Dosing
WRITTEN BY: Melissa Moore
Meet Mary, Mary takes one hit from a joint and she is stoned, but her friend Janice can smoke the rest of the joint and hardly feel different. Meet Joe, Joe can drink a beer and feel chatty, but if Joe finishes a six pack he's crying in the bathroom and passing out in the stall. This is called the biphasic effect.
Many compounds produce a biphasic effect, which means low and high doses can produce opposite effects. When Mary inhaled a small amount of cannabis smoke it was very effective, but when Janice inhaled a large dose of cannabis smoke the results just weren't there and she probably could have smoked another and felt fine. When a compound has a biphasic effect what can be relieved at a small dose can also be amplified at a high dose.
Often anxiety is prone to this effect, and one may become paranoid and feel uneasy.
When one begins using cannabis to help relieve what ails them the protocol is to start low and go slow. What that means is you start at a low amount such as 1-2 milligrams and you increase either every dose or every few days. This will depend on the side effects felt.
If a person is feeling dizzy or lethargic they should either stay at that dose or lower the dose and stay at that measurement for a few days before increasing.
Average optimum dosing is between 3-10 milligrams. This dose level is referred to as microdosing. It is reported that people experience better mood, reduced anxiety, and less pain without any adverse effects at these levels.
When titrating up to find your optimal dose it is ideal to stay at 5 milligrams for a week so one may feel comfortable with the effects that are experienced at this dose. It is good to discover how you react to a certain dose so you can ascertain on whether a higher dose is giving you more relief or less relief.
If you look at the graph above you will see that a bell curve forms when comparing the strength of dose versus benefits. One will actually experience a loss of benefits at a high concentration of cannabis, this concentration will differ for everyone based on their endocannabinoid tone.
Endocannabinoid tone is an equation that contains the number of endocannabinoids, receptors, and enzymes that metabolize the cannabinoids. We are beginning to understand that if you oversaturate the receptors the body will actually turn the receptors off or even metabolize them, and an increase of enzymes to metabolize the cannabinoids will be excreted into the blood. When homeostasis is reached the receptors will "turn back on". Finding this spot of homeostasis is finding your optimal dose or otherwise referred to as your sweet spot.
There are cases where people need high doses to achieve results such as the apoptosis of cancer cells. Clinical studies are produced with doses at or above 50 milligrams. An average of 50- 800 milligrams a day of total cannabinoid count is what is used in cancer treatments.
If one is using cannabis to just help relieve the symptoms of cancer and conventional treatments the dose is more averaged at 20-50 mg. This is for symptom relieve such as nausea, bone pain, and appetite stimulation.
It is very individual as to what someone's optimum dose is, one must start low and titrate the dosage over weeks of time. One must also experiment with what ratio works best for them.
It has been seen that when CBD and THC are combined in the same dose that greater reduction in pain is seen versus using the cannabinoids separately, but what also is seen is that the strength of the dose is higher overall. In a study of 177 patients with cancer pain, the group that received a treatment of just THC used an average of 27 mg whereas the group that used a 1:1 ratio of THC: CBD used an average of 60 mg but reported a superior reduction in pain.
All in all the sum is larger than its parts. This is not across the board treatment. When finding your optimum dose and ratio one must experiment by consulting experts, trying different ratios, and titrating their dosage.
OK.... I’m happier with that. I can be so anal. Lol!
Source: Labroots.com
JUL 06, 2018 12:10 PM PDT
How the Biphasic Effect of Cannabinoids Controls Dosing
WRITTEN BY: Melissa Moore
Meet Mary, Mary takes one hit from a joint and she is stoned, but her friend Janice can smoke the rest of the joint and hardly feel different. Meet Joe, Joe can drink a beer and feel chatty, but if Joe finishes a six pack he's crying in the bathroom and passing out in the stall. This is called the biphasic effect.
Many compounds produce a biphasic effect, which means low and high doses can produce opposite effects. When Mary inhaled a small amount of cannabis smoke it was very effective, but when Janice inhaled a large dose of cannabis smoke the results just weren't there and she probably could have smoked another and felt fine. When a compound has a biphasic effect what can be relieved at a small dose can also be amplified at a high dose.
Often anxiety is prone to this effect, and one may become paranoid and feel uneasy.
When one begins using cannabis to help relieve what ails them the protocol is to start low and go slow. What that means is you start at a low amount such as 1-2 milligrams and you increase either every dose or every few days. This will depend on the side effects felt.
If a person is feeling dizzy or lethargic they should either stay at that dose or lower the dose and stay at that measurement for a few days before increasing.
Average optimum dosing is between 3-10 milligrams. This dose level is referred to as microdosing. It is reported that people experience better mood, reduced anxiety, and less pain without any adverse effects at these levels.
When titrating up to find your optimal dose it is ideal to stay at 5 milligrams for a week so one may feel comfortable with the effects that are experienced at this dose. It is good to discover how you react to a certain dose so you can ascertain on whether a higher dose is giving you more relief or less relief.
If you look at the graph above you will see that a bell curve forms when comparing the strength of dose versus benefits. One will actually experience a loss of benefits at a high concentration of cannabis, this concentration will differ for everyone based on their endocannabinoid tone.
Endocannabinoid tone is an equation that contains the number of endocannabinoids, receptors, and enzymes that metabolize the cannabinoids. We are beginning to understand that if you oversaturate the receptors the body will actually turn the receptors off or even metabolize them, and an increase of enzymes to metabolize the cannabinoids will be excreted into the blood. When homeostasis is reached the receptors will "turn back on". Finding this spot of homeostasis is finding your optimal dose or otherwise referred to as your sweet spot.
There are cases where people need high doses to achieve results such as the apoptosis of cancer cells. Clinical studies are produced with doses at or above 50 milligrams. An average of 50- 800 milligrams a day of total cannabinoid count is what is used in cancer treatments.
If one is using cannabis to just help relieve the symptoms of cancer and conventional treatments the dose is more averaged at 20-50 mg. This is for symptom relieve such as nausea, bone pain, and appetite stimulation.
It is very individual as to what someone's optimum dose is, one must start low and titrate the dosage over weeks of time. One must also experiment with what ratio works best for them.
It has been seen that when CBD and THC are combined in the same dose that greater reduction in pain is seen versus using the cannabinoids separately, but what also is seen is that the strength of the dose is higher overall. In a study of 177 patients with cancer pain, the group that received a treatment of just THC used an average of 27 mg whereas the group that used a 1:1 ratio of THC: CBD used an average of 60 mg but reported a superior reduction in pain.
All in all the sum is larger than its parts. This is not across the board treatment. When finding your optimum dose and ratio one must experiment by consulting experts, trying different ratios, and titrating their dosage.
OK.... I’m happier with that.
I can be so anal. Lol!- Thread starter
- #758
The biphasic nature of cannabis is nothing more than an acknowledgement that relief is dose-dependent. Start low, go slow, stay low.
We got this.
We got this.
- Thread starter
- #759
Open Access
Molecules 2019, 24(5), 918; Cannabinoid Signaling in the Skin: Therapeutic Potential of the “C(ut)annabinoid” System
Review
Cannabinoid Signaling in the Skin: Therapeutic Potential of the “C(ut)annabinoid” System
by Kinga Fanni Tóth, Dorottya Ádám, Tamás Bíró, and Attila Oláh
Department of Physiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
Department of Immunology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
HCEMM Nonprofit Ltd., 6720 Szeged, Hungary
Correspondence: olah.attila@med.unideb.hu; Tel.: +36-52-255-575
These authors contributed equally.
Received: 12 February 2019 / Accepted: 1 March 2019 / Published: 6 March 2019
Look what I stumbled upon!
“2.5.6. Selected Inflammatory Diseases: Psoriasis (PSO)
Psoriasis (PSO) is a chronic inflammatory skin disorder, often accompanied by additional non-cutaneous symptoms (e.g., arthritis), and its pathogenesis is still not fully understood. Indeed, genetic [247] and epigenetic [248] abnormalities, as well as alterations in the cutaneous microbiota [249], pH [250], or, most importantly, IL-17 signaling [251,252] are known to be involved in its development, and it is surely accompanied by a disturbance in the dynamic cross-talk between epidermal keratinocytes and professional cutaneous immune cells. This inappropriate communication then leads to pathological inflammatory processes and to a disturbance in the proliferation/differentiation balance of epidermal keratinocytes [249,253,254,255,256].
Since, as discussed above, proliferation/differentiation as well as immune activity of epidermal keratinocytes are under the tight control of the eCB signaling, it is not surprising that therapeutic exploitation of various cannabinoids in PSO has already been suggested by multiple authors [237,257,258,259,260,261].
Beyond of the abovementioned theoretical reasons (i.e., dose-dependent differentiation- modulating, as well as anti-proliferative and anti-inflammatory effects of various cannabinoids in the skin), there are a few additional pieces of evidence supporting the concept that eCB-dysregulation may contribute to the development of PSO. Indeed, the promoter of the PTPN22 gene was found to be hypomethylated resulting in its strong up-regulation in lesional skin of PSO patients as compared to the adjacent non-lesional skin [262]. Intriguingly, however, the C1858T substitution (“R620W variant”; “rs2476601”; a loss-of-function single-nucleotide polymorphism) in PTPN22 was found to be positively associated with PSO in Saudi patients [263], and other SNPs (“rs3789604”, “rs1217414”, “rs6679677”) were also found to be related to PSO in other subjects [264,265,266]. Others, however, found that C1858T substitution is only associated with higher susceptibility of psoriatic arthritis, but not of PSO itself [267,268,269], whereas again others did not find any significant association between PTPN22 and PSO [270,271,272,273,274], leaving the putative role of PTPN22 dysfunction in PSO rather controversial.
A much more important indicator of the potential involvement of eCB dysregulation in the pathogenesis of PSO is that a recent study found elevated AEA and 2-AG levels in the plasma of these patients. Moreover, in the granulocytes of the patients, activities of FAAH and MAGL were increased, and GPR55 expression was also up-regulated. With respect to the “classical” receptors, the authors found that expression CB1 was only increased in granulocytes of patients suffering from psoriatic arthritis, whereas CB2 was up-regulated in those PSO patients, who had no joint complications [275]. Moreover, RNAseq of skin biopsies obtained from 25 PSO patients revealed that, compared to region-matched skin of healthy subjects, several important “cannabinoid- relevant” genes were differentially expressed. Findings in this study include, but are not limited to down-regulation of adenosine A1, A2A, A2B and A3 receptors, CB1, CB2, PPARα and PPARγ, whereas FAAH1 (but not FAAH2), TRIB3, TRPV1 and TRPV3 were up-regulated at the mRNA level in itchy lesional skin of PSO patients [276]. Thus, alterations in the ECS can indeed be observed in PSO patients, indicating that certain cannabinoids may possess therapeutic potential.
Along this line, it is important to emphasize that NRIP1, which has previously been shown to be an important CBD target gene [120], was found to be overexpressed both in skin and peripheral blood monomorphonuclear cells (PBMC) of PSO patients [277]. Importantly, its down-regulation in HaCaT keratinocytes could significantly suppress proliferation and induce apoptosis, whereas in isolated CD4+ T cells it reduced RelA/p65 NF-κB expression and IL-17 release [277]. Moreover, in NRIP1−/− mice, the PSO-mimicking inflammation induced by imiquimod (a TLR7/8 agonist widely used to trigger PSO-like cutaneous symptoms in mice [278]) was delayed, and RelA/p65 NF-κB expression was also reduced in the lesions [277]. Collectively, these data suggested that NRIP1 may be a multifaceted therapeutic target in PSO. Since CBD was found to TRPV4-dependently down-regulate NRIP1 in human sebocytes [120], one might speculate that, by activating the same signaling axis, it could exert beneficial effects in PSO as well. On the other hand, it is also important to note that another CBD target gene, namely TRIB3, which was shown to be adenosine A2Areceptor-dependently up-regulated in human sebocytes [120], was found to be up-regulated in PSO lesions compared to non-lesional skin, and TRIB3-silencing exerted anti-proliferative effects in HaCaT keratinocytes [279]. Further studies are therefore invited to explore how CBD regulates these PSO-relevant signaling pathways in actual patients.”
Molecules 2019, 24(5), 918; Cannabinoid Signaling in the Skin: Therapeutic Potential of the “C(ut)annabinoid” System
Review
Cannabinoid Signaling in the Skin: Therapeutic Potential of the “C(ut)annabinoid” System
by Kinga Fanni Tóth, Dorottya Ádám, Tamás Bíró, and Attila Oláh
Department of Physiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
Department of Immunology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
HCEMM Nonprofit Ltd., 6720 Szeged, Hungary
Correspondence: olah.attila@med.unideb.hu; Tel.: +36-52-255-575
These authors contributed equally.
Received: 12 February 2019 / Accepted: 1 March 2019 / Published: 6 March 2019
Look what I stumbled upon!
“2.5.6. Selected Inflammatory Diseases: Psoriasis (PSO)
Psoriasis (PSO) is a chronic inflammatory skin disorder, often accompanied by additional non-cutaneous symptoms (e.g., arthritis), and its pathogenesis is still not fully understood. Indeed, genetic [247] and epigenetic [248] abnormalities, as well as alterations in the cutaneous microbiota [249], pH [250], or, most importantly, IL-17 signaling [251,252] are known to be involved in its development, and it is surely accompanied by a disturbance in the dynamic cross-talk between epidermal keratinocytes and professional cutaneous immune cells. This inappropriate communication then leads to pathological inflammatory processes and to a disturbance in the proliferation/differentiation balance of epidermal keratinocytes [249,253,254,255,256].
Since, as discussed above, proliferation/differentiation as well as immune activity of epidermal keratinocytes are under the tight control of the eCB signaling, it is not surprising that therapeutic exploitation of various cannabinoids in PSO has already been suggested by multiple authors [237,257,258,259,260,261].
Beyond of the abovementioned theoretical reasons (i.e., dose-dependent differentiation- modulating, as well as anti-proliferative and anti-inflammatory effects of various cannabinoids in the skin), there are a few additional pieces of evidence supporting the concept that eCB-dysregulation may contribute to the development of PSO. Indeed, the promoter of the PTPN22 gene was found to be hypomethylated resulting in its strong up-regulation in lesional skin of PSO patients as compared to the adjacent non-lesional skin [262]. Intriguingly, however, the C1858T substitution (“R620W variant”; “rs2476601”; a loss-of-function single-nucleotide polymorphism) in PTPN22 was found to be positively associated with PSO in Saudi patients [263], and other SNPs (“rs3789604”, “rs1217414”, “rs6679677”) were also found to be related to PSO in other subjects [264,265,266]. Others, however, found that C1858T substitution is only associated with higher susceptibility of psoriatic arthritis, but not of PSO itself [267,268,269], whereas again others did not find any significant association between PTPN22 and PSO [270,271,272,273,274], leaving the putative role of PTPN22 dysfunction in PSO rather controversial.
A much more important indicator of the potential involvement of eCB dysregulation in the pathogenesis of PSO is that a recent study found elevated AEA and 2-AG levels in the plasma of these patients. Moreover, in the granulocytes of the patients, activities of FAAH and MAGL were increased, and GPR55 expression was also up-regulated. With respect to the “classical” receptors, the authors found that expression CB1 was only increased in granulocytes of patients suffering from psoriatic arthritis, whereas CB2 was up-regulated in those PSO patients, who had no joint complications [275]. Moreover, RNAseq of skin biopsies obtained from 25 PSO patients revealed that, compared to region-matched skin of healthy subjects, several important “cannabinoid- relevant” genes were differentially expressed. Findings in this study include, but are not limited to down-regulation of adenosine A1, A2A, A2B and A3 receptors, CB1, CB2, PPARα and PPARγ, whereas FAAH1 (but not FAAH2), TRIB3, TRPV1 and TRPV3 were up-regulated at the mRNA level in itchy lesional skin of PSO patients [276]. Thus, alterations in the ECS can indeed be observed in PSO patients, indicating that certain cannabinoids may possess therapeutic potential.
Along this line, it is important to emphasize that NRIP1, which has previously been shown to be an important CBD target gene [120], was found to be overexpressed both in skin and peripheral blood monomorphonuclear cells (PBMC) of PSO patients [277]. Importantly, its down-regulation in HaCaT keratinocytes could significantly suppress proliferation and induce apoptosis, whereas in isolated CD4+ T cells it reduced RelA/p65 NF-κB expression and IL-17 release [277]. Moreover, in NRIP1−/− mice, the PSO-mimicking inflammation induced by imiquimod (a TLR7/8 agonist widely used to trigger PSO-like cutaneous symptoms in mice [278]) was delayed, and RelA/p65 NF-κB expression was also reduced in the lesions [277]. Collectively, these data suggested that NRIP1 may be a multifaceted therapeutic target in PSO. Since CBD was found to TRPV4-dependently down-regulate NRIP1 in human sebocytes [120], one might speculate that, by activating the same signaling axis, it could exert beneficial effects in PSO as well. On the other hand, it is also important to note that another CBD target gene, namely TRIB3, which was shown to be adenosine A2Areceptor-dependently up-regulated in human sebocytes [120], was found to be up-regulated in PSO lesions compared to non-lesional skin, and TRIB3-silencing exerted anti-proliferative effects in HaCaT keratinocytes [279]. Further studies are therefore invited to explore how CBD regulates these PSO-relevant signaling pathways in actual patients.”
- Thread starter
- #760
Damn! That’s a lot to take in. 