Benzodiazepines May Be Strong Serotonin Antagonists. Are They Really That Dangerous?

[Nemo]

This was a very helpful thread. I am passing the info to a friend.

@SonOfEurope, are you fully off the benzos now?

 

[CoconutEffect]

bump

 

[Gûs80]

My doc keep pushing SSRIs and avoiding benzos, even though he knows I would never take a SSRI... Probably gonna get an appointment with another psychiatrist as I suspect he gets profit by selling certains brands.
Does anyone have some experience with benzos, especially Clonazepam to share? Clonazepam makes me feel so good ,the anti anxiety/depression effect is really strong.

Also I found some interesting studies:
Benzodiazepines: Anxiety-Reducing Activity by Reduction of Serotonin Turnover in the Brain - PubMed
The anxiety-reducing effects of minor tranquilizers in the rat conflict test were mimicked by serotonin antagonists and by p-chlorophenylalanine, an inhibitor of serotonin synthesis; the depressant effects of the minor tranquilizers were mimicked by norepinephrine antagonists. Intraventricular injections of serotonin led to a suppression of behavior, and also antagonized the anxiety-reducing action of benzodiazeprines.
Tranquilizers may exert their anxiety-reducing effects by a reduction of serotonin activity in a behaviorally suppressive punishment system, and they may exert their depressant effects by a reduction of norepinephrine activity in a behaviorally facilitatory reward system.

Effects of Benzodiazepines on Central Serotonergic Mechanisms - PubMed

If the rat conflict test were a valid animal model of anxiety neurosis, evidence which implicates serotonin systems in the anxiety-reducing actions of benzodiazepine tranquilizers could be summarized as follows: (1) The punishment-lessening effects of benzodiazepines in the conflict test are mimicked by serotonin antagonists (methysergide, cinanserin, bromolysergic acid), serotonin synthesis inhibition (PCPA), and serotonin nerve terminal damage (5,6-dihydroxytryptamine). (2) Punishment effects may be intensified by the serotonin precursor, 5-hydroxytryptophan (in combination with a monoamine oxidase inhibitor), serotonin agonists (alpha-methyltryptamine), or intraventricular injections of serotonin itself. Intraventricularly administered serotonin also antagonizes the punishment-lessening effects of benzodiazepines. (3) Stimulation of the serotonergic cell bodies in the dorsal raphe nucleus by local application of crystalline carbachol causes intense suppression of behavior. The suppressive effects of raphe stimulation are antagonized by systemic administration of benzodiazepines. (4) In biochemical experiments, the decrease in norepinephrine turnover induced by oxazepam rapidly undergoes tolerance, whereas the decrease induced in serotonin turnover is maintained over repeated doses. These results parallel findings in the conflict test which indicate that the depressant action of oxazepam rapidly undergoes tolerance, whereas the anxiety-reducing action is maintained over repeated doses. Although central serotonin neurons are thus implicated in the therapeutic actions of benzodiazepine tranquilizers, it is quite possible that the drugs actually act indirectly to reduce serotonin activity. The concept that benzodiazepines may exert a primary action on GABA-containing neurons, which in turn regulate serotonergic transmission, was supported by preliminary psychopharmacological evidence. The GABA-antagonist picrotoxin, at doses that do not disrupt unpunished behavior, fully antagonizes the punishment-lessening effects of benzodiazepines in the conflict test.

​

Old topic, but I want to contribute. My uncle used alprazolam for decades until his death from covid at age 85, he was a cardiologist. What he did and indicated was to alternate benzos with antihistamines, thus avoiding dependence and any rebound. In his view, going without sleep is infinitely worse than using small doses of benzos and antihistamines.

I agree with him, as I have had chronic insomnia since I was 15 years old, and I have tried to control it without medication for over 25 years, and I say that the consequences have been devastating. Sleep doctors push Generation Z meds or quetiapine, which in my opinion are much more harmful to health than benzos. I used zolpidem for a few years and even after 1 decade without using it I still couldn't fully reverse the chronic fatigue developed during its use. All sleep medications are histaminics antagonists.

Lately I've been alternating alprazolam 0.5mg with dramamine 50 to 100mg and polaramine. I use alprazolam for a maximum of 3 days and use antihistamines for longer. I only use alprazolam because I feel that the antihistamines lose their potency after 2 or 3 weeks. I unfortunately was never able to fall asleep without using some medication or supplement.

Cycling benzos is extremely helpful and gentle. The anxiolytic effects remind me of the effects of wine.

 

[Gûs80]

Complementing.

I have initial insomnia since I was 15 years old (42 today), without medication I can only sleep around 3am.
Sleep with dramamine for me is much deeper and more restful, even sleeping less. I usually get 6 hours of deep sleep on dramamine and wake up early and fresh.
I wake up at 5am and have energy to go to the gym.

Alprazolam, even in low doses, makes me very relaxed, a pleasant laziness, many hours in bed and lack of motivation to train. I believe that with prolonged use this daytime lethargy lessens, but I prefer to follow my uncle's wisdom and only use it for a few days at a time.

 

[Sampa]

Complementing.

I have initial insomnia since I was 15 years old (42 today), without medication I can only sleep around 3am.
Sleep with dramamine for me is much deeper and more restful, even sleeping less. I usually get 6 hours of deep sleep on dramamine and wake up early and fresh.
I wake up at 5am and have energy to go to the gym.

Alprazolam, even in low doses, makes me very relaxed, a pleasant laziness, many hours in bed and lack of motivation to train. I believe that with prolonged use this daytime lethargy lessens, but I prefer to follow my uncle's wisdom and only use it for a few days at a time.

Gus, have you ever tried trazodone (donaren here in Br)?

 

[Gûs80]

Gus, have you ever tried trazodone (donaren here in Br)?

I have never tried Trazodone, but I have tried other antidepressants with very poor results. Low dose quetiapine and mirtazapine were the best, but they seem to wear off and the daytime drowsiness is extremely strong.

I have preferred to sleep little and compensate for drowsiness with higher doses of creatine. Something that Dr. Paulo Muzy does, as he sleeps less than 5 hours a night. The studies I read support its use in circadian cycle disorders and chronic insomnia. Decreases daytime drowsiness and the negative impact of a sleepless night or little sleep.
I am now studying the impact of creatine on thermogenesis, from what I understand it can act as an uncoupler.

 

[Gûs80]

I'm doing a test, eating 60 to 70% of my calories in the morning in order to regulate the circadian cycle, concomitant with the use of high doses of creatine.


"Thermogenesis is largely regulated by a protein called uncoupling protein 1 (UCP1), which rewires the production of adenosine triphosphate (ATP), the energy currency of the cell. However, thermogenesis can also occur without UCP1, using a “futile creatine cycle” – a metabolic pathway that was increased in the mice in the dark-restricted feeding group.



On the other hand, light-restricted feeding impaired thermogenesis and futile creatine cycling, making these mice more susceptible to diet-induced weight gain."





“We discovered that there are daily circadian rhythms of creatine metabolism in fat cells,” explained Dr. Chelsea Hepler, lead author of the study and postdoctoral fellow at Northwestern University. “When mice eat only during their normal active period, they expend more energy through elevated creatine futile cycling. However, when food is provided only during the time when mice are normally sleeping, the mice have reduced energy expenditure since the timing of their food intake is misaligned with creatine metabolism.”



“Our findings reveal that aligning food intake with circadian rhythms in adipocyte creatine thermogenesis improves metabolic health,”

 

[Vinny]

I have preferred to sleep little and compensate for drowsiness with higher doses of creatine. Something that Dr. Paulo Muzy does, as he sleeps less than 5 hours a night. The studies I read support its use in circadian cycle disorders and chronic insomnia. Decreases daytime drowsiness and the negative impact of a sleepless night or little sleep.
I am now studying the impact of creatine on thermogenesis, from what I understand it can act as an uncoupler.

Hi,
Can you elaborate more on that, please?
Do you mean that creatine eliminates daytime drowsiness and you eventually get more efficient sleep at night? And what are for you high doses - how many grams per day, how many doses and at what time?
I`d really appreciate some detailed input from you. Daytime drowsiness and sleep disorders had been huge issues for me for ages....

 

[TruffleGnocchi]

I would also like to know more about the creatine effects you write about. Never heard this.
I do better when I sleep less, compared to when I sleep too much. If I had to choose between 3-4H of sleep, vs 10-12H of sleep I would choose 3-4H.
Do benzos make you dumb like alcohol supposedly does? Acutely and long term?

 

[Gûs80]

I would also like to know more about the creatine effects you write about. Never heard this.
I do better when I sleep less, compared to when I sleep too much. If I had to choose between 3-4H of sleep, vs 10-12H of sleep I would choose 3-4H.
Do benzos make you dumb like alcohol supposedly does? Acutely and long term?

I really like the immediate effect of alprazolam, very relaxing and I feel a decrease in anxiety several days after. Apparently they are harmful to the brain if used long term. But for sporadic use, in moments of high anxiety, I think they are very valid.

At the same time, creatine seems to restore the GABAergic system, particularly after TBI. Other evidence shows that creatine works in tune with the dopaminergic system, in addition to acting as an anti-inflammatory.

 

[Gûs80]

Hi,
Can you elaborate more on that, please?
Do you mean that creatine eliminates daytime drowsiness and you eventually get more efficient sleep at night? And what are for you high doses - how many grams per day, how many doses and at what time?
I`d really appreciate some detailed input from you. Daytime drowsiness and sleep disorders had been huge issues for me for ages....

Creatine-supplementation reduces sleep need and homeostatic sleep pressure in rats

Sleep has been postulated to promote brain energy restoration. It is yet unknown if increasing the energy availability within the brain reduces the sleep need. The guanidine amino acid creatine (Cr) is a well-known energy booster in cellular energy homeostasis. ...

www.ncbi.nlm.nih.gov

Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol - PubMed

Following 24-h sleep deprivation, creatine supplementation had a positive effect on mood state and tasks that place a heavy stress on the prefrontal cortex.

pubmed.ncbi.nlm.nih.gov

Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial.

Creatine supplementation is in widespread use to enhance sports-fitness performance, and has been trialled successfully in the treatment of neurological, neuromuscular and atherosclerotic disease. Creatine plays a pivotal role in brain energy homeostasis, ...

www.ncbi.nlm.nih.gov

https://www.tandfonline.com/doi/abs/10.1080/09291016.2017.1333198?journalCode=nbrr20

Apparently creatine does not improve sleep, but corrects the problems involving sleep restriction, probably acting as an anti-inflammatory, and decreasing brain Ca+ cytotoxicity. Also remembering that creatine acts on adenosine in a similar way to caffeine, also reducing daytime sleepiness.

In practice, it allows you to have a normal day, being productive even with few hours of sleep. This is my experience, I have 25 years of insomnia and sleep apnea. I usually get sleepy only at 3 am, I spent my life sleeping very little and waking up terrible. Creatine in larger doses has been fantastic.

The Brazilian doctor I mentioned, Dr Paulo Muzy, sleeps 5 hours a night since he was a teenager. The guy is a study machine, has 6 specializations and does weight training and light cardio daily, even with little sleep. In his lives it is possible to observe an incredibly high cognitive capacity, he speaks intermittently without pauses and with an absurdly sharp memory. He uses 3g in after 3 meals for a total of 9g.

I had already used creatine several times throughout my life. But everything improved with higher doses. I've been using 20g for about 3 weeks now and the cognitive and athletic improvements are really impressive. He had severe pain in the tendons of his elbows and knees, in addition to repeated injuries to his calves that did not improve even with prednisone and acupuncture. After this short period with high doses all the pain improved, the post-workout recovery is incredible, the mood is much better (there are studies about the benefits of creatine in depression).

Test with 20g for 7 days, followed by 5g/day and come back to report what you think.

Creatine is quickly absorbed by the body and as it competes for adenosine receptors, it is advisable to avoid using both at the same time. So I've been leaving the caffeine 1 hour after the creatine. Unlike caffeine, creatine has no stimulant effect, it improves cognition and strength without causing anxiety. I tend to react badly to caffeine, but after the creatine saturation this changed, I tolerate much more caffeine and clearly feel a greater dopaminergic boost. I feel more motivated and in a better mood.

The higher dose I am using is based on studies in tbi. I intend to keep it that way for longer as I had TBI as a child and a concussion as a teenager, as well as the sleep apnea that produces a lot of ROS.

 

[Gûs80]

International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine - Journal of the International Society of Sports Nutrition

Creatine is one of the most popular nutritional ergogenic aids for athletes. Studies have consistently shown that creatine supplementation increases intramuscular creatine concentrations which may help explain the observed improvements in high intensity exercise performance leading to greater...

jissn.biomedcentral.com

"International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine​

Abstract​

Creatine is one of the most popular nutritional ergogenic aids for athletes. Studies have consistently shown that creatine supplementation increases intramuscular creatine concentrations which may help explain the observed improvements in high intensity exercise performance leading to greater training adaptations. In addition to athletic and exercise improvement, research has shown that creatine supplementation may enhance post-exercise recovery, injury prevention, thermoregulation, rehabilitation, and concussion and/or spinal cord neuroprotection. Additionally, a number of clinical applications of creatine supplementation have been studied involving neurodegenerative diseases (e.g., muscular dystrophy, Parkinson’s, Huntington’s disease), diabetes, osteoarthritis, fibromyalgia, aging, brain and heart ischemia, adolescent depression, and pregnancy. These studies provide a large body of evidence that creatine can not only improve exercise performance, but can play a role in preventing and/or reducing the severity of injury, enhancing rehabilitation from injuries, and helping athletes tolerate heavy training loads. Additionally, researchers have identified a number of potentially beneficial clinical uses of creatine supplementation. These studies show that short and long-term supplementation (up to 30 g/day for 5 years) is safe and well-tolerated in healthy individuals and in a number of patient populations ranging from infants to the elderly."

 

[Gûs80]

"Conversely, larger athletes engaged in intense training may need to consume 5–10 g/day of creatine to maintain optimal or capacity whole body creatine stores [22] and clinical populations may need to consume 10–30 g/day throughout their lifespan to offset creatine synthesis deficiencies and/or provide therapeutic benefit in various disease states [13, 19, 23]."

 

[Vinny]

Creatine-supplementation reduces sleep need and homeostatic sleep pressure in rats

Sleep has been postulated to promote brain energy restoration. It is yet unknown if increasing the energy availability within the brain reduces the sleep need. The guanidine amino acid creatine (Cr) is a well-known energy booster in cellular energy homeostasis. ...

www.ncbi.nlm.nih.gov

Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol - PubMed

Following 24-h sleep deprivation, creatine supplementation had a positive effect on mood state and tasks that place a heavy stress on the prefrontal cortex.

pubmed.ncbi.nlm.nih.gov

Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial.

Creatine supplementation is in widespread use to enhance sports-fitness performance, and has been trialled successfully in the treatment of neurological, neuromuscular and atherosclerotic disease. Creatine plays a pivotal role in brain energy homeostasis, ...

www.ncbi.nlm.nih.gov

https://www.tandfonline.com/doi/abs/10.1080/09291016.2017.1333198?journalCode=nbrr20

Apparently creatine does not improve sleep, but corrects the problems involving sleep restriction, probably acting as an anti-inflammatory, and decreasing brain Ca+ cytotoxicity. Also remembering that creatine acts on adenosine in a similar way to caffeine, also reducing daytime sleepiness.

In practice, it allows you to have a normal day, being productive even with few hours of sleep. This is my experience, I have 25 years of insomnia and sleep apnea. I usually get sleepy only at 3 am, I spent my life sleeping very little and waking up terrible. Creatine in larger doses has been fantastic.

The Brazilian doctor I mentioned, Dr Paulo Muzy, sleeps 5 hours a night since he was a teenager. The guy is a study machine, has 6 specializations and does weight training and light cardio daily, even with little sleep. In his lives it is possible to observe an incredibly high cognitive capacity, he speaks intermittently without pauses and with an absurdly sharp memory. He uses 3g in after 3 meals for a total of 9g.

I had already used creatine several times throughout my life. But everything improved with higher doses. I've been using 20g for about 3 weeks now and the cognitive and athletic improvements are really impressive. He had severe pain in the tendons of his elbows and knees, in addition to repeated injuries to his calves that did not improve even with prednisone and acupuncture. After this short period with high doses all the pain improved, the post-workout recovery is incredible, the mood is much better (there are studies about the benefits of creatine in depression).

Test with 20g for 7 days, followed by 5g/day and come back to report what you think.

Creatine is quickly absorbed by the body and as it competes for adenosine receptors, it is advisable to avoid using both at the same time. So I've been leaving the caffeine 1 hour after the creatine. Unlike caffeine, creatine has no stimulant effect, it improves cognition and strength without causing anxiety. I tend to react badly to caffeine, but after the creatine saturation this changed, I tolerate much more caffeine and clearly feel a greater dopaminergic boost. I feel more motivated and in a better mood.

The higher dose I am using is based on studies in tbi. I intend to keep it that way for longer as I had TBI as a child and a concussion as a teenager, as well as the sleep apnea that produces a lot of ROS.

Thank you!
What time of the day should one take it?

 

[Gûs80]

Thank you!
What time of the day should one take it?

Studies show increased absorption when taken after a carbohydrate and protein meal. In this scenario, insulin provides greater muscle absorption and creatine increases the increase in muscle glycogen.

But the most important thing is continuous use, because what matters is that it accumulates in the body and brain.

I use it after breakfast and lunch. I leave the caffeine for the morning snack, when cortisol tends to decrease and thus not compete with creatine.

 

[WonMore]

Sleep doctors push Generation Z meds or quetiapine, which in my opinion are much more harmful to health than benzos. I used zolpidem for a few years and even after 1 decade without using it I still couldn't fully reverse the chronic fatigue developed during its use. All sleep medications are histaminics antagonists.

Interesting, what mechanism do you ascribe to Z drugs for this fatigue effect? Tinkering with GABA or some other mode of action? Have you ever tried pregabalin, or gabapentin, or baclofen? Do you have opinion on those?

 

[Ktbridge]

How to get off of them , my relative is in a bad place, help I don’t know what to do?

 

[Gûs80]

Interesting, what mechanism do you ascribe to Z drugs for this fatigue effect? Tinkering with GABA or some other mode of action? Have you ever tried pregabalin, or gabapentin, or baclofen? Do you have opinion on those?

Sorry, for some reason I only read your question today. I'm not sure about it, but it apparently increases serotonin and depletes dopamine. In addition to reinforcing bad memories. I had terrible sleep with zolpidem, I really regret using it.

I don't think benzos are innocent, but I have known some people who have been able to live normal lives using alprazolam. I don't know if I've already said this here on the forum, but my uncle used it for decades, he was a doctor, he worked until the weeks before his death, he died at over 80 years old with Covid. He always said that a lost night's sleep is much worse than taking a dose of alprazolam.
If you go to drug.com and look at the reviews, it's the highest rated drug. Many reports of people using it for decades.

I strongly believe that most of the studies that talk bad about benzos are similar to those that talk bad about aspirin. They are funded by big pharma to promote new, much more harmful drugs.

Obviously, it will always be better to try to treat with niacinamide, sucrose, cyproheptadine, etc.

Zolpidem Maintains Memories for Negative Emotions Across a Night of Sleep - Affective Science

Zolpidem, a common medication for sleep complaints, also shows secondary, unexpected memory benefits. We previously found that zolpidem prior to a nap enhanced negative, highly arousing picture memory. As zolpidem is typically administered at night, how it affects overnight emotional memory...

link.springer.com

 

[WonMore]

@Gûs80 No worries, thanks for your response!