PCT: A Clinician's View Part III and 1/2 - On Site in St. Louis

[dinoiii]

PCT: A Clinician’s View Part III ½
Special Edition I - On Site in St. Louis

- article originally published on-line March 5, 2006

Dana Houser, MD, MHSA, CISSN

Author's Note: If you have yet to visit the PRIMER or PARTS I, II, and III of this series, please do so at the following addresses before proceeding.


Introduction

It has become apparent to me while receiving numerous emails (avg. 60 per day since the release of PCT: ACV Part III), that even at a running tally of about 80 pages, PCT: ACV Parts I-III still seemingly have fallen short of my intended purpose (to be the virtual best, evidence-based set of information you could get your hands on for many, if not all of your PCT questions). While entertaining a new St. Louis client base coupled with continuing my medical endeavors, I unfortunately had some issues getting back up live and yet the questions continued to come. Instead of addressing each of them one by one, I simply started keeping note and if they showed up three or more times, it was an outward cry that board members would like more. Some are presented in Q&A format below while others are a “cliff notes” offering of pertinent PCT comments surrounding various supplements that kept cropping up in your questions. About ninety emails came through surrounding use of something for insomnia during PCT and various sleep aids with the usual format evidence-based approach to efficacy (similar to PCT: ACV III) was used in depicting this important post-cycle concern.

Welcome the birth of the “Special Edition Series” (SES) - NOT to be confused as either part of a particular popular ligand molecule nor another company that goes by an abbreviation of similar sound (replacing the “E” with a “N).”

[dinoiii]

The Best of the Rest

Fenugreek

“Cliff Notes” Summary:

There are many reports of this particular substance having the potential to uh, hem..."bring the boys back" as I have heard it so whimsically described. The efficacy studies show no such support, however, in regards to this claim. IN FACT, I CHALLENGE THAT THEY SHOW EXACTLY THE OPPOSITE WITH SUPPORTING RATIONALE BELOW!!!

So, is it useless during PCT? Well, the studies do show ideal glucose management provided the fenugreek extract has a 60-80% galactomannan content - but this is ideal to add in a delayed manner (much of which I will address in part VII - I'm sorry, but it simply does get this complex...is it a wonder people don't "respond" to things that truly have backing?).

So, what the heck do studies really show:
(1) The galactomannan ratio of galactose and mannose in fenugreek reduced urinary sugar levels of participants by as much as 54% which has been speculated to lower the glycemic index of food.
(2) Decreased insulin response to food
(3) Helps maintain normal serum glucose levels (by slowing down the absorption rate of carbohydrates <see #2>, thereby lowering the insulin requirement. Hypoglycemic effects of fenugreek observed in animal studies have been associated with a fraction that contains the testa and endosperm of the defatted seeds, called the A subfraction. These effects have NOT been observed with the lipid extracts. Hypoglycemic effects have been attributed to several mechanisms: Sauvaire, et al. demonstrated that the unique amino acid 4-hydroxyisoleucine in fenugreek seeds increases glucose-induced insulin release in vitro in human and rat pancreatic cells. This amino acid appeared to act only on pancreatic beta cells, as somatostatin (delta cells) and glucagon (alpha cells) were not altered in the study. In human studies, fenugreek reduced the area under the curve (AUC) for plasma glucose and increased the number of insulin receptors via an unclear mechanism. Fenugreek seeds have also been postulated to exert hypoglycemic effects by stimulating glucose-dependent insulin release by beta cells or via inhibition of alpha-amylase and sucrase activity. Without significant ingestion of simple carbohydrates, the benefits of this supplement can be largely debated..
(4) Inhibition of the absorption of fats. In animal studies, fenugreek has been found to lower triglycerides, total cholesterol, and LDL levels. These effects may be due to saponins, which is transformed in the gastrointestinal tract to sapogenins. Sapogenins increase biliary cholesterol secretion, potentially leading to lower serum levels. DID YOU READ THAT ALL YEE “BRINGING THE BOYS BACK” SUPPORT CLUB MEMBERS - decreasing cholesterol LOWERS SUBSTRATE FOR ANDROGEN PRODUCTION ... DELAYING UHHHH “BOY INFLATION.”
(5) Increased sense of fullness. This couldn’t come at a better time as caloric adjustments need be made - but this is why it is required in a delayed manner as you should remain somewhat hypERcaloric initially.

__________________________________________________

Corosolic Acid/Colosolic Acid

“Cliff Notes” Summary:

STANDARDIZATION MUST BE UPHELD. Better brands standardize to 1% corosolic acid from Banaba! - I have spoken about this at length in previous posts as well as in Part II.

What do the studies show here:
Well, First let's separate results by: cell culture, animal and human studies.

Cell culture:
In isolated cells, it is known to stimulate glucose uptake.

Animals:
In diabetic mice, rats and rabbits, banaba feeding reduces elevated blood sugar and insulin levels to normal.

Humans:
In humans with type II diabetes, banaba extract, at a dose of 16-48 mg per day for 4-8 weeks, has been shown to be effective in reducing blood sugar levels (5%-30% reduction) and maintaining tighter control of blood sugar fluctuations. An interesting “side-effect” of tighter control of blood sugar and insulin levels is a significant tendency of banaba to promote weight loss (an average of 2-4 lbs. per month) – without significant dietary alterations. It is likely that modulation of glucose and insulin levels reduces total caloric intake somewhat and encourages moderate weight-loss.

Pertinent PCT info:
Application of this product during PCT would be a good idea for various reasons. Most notably as adrenal function comes back in order, the pancreas tends to follow suit for realignment of homeostatic balance of anabolic/catabolic processes. You must start it IMMEDIATELY after or better yet in the last week of a cycle to ensure its blood sugar-lowering properties to be beneficial, and it must NOT be used in the immediate post-workout time frame (any other time of day is a better bet, first thing in the morning most likely superior).

_________________________________________________

Eurycoma longfolia
Another standardization likely to be tricky to find: Standardized Tongkat Ali Extract (22% quassinoids - eurycomanone, eurycomanol, eurycomalactone; registered as the ever-infamous EuryPeptides® by one company, various canthine-6-one alkaloids, and 40% Glyco Saponins).

The original research centered on malarial treatments in Malaysia. A ton of research soared onto the scene shortly thereafter from the Ang camp with various authors regarding its multitudes of touted benefit in the realm of sexual enhancement, etc... Unfortunately the group does have some vested interest so take their findings with a grain of salt, though many have followed blindly.

After finding it having the potential to turn duds to studs (side effect in Malaria patients, not truly testing for these effects up front), we turned to our middle-aged rat friends (of course, they were Malaysian rats, so there is potential for sampling bias to have skewed the values) and low and behold time and time again, them there rats became - well promiscuous (I know, should have been an interesting set of experiments to figure this out). Many animal studies, both in rats and mice actually, have found administration of E. longifolia extracts to increase sexual arousal and motivation and frequency of sexual activity. These effects are similar to those caused by administration of testosterone, although the effect of Tongkat Ali is not as strong.

Years later, it seeped into human ingestion in search of increased virility and sexual prowess with even, perhaps, improvement in strength and power during sexual activities. There are no human studies published in peer-reviewed journals yet, although there are many anecdotal reports that would indicate that the aphrodisiac qualities are retained in humans.

A related property that Tongkat Ali is reputed to have is a testosterone-increasing effect. Tongkat Ali does have androgenic effects in male rats, either directly or indirectly, such as increasing the weight of “sexual accessories” as one study puts it finely. In vitro, ethanolic extracts (mind you, NOT all extracts are created equal) of E. longifolia increase hCG-induced production of testosterone by rat leydig cells. There are many anecdotal reports on the internet where people indicate that they had testosterone levels tested before and during Tongkat Ali supplementation, and it caused an increase. The present evidence indicates that this is a likely property of this plant, but how great the effect is, dose-dependency, and whether or not it contributes significantly to the aphrodisiac qualities of Tongkat Ali can only be established with more research. Until then, Tongkat Ali should not be treated as a reliable way to increase testosterone levels.

[dinoiii]

SLEEP AIDS

What is known to us surrounding the post-cycle environment is that there is a high-frequency of changes associated with sleep patterns in many users. Sometimes this is an extension of increased testosterone levels and would be likely extinguished as hormonal harmony is regained, or is it? There are multiple pattern variations seen (i.e. - decrease in the number of hours of sleep, decrease in the time spent in REM, decrease in ability to induce sleep, etc...). Is this surprising? Not at all - HOWEVER, there is completely different rationale usually supporting what I call peri-cycle insomnia (PeCI) and post-cycle insomnia (PoCI) should they occur. [author’s note: a definition of the terms “peri” implies “next to” in the literal sense and “during” as read as I have chosen to use it in this piece]. It is imperative to note that exact timing of this side effect has a particular etiology and amendment of such allows appropriate addressing of the problem.

PeCI

Etiology finds three-fold rationale depending on (1) aromatizing capability of the compound, (2) shifts in dose-response curve [i.e. - once again, volume of distribution plays a direct role], and (3) various negative feedback mechanisms directly proportionate to cycle length. Unfortunately, discussion of these is beyond the scope of this article and I would like to turn our attention to the post-cycle time frame.

PoCI

If a patient notes “SOLITARY” post-cycle development of sleep loss, our attention turns to the pineal gland as the predominant etiologic rationale for our newfound deficiency. Trading in one hormonal deficiency for another may seem like a huge contradiction of terms, but it too is part of the hormonal chaos you create while on cycle. Understanding our deficiency means we have to visit semi-equivalent research done in the area of pineal gland tumors and deficiency and their association with abnormal pubertal development for answers. The original hypothesis to explain precocious puberty in boys with pineal tumors was that the tumors destroyed the capacity of the pineal gland to inhibit sexual development. In fact, much evidence suggests that precocity is due to production of the beta subunit of human chorionic gonadotropin (beta-hCG) by germ cell tumors of the pineal gland. This relationship has nevertheless stimulated much work on the possible role of the pineal gland through the secretion of melatonin as a means of timing human puberty. It has been shown that both precocious and delayed puberty have been associated with pineal tumors.

So what about PCT? Let’s see what happens in the dinoiii model. Oh yeah, those that get real scared to see science...turn away now.

Melatonin secretion is actually a response to various light input on retinal receptors and a complex cascade of events thereafter that follow:

Step 1) Light –> eye –> (+) Hypothalamic suprachiamatic nucleus / (+) Hypothalamic paraventricular nucleus –> hindbrain –> spinal cord –> superior cervical ganglion –> divergent outflow tracts [go to Step 2a OR 2b]

Step 2a) Superior Cervical ganglion –> Norepinephrine –> Beta-adrenergic receptor [go to Step 3a]

Step 2b) Superior Cervical ganglion –> Norepinephrine –> Alpha-adrenergic receptor [go to Step 3b]

Step 3a) (beta-adrenergic sequelae) ATP –> cAMP-dependent phosphorylation via AA-NAT promotor binding –> 5-HT N-Acetyl Transferase - 5-HT NAT [move on to Melatonin-processing cascade]

Step 3b) (alpha-adrenergic sequelae) C-kinase input into beta-adrenergic cAMP phosphorylation crossover [Return to Step 3a]

Melatonin-Processing Cascade:
1. Tryptophan –> 5-HTP
2. 5-HTP –> 5-HT
3. 5-HT –> N-Acetylserotonin (via 5-HT NAT from Step 3a)
4. N-Acetylserotonin –> Melatonin (via hydroxyindole-O-methyltransferase - HOMT)

The model is consistent with the suggestions offered in PCT: ACV III regarding hypOadrenalism in the “immediate” post-cycle realm contributing to a DECREASE in catabolic balance in roughly the first 2.5 weeks of post-cycle era, inclusive of not only cortisol, BUT also catecholamine (i.e. - NE) output. This is where the difference arises in PoCI - outisde of its intimate connection with serum gonadotropin-effects, you also have changes in enzymatic processing unique to PCT.

So Dana, melatonin supplementation would be the simple answer, right? NOT SO FAST! You really don’t think I spent all that time on the melatonin processing cascade to talk about simple melatonin supplementation, did you? Now, remember with our crossover pathway, melatonin has crossover feedback to follow suit and a subsequent DECREASE in serum gonadotropin [FSH + LH] via GNRH outflow during the sleep hours as shown in most current research. Decreased Melatonin is actually a good thing in PCT as the body’s own mechanism for restoring balance [though beyond our scope here it may be a GH deficiency you have then to worry about if sleep deprivation results - quite complex, huh? Though the hormonal chaos always gets oversimplified! ALL HOMRONES DO NOT ACT IN A VACUUM, THERE ARE ALWAYS ATTEMPTS AT HOMEOSTATIC BALANCE! Disrupt it, and its like tipping a scale where but another hormonal pathway will suffer]. In people experiencing PoCI, the likelihood of reaching serum gonadotropin suppression is nearly 100%.

What’s more...Melatonin 1 [MT1, not to be confused with M1T] receptor subtypes are also present in the pars tuberalis to increase prolactin output possibly potentiating post-cycle galactorrhea (nipple discharge).

[author’s note: melatonin conveys photoperiodic info influencing the pattern of something called mPer expression in the pars tuberalis for the control of seasonal variations of that MT1 receptor - which is way beyond the scope of this article, but explains even furthermore why simple supplementation here is NOT warranted in everyone].

These effects seem to dissipate, however, with long-term supplementation BUT it is likely NOT a good plan in the post cycle era to be trying melatonin or secretagogues (i.e. - 5-HTP, et al.] for the first time.

So, what you’re telling me is that should insomnia crop up in the post-cycle era, I am left to suffer, right? Nah, there are some potential alternatives which offer sedative effects that could override this melatonin system.

[dinoiii]

CLIFF NOTES SUMMARY OF POTENTIAL MELATONIN ALTERNATIVES in the POST-CYCLE time frame

Ashwaganda

BASIC MOA: withanolides are the active ingredients, purported to do a number of things, which include everything from libido enhancement to sedative-like effects.

EVIDENCE-BASED EFFICACY: Used as general “cure-all” in Ayurvedic medicine of India. There are NO clinical studies to support efficacy in this manner, but continued folk use may change that.

FORMS & DOSAGES: 150-600mg of standardized extract are needed DAILY or 2-3 grams of powdered root are what has been stated to be accurate dosing parameters for the duration of a week or two prior to seeing results which may not actually offer rationale for its use as a primary means to overcome insomnia in the post-cycle time frame and I would suggest against it at this time.

POTENTIAL SIDE EFFECTS/INTERACTIONS: May heighten the effects of barbiturates, alcohol, or GABAergic products. Please avoid concurrent use of any of these substances.

______________________________________________

Catnip

BASIC MOA: Nepetalactone isomers are the actives here, somewhat like (BUT NOT EXACTLY) the active ingredients in valerian and mild sedatives.

EVIDENCE-BASED EFFICACY: A few poorly-controlled studies suggest multiple administrations throughout the day to be an effective dosing pattern which does have the potential to decrease compliance.

FORMS & DOSAGES: 2-4 grams taken in a titrated up matter to assess tolerance and avoid the potential for groggy “morning-after” feeling.

POTENTIAL SIDE EFFECTS/INTERACTIONS: None reported to date.

[dinoiii]

Kava

BASIC MAO/Chemistry: Extracts of Kava root contain both lipophilic and hydrophilic components. The active components are referred to as kavalactones or kavapyrones. The active enolides + dienolides are thought to be kawain (kavain), methysticin (+ its dihydro active metabolite), and to a lesser extent, yangonin. These active byproducts are hypothesized to do a number of things in the central nervous system (CNS). While it is generally argued to have a MOA unknown, theories have emerged and gained support around this substance. In vitro, kavalactones have been shown to readily bind GABA-A receptors located in the hypothalamus and amygdala, areas thought to be largely responsible for emotion and memory rather than cognition and movement. KAVA may also increase the number of GABA-binding sites. Other suggested mechanisms include reduced excitatory neurotransmission by decreasing the release of glutamate, inhibition of norepinephrine uptake, reversible MAO-B inhibition, or dopamine antagonism. KAVA has also been shown to have mild anticonvulsant properties in animals, possibly involving voltage-dependent sodium channels. There have been reported analgesic effects in humans with animal data suggesting opioid receptors NOT be involved - therefore the jury is still out as to how this effect is seen.

EVEIDENCE-BASED EFFICACY: This substance has undergone several true well-conducted placebo-controlled trials in Europe and the United States for the treatment of anxiety. Most show significant improvements in anxiety symptoms in patients with moderate to severe anxiety within 8 weeks after starting treatment.

One study in particular put the supp head-to-head with a leading drug of an equivalent class:
KAVA vs. Oxazepam (a benzodiazepine) yielded similar reductions in anxiolytic effects BUT fewer adverse effects were seen in the KAVA group.

FORMS & DOASGES: Unfortunately, KAVA appears to have a slow onset of action for treatment of anxiety (which can extend to similar efficacious results in sedative-promoting effects, at which time many users may give up on the supp attributing their stoppage to its not “working”), most patients only responding after 4-8 weeks of therapy. It would therefore best be started during or before a cycle with a lot of cytochrome interactions to boot. It is reasonable to assume with all the frivolous information about PCT out there already (i.e. SERMs et al), I CANNOT recommend KAVA in the post-cycle time frame.

POTENTIAL SIDE EFFECTS/INTERACTIONS: Dinoiii’s EXTREME CAUTIONARY WARNING: One of the kavalactones, kavain, has in-vitro COX-inhibitory activity and the potential for antiplatelet and anti-inflammatory effects needs further study. I strongly urge NOT to use this supplement in the post-cycle time frame or anytime for that matter with NSAIDs, Fish Oil, Vitamin E, plus MOST pharmaceutics due to various cytochrome p450 interactions in the liver.

______________________________________________

Chamomile

BASIC MOA: For purposes of sleep, you ay desire to opt for the German/Hungarian variety (there is a Roman variety almost indistinguishable, but alas falls in a different genus and species.).They have tried to isolate the single most active substance in chamomile, with apigenin and other flavones, chamazulene, and a-bisabolol often identified. But most studies have concluded that a whole herb extract is better than any individual phytochemicals. Outside of its insomnia therapy use, chamomile finds use as an anti-inflammatory as well - VERY comparable, if not better than hydrocortsione!

EVIDENCE-BASED EFFICACY: One study shows induction of a deep sleep in 10 out of 12 cardiac catheterization patients, but otherwise data on a larger scale remains unfortunately deficient.

FORMS & DOSAGES: Two or three 250mg caps three times per day is what were used in the studies which makes for an exhaustive dosing protocol to follow. If you can keep up with it, however, then by all means.

POTENTIAL SIDE EFFECTS/INTERACTIONS: None reported, however, cross-reactions may be seen in anyone allergic to ragweed, celery, or aster-family herbs. Again, this is yet another one that should be avoided with NSAIDs, fish oil, vitamin E and other blood thinners due to a coumadin-like property. Minor allergic reactions have been discussed alongside nausea but dosing to induce these symptoms is highly unlikely in most people.

______________________________________________

Hops

BASIC MOA: This is a close relative of stinging nettle and the cannabis genus, which obviously gives us marijuana (see previous posts for much more here). It has got to be the most eccentric name for something to induce sleep, no? But in fact, that’s what it does and does it well. In 15th and 16th century Europe, it was banned for NOT only inducing sedation, but also sadness (of the melancholy variety). Only in 17th century did Hops become a common ingredient in English beer. A number of chemicals in Hops possess sedative and muscle-relaxing qualities, whereas other compounds depress the CNS. It is likely this is yet another one to actually ingest the entire herb versus a simple phytochemical component due to potential synergism.

EVIDENCE-BASED EFFICACY: While there are no well-controlled studies, there are multitudes of reports to suggest this has significant efficacious property.

FORMS & DOSAGES: 500mg is what I believe it would take. Any more and you could be talking that infinite sadness (as above).

POTENTIAL SIDE EFFECTS/INTERACTIONS: One reason I may suggest against this herb is the tendency for many post-cyclers to report depressive symptoms once off exogenous androgen. The concurrent potential to exacerbate this would not be ideal. Furthermore, it does tend to stimulate appetite, so it is likely in your best interest to guard against that as your BMR readjusts. Respiratory allergies and other various allergic reactions have been reported in some.

______________________________________________

[dinoiii]

Valerian

BASIC MOA: The Greeks, beginning with Hippocrates, used valerian roots (translated as phu based on its pugnant smell beneath the surface - i.e. - the root which held the medicinal properties) to help them fall asleep, an application that still holds up under scientific scrutiny. We know conclusively that valerian sedates, quiets the CNS, and minimizes muscle spasms - just like pharmaceutical tranquilizers. After a few thousand years of study, though, we still don’t know why. At first, researchers referred to just two phytochemical classes - valeoptriates and the bornyl esters as contributing to 100% of the active properties, now we know there are at least several more - valeranone and the kessyl esters. Another example of the whole herb being better than the sum of its parts.

EVIDENCE-BASED EFFICACY: Combined with St. John’s Wort, Valerian bested diazepam (Valium) in a 2-week trial involving 100 people being treated for anxiety. A different double-blind coupled Valerian with hops (see above) showing superiority to triazolam (Halcion), another benzodiazepine, for relieving sleep disorders. When I mention superiority here, the results on efficacy were not what contributed to that dubbing - as efficacy was NOT statistically significant in its difference. However, the safety (i.e. - less side effects associated with the non-habit-forming supplements) profile is what allows for superior rating.

FORMS & DOSAGES: About 300-500 mg of standardized extract before bedtime. 1, 425-2,780 mg of non-standardized supplement for insomnia relief before bed.

POTENTIAL SIDE EFFECTS/INTERACTIONS: Hepatotoxicity (liver toxicity) has been reported in a few multi-herb preparation formulas. It remains unclear as to whether this side effect is evident with Valerian alone. A compound called scullcap is usually the culprit I think - because the more hepatotoxic herb germander is often mistakenly harvested as scullcap. Furthermore, reports on 50 cases of overdose with a combination preparation containing hyoscine, cyproheptadine, and valerian indicated the expected symptoms of cyproheptadine and hyoscine toxicity, but no signs of hepatotoxicity developed in the short or long term. So, to use or not use - especially post C17 alkylated usage is debatable.

Mild, transient stomach upset as well as nausea and vomiting have been reported anecdotally. Large doses may be associated with decreased intestinal motility - perhaps offsetting some of the appetite stimulating effects of hops when used in combo.

Valerian has also been reported to cause headache, excitability, insomnia, uneasiness, ataxia, and hypothermia, although the level of adverse effects reported in clinical trials has not been greater than for a placebo. Short-term mild impairments in vigilance, concentration, and processing time for complex thoughts, as well as mild fatigue, have been reported in trials (lasting for several hours), although residual sedative effects appear to be less pronounced than those for benzos (i.e. - no hangover drowsiness). The problem is that preliminary evidence suggests that valerian is non-sedating in recommended doses. With higher dosing protocols, the evolution of this “hangover” effect cannot be excluded. Chronic high-dose actually leads to a similar “Valerian withdrawl” similar to that seen with benzos. Delirium, ameliorated by benzos, was reported in a single patient undergoing withdrawl from high-dose valerian. Dizziness and headache have been reported rarely in human studies. Anecdotally, some people may develop a “paradoxical reaction” leading to nervousness or excitability but it is highly unlikely for normal PCT durations.

dinoiii’s tip(s): Be careful to wean off (titrate down) of valerian at the end of PCT should you chose to use it in this manner as you can avoid some of these adverse valerian withdrawl effects. Another valerian withdrawl effect that may be seen in someone in the PCT time frame is tachycardia (fast heart beat) and high-output cardiac failure. Bradycardia (slow heart beat has also been seen). Again, it is usually long-term and high-dose. But “high-dose” interpretations are NOT standardized and as I have said above...high-dose may be necessary to induce sedative nature of the supplement.

A whole slew of drug-herb interactions are possible:
(1) Sedative drugs / CNS depressants (this includes alcohol gentlemen)
(2) SSRIs
(3) beta blockers (recall the herbal actions of some of the antihypertensives from PCT: ACV II and III having this action - the same rules apply to those compounds)
(4) Antiseizure agents (though you likely should not be ever attempting a cycle in this scenario)
(5) Loperamide (Immodium - OTC)
(6) Disulfaram (Antabuse)
(7) Mtronidazole (Flagyl)
(8) Vasopressin (positive interaction: in rabbits, given vasopressin, valepotriates have been found to reduce the incidence of cardiac arrhythmias - though the human significance remains unclear to my knowledge)
(9) St. John’s Wort
(10) Kava
(11) Sedative-type / CNS-depressant herbs


While this is NOT an exhaustive list of all of the agents and/or options you have for sleep induction and maintenance (if using sedative), it is sufficient, I am sure.

[dinoiii]

Q&A

Q: In PCT: ACV II and III you seemed to support ZMA supplements. I read at [website omitted] that this is