written by reader Sleep: Getting Enough When We Need It

Doc Gumshoe Counts Sheep

By mjorrin, October 7, 2014

[ed note: Michael Jorrin, who I like to call “Doc Gumshoe”, is a longtime medical writer (not a doctor) who shares his thoughts with us from time to time, generally on non-financial topics in health and medicine (as today, though he mentions a couple publicly traded companies). His words and opinions are his own.]

Let’s start with a little case study. Our subject is a healthy male in his 20s. On Saturday night, he and his wife go to a triple feature (three excellent French movies from the 1930s, Marius, Fanny, and César, directed by Marcel Pagnol and starring the famous Raimu), which lets out at about 3:00 AM. They then go to a neighborhood all-night coffee-shop, appropriately called “Fanny’s Say No More,” for a little something, because they have developed a lively appetite. They fall into bed about 5:30 AM, and don’t rouse themselves until almost 3:00 in the afternoon the next day. They laze about on Sunday and hit the sack at a more or less normal hour, elevenish, because Monday morning looms.

However, our young man (okay, I’ll confess, it’s me) gets a truly lousy night’s sleep Sunday night – tosses and turns, lies awake and listens to the tiny hum of the electric clock and the creaking of the bed-springs, falls into a deep sleep just as the alarm goes off, and is a zombie all day Monday.

So Monday night, he and his spouse, who also slept badly Sunday night, determine to get a really good night’s sleep. They grab a quick bite and are tucked in by about 9:00 PM, expectantly waiting to be enfolded in the arms of Morpheus. But Morpheus doesn’t do his job. Sleep comes in snatches, far from satisfactory. Our young man’s spouse gets up and takes something from the medicine cabinet, comes back to bed and goes to sleep, but our subject abstains and suffers. Tuesday is another zombie day for him.

Tuesday night comes. Our subject is understandably anxious. Has he become, suddenly, an insomniac? Where has balmy sleep gone? His wife doesn’t seem overly concerned – she, after all, slept pretty well. They have dinner and get ready for bed. As they are about to get under the covers, our subject’s wife suggests that our young man might just consider taking half a Valium tablet, which is what she took the preceding night. He reluctantly agrees, cuts the tablet in half with his nail scissors, and swallows the mutilated pill. And almost before he takes the few steps back to bed, he feels the waves of blessed sleep washing over him.

So, what does this tell us, if anything, about dealing with sleep issues?

First, and most obvious, it tells us that at least some of the efficacy of sleep medications is due to the placebo effect. Valium (diazepam) is not, strictly speaking, a “sleeping pill.” It is a drug in the benzodiazepine class and is classified as an anxiolytic, meaning that the specific mechanism is to reduce anxiety, which of course can be a cause of insomnia. We’ll talk later on about the different types of drugs, medications, supplements, that can be used to help with sleep problems. But it clearly was not the physiologic effect of the drug that put me to sleep – it was the feeling of relief that swept over me that I had taken a drug that would put me to sleep.

For many people, I suspect, taking a sleeping pill is just part of their bedtime routine, like brushing their teeth. The physiologic effect of the medication combines with the comforting sense that they have made the necessary preparations for enjoying a good night’s sleep. And, indeed, that combination works fairly well.

Second, and also fairly obvious, is that when I went to bed on that Sunday, I wasn’t anywhere near feeling “sleepy.” I hadn’t done much of anything at all that day – no work, no exercise, just a lazy day with the Sunday paper. I’d only been awake for about 8 hours, and I didn’t need any sleep just then.

Third, and not so obvious, but something that points to one of the fundamental issues in sleep, is that we humans seem to be programmed to sleep in the night and be awake in the daytime. As far as we know, every organism on our planet demonstrates some kind of response to the earth’s 24-hour rotation and the alternation of light and darkness, although not every species manifests the same sleeping-waking response as we humans.

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This response is known Baby sleepingas the Circadian rhythm, and in our species it’s controlled by a cluster of brain cells called the suprachiasmatic nucleus, or SCN. This little bundle dwells close to the optic nerve, which tell the SCN whether it’s light or dark. In turn, the SCN sends little signals to other brain departments. When it’s dark, the SCN signals the pineal gland to secrete melatonin, which makes us sleepy. When it’s light, the SCN triggers the release of cortisol, which is involved in a number of wakeful and active responses.

Related to this is the activity of the two divisions of our autonomic nervous system. The autonomic nervous system, in case you had forgotten, is the one that keeps our body functioning without our consciously having to tell it to function. It regulates our breathing, our heartbeat, our digestion, our vision, our glands, our bladders, our metabolism – in fact, most of what keeps us going. The autonomic nervous system has two separate and independent components – the sympathetic nervous system, and the parasympathetic nervous system. The sympathetic nervous system runs through the spinal nerve and its branches, while the parasympathetic nervous system takes off from the cranial nerves and mostly operates through a separate system, employing the vagus nerve for about 75% of its functions.

This is important, or at least interesting, because the functions that the sympathetic nervous system manages are primarily associated with waking, and those the parasympathetic nervous system manages are associated with sleeping. Here’s a quick breakdown:

Effects of the autonomic nervous system on various organs

Organ system</td> Sympathetic nervous system Parasympathetic nervous system
Eye pupil Dilated Constricted
Blood vessels Constricted Dilated
Heart muscle Increased rate and force of contraction Slowed rate and force of contraction
Lungs – bronchi Dilated Constricted
Lungs – vasculature Mildly constricted Mostly dilated
GI tract Decreased peristalsis and tone Increased peristalsis and tone
Liver Glucose release Slight glycogen synthesis
Kidney Decreased output and renin secretion None
Basal metabolism Increased as much as 100% None
Skeletal muscle Increased strength None

So what does that tell us? The sympathetic nervous system prepares us to deal with the needs of our waking, daytime activities. The heart beat is faster and stronger, blood pressure increases, lung capacity increases, the liver releases more glucose for energy, and our skeletal muscles are stronger. In contrast, the parasympathetic nervous system takes over while we rest and sleep. The heart slows down, blood pressure drops, breathing slows, the liver stores glucose as glycogen, and we continue to digest whatever food we’ve taken in during the day.

Regardless of when we actually tumbled into bed, the sympathetic nervous system generally starts to get us ready for the new day quite early in the morning. It doesn’t wait for the alarm clock or the morning coffee. Many people are familiar with the sensation of a somewhat more rapid heartbeat well before they’re ready to hop out of bed, and in people who are at risk for cardiac issues, the dawn hours are prime time for acute coronary syndromes.

Without going into more abstruse medical detail, the particular agents responsible for these sympathetic nervous system effects are known as adrenergic agents – norepinephrine and epinephrine – and these act on adrenergic receptors, designated as alpha and beta receptors. The beta adrenergic receptors in particular are the ones that activate those waking-up effects – the faster heartbeat, the greater lung capacity.

The parasympathetic nervous system works mostly through acetylcholine, and its effects are termed cholinergic. Besides the effects of acetylcholine on the sleeping / waking cycle, acetylcholine is also involved in memory and learning. There’s a theory that we take in information when we’re in the waking phase and the adrenergic agents are in control, and we process it and file it away when we’re in the sleeping phase and acetylcholine is doing its job. Of course, it’s not as though there’s a moment when one phase switches off and the other switches on – we secrete both neurotransmitters most of the time. It’s just a question of which phase is dominant.

So, returning to our case study, it seems that our subject went to bed at 5:30 AM on that Sunday just about when his sympathetic nervous system was prompting him to rise and shine. He then spent more than 8 hours in bed, and he was definitely zonked. But it wasn’t the most restful sleep. In this sense, his experience was similar to that of lots of people who have sleep problems due to such things as jet lag and shift work.

Dealing with jet lag and shift work

 

The challenges presented by these two situations are different in a number of respects, one of which is fundamental. The individual taking an all-night flight from Logan to Heathrow, arriving at 6:15 AM GMT, and expecting to make a coherent presentation at that eminent institution on Threadneedle Street at half-past nine, does indeed face a staggering challenge. But she ought to have taken the plane a day before, had a nap in her hotel, done a bit of shopping at Jigsaw, and had a bite of dinner at Simply Nico’s. If she had then gotten up in the morning (and if it has been a tolerably nice day in London), exposure to daylight might have got her cortisol flowing just a bit in time to perform decently. It would also have helped a good deal if in the days prior to setting off on her trans-Atlantic jaunt, she had tried to go to bed and get up just a bit earlier, so as to reset her own Circadian rhythms to sync up with Greenwich Mean Time. Granted, this is not easy, and life definitely gets in the way.

Jet lag is not a long-term sleep problem, even for people who are constantly jetting around the planet on highly important missions. I know of people who make a point of staying on Eastern Standard Time no matter where they are. They fly to London and take their morning meeting at 3:00 PM EST, have lunch at 6:00 PM, dinner at midnight, and fly back to Eastern time without losing much sleep. There are ways to lick jet lag.

Shift work is much more difficult. Persons on the midnight-to-8:00 AM shift not only have to stay awake at work, but then go home and try to get some sleep during the hours when they would prefer to be awake. They’re in conflict with their Circadian rhythms, and also possibly with family members, noisy neighbors, and the matitudinal chirping of the birdies. Also, shift work usually is on a rotating basis, so that the person who’s on the graveyard shift for a month or so then changes over to the 8:00 AM to 4:00PM shift for a month, and then to the 4:00 PM to midnight shift. (I’m treating these as though they were simple 8-hour shifts, but of course the shifts are longer, to permit meal breaks, and they also often overlap.) In any case, what happens to shift workers is that just about when they get slightly adjusted to their disjointed sleeping / waking cycle, it gets disrupted again. And again and again.

For shift workers, staying awake during the graveyard shift, and then while driving home, may be a bigger challenge than getting some sleep during their off hours. The usual remedy is coffee, and there’s no question that caffeine helps some people stay awake and alert. For people who don’t like coffee, there are lots of ways to get caffeine without drinking coffee. Straight caffeine is available over the counter in the form of tablets such as No-Doz, each tablet of which consists of 100 mg of caffeine – approximately the same as a cup of coffee. Energy drinks, e.g., Red Bull, contain just a bit less caffeine per serving – about 80 mg. Drip coffee contains more caffeine than perked coffee, and espresso even more. Dry tea contains more caffeine by weight than coffee beans, but brewed tea doesn’t use that much dry tea, and a cup of tea usually has only a bit more caffeine than a cup of decaf coffee.

How does caffeine keep us awake?

 

The chief mechanism of caffeine is to dial down the activity of a neurotransmitter called adenosine. Adenosine plays a number of different roles in the body, and the adenosine phosphates – mono-, di-, and tri-, or AMP, ADP and ATP – are central to our metabolism. In the brain, one of the things adenosine tends to do is put a sort of damper on some forms of neuronal activity – in other words, it quiets down the brain and permits us to go to sleep. Caffeine blocks adenosine receptors, inhibits that quieting effect, and helps keep us alert and awake.

The effects of caffeine vary considerably among members of our species. I, for one, rely on my morning coffee to get me going (although that might be a kind of placebo effect – it’s the blissful aroma of that blend of Kenya and Vienna Roast coffee that starts my day). But I can usually drink a double espresso after dinner and sleep the sleep of the just. My wife, however, is reluctant to drink any coffee at all much past noon lest she have a problem falling asleep.

Which takes us back to the shift-workers’ dilemma: if they rely on coffee or caffeine in any form to stay alert during their shifts, how long will it be before they feel dozy and relaxed?

Perhaps because of the unpredictability of caffeine, many people employ other strategies to stay awake, whether for shift work, studying, driving, or any other activities. We will avoid discussing the extreme cases, since after all our principal focus in this piece is sleep, and not staying awake. In passing, we should acknowledge the use of amphetamines and similar agents that are primarily intended for the treatment of attention deficit disorder, e.g., Adderall, Ritalin, Vyvanse and the like. Short-acting formulations of these drugs may be used to keep a person awake and alert without carrying over and seriously interfering with sleep time. The abuse of these drugs is widely recognized, and is related to what many consider the over-diagnosis of ADD and ADHD – which is another subject for another time.

However, the need for something that helps people stay awake brings me to a relatively new drug, with an entirely different mechanism of action, which, as it happens, may also be employed to help people get good sleep.

Modafinil and orexins

Modafinil (Provigil, Alertec) and armodafinil (Nuvigil), both from Cephalon, wholly owned by Teva Pharmaceuticals, are relatively new stay-awake drugs that have gotten a great deal of attention lately. Modafinil was FDA approved for narcolepsy in 1998 and for shift-work sleep disorder in 2003. Armodafinil is the R-enantiomer of modafinil, meaning that it consists of only the right-handed version of the molecule (thus R-modafinil or armodafinil) . In many instances, the effectiveness of a drug depends on the precise shape of the molecule, and the precise way it locks with its targets. Two molecules can have the identical chemical composition, but be exact mirror images of each other. One locks with the target while the other does not. Think of the way a key fits into a lock: it can be cut in the same way, but if the grooves are on the wrong side, it will simply not go into the lock. Modafinil is the so-called racemic compound, consisting of both the right- and left-handed molecules, while armodafinil consists of only the molecules that fit the target.

Modafinil (and armodafinil) have been referred to as Viagra for the brain – they are stimulants, and may work by activating neurons called orexins (sometimes also called hypocretins, but we’ll stick with orexins). Orexins extend their axons to various parts of the brain that are involved with wakefulness and attention, and activation of orexins increases the levels of dopamine and norepinephrine in those areas. And, as noted earlier, norepinephrine in particular is the neurotransmitter that stimulates waking physiologic functions such as heart rate, lung capacity, energy production, and muscle strength. So far, these agents have not demonstrated much risk for abuse, unlike the amphetamines and other stimulants, which are commonly abused.

The side effects of any stay-awake medication are difficult to separate from the inherent effects of not getting enough sleep. The most frequent adverse event in clinical trial patients taking modafinil was headache, experienced by 34%; however, 23% of patients taking placebos also experienced headaches. Most other adverse effects were in the single digits.

What is particularly interesting about modafinil is that it gives us insight into the connection between orexins and sleep. If activating orexins can help promote wakefulness, would it not be possible that blocking the activity of orexins would promote sleep?

Sleep promoting mechanisms

 

Most sleep medications have worked by means of the neurotransmitter gamma-aminobutyric acid, or GABA, which is the chief inhibitor of neurons. The drugs that had this effect were discovered long before the identification of the mechanism. It was found that barbiturates induced sleep; only later was the inhibitory mechanism of GABA identified and studied. Barbiturates, such as Phenobarbital, Seconal, or Veronal, really do induce sleep. They do this by greatly slowing all transmission of signals in the cortex. Their defects are well known, including a tendency to be addictive; the celebrities who were hooked on barbiturates are many and notorious, e.g., Marilyn Monroe. And there is a tendency to overdose. It’s not easy to get the dose just right; people wake up sooner than they want to, or else they wake up feeling drugged.

Several other classes of sleep-inducing drugs also addressed GABA receptors, even though they may have different mechanisms of action. The benzodiazepines, such as Ativan (lorazepam), Dalmane (flurazepam), Halcion (triazelam), Restoril (temazepam), and others. These agents have a somewhat different effect than the barbiturates; their goal, rather than knocking you out, is to ease you into sleep by quieting down your anxieties. As noted earlier, they are primarily anxiolytics. Some people get habituated to drugs of this class; they find that to achieve the desired effect, they have to keep upping the dose. This might be considered a form of addiction.

And some antihistamines induce sleepiness, such as Benadryl (diphenhydramine), Desyrel (trazodone) and others; a major drawback of these is that in some people the effect lingers past the desired sleep period – i.e., you’re dopey the next day.

The blockbuster entry – I am not using that term loosely – was Ambien (zolpidem) from Sanofi, which also targeted GABA receptors. Currently, Ambien and Ambien CR account for about 70% of the 60 million or so prescriptions for sleep medications in the US. However, Ambien’s drawbacks are widely recognized, including a range of erratic behavior that has been widely publicized in the media. Some people take the drug with no intention at all of going to sleep – instead they enjoy a feeling of disinhibition that permits them to engage in all manner of activities, ranging from the merely silly (gorging on cupcakes) to the genuinely risky (reckless driving).

Ambien’s problems have led the FDA to issue a number of warnings and also reduce the dosage. In the meantime, Sanofi has introduced a controlled release formulation (Ambien CR) that is meant to offset one of Ambien’s problems, namely, that it is a relatively short-acting drug. Ambien tends to put people to sleep, but it’s not so good at keeping people asleep. The CR formulation keeps releasing the drug into the system over a longer period.

The way Ambien induces sleep might be compared with stopping a machine by filling the works with a dense, sticky liquid. Addressing the orexin system is a fundamentally different mechanism. Orexins promote wakefulness; thus, an orexin antagonist is like pressing the snooze button on the alarm clock. Or, to return to the machine analogy, it stops the machine by simply interrupting the power supply.

Suvorexant (Belsomra): an orexin antagonist

 

This new drug, from Merck, was approved by the FDA just this August, and will start becoming available around the end of the year. It was approved on the basis of three Phase 3 clinical trials in more than 500 subjects, including individuals who had been diagnosed with primary insomnia. Sleep-lab results demonstrated that the subjects taking the active drug did actually spend more time in slow-wave sleep than did patients taking the placebo; their subjective perception of how much sleep they were getting didn’t differ a great deal, but the sleep-lab data were enough to persuade the FDA to approve the drug for the treatment of insomnia.

Suvorexant has also been studied, with encouraging results, in patients with chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea.

An important difference between Belsomra (suvorexant) and Ambien (zolpidem) is that Belsomra does not result in feelings of euphoria or disinhibition – it just shuts off that internal alarm clock without giving people that Ambien joy ride.

But, speaking of joy rides, it does appear to be the case that subjects who had taken suvorexant did demonstrate impaired driving upon waking up; this has prompted the FDA to issue the usual caution against driving or “engaging in activities requiring full mental alertness” subsequent to taking the drug.

There was a lengthy back-and-forth between Merck and the FDA on the matter of dosage. Because there is a very big placebo effect in clinical trials with sleep medications, the dose of the active drug in the clinical trials has to be big enough to elicit a clear distinction between active drug and placebo. Merck tested dosages from 10 mg to 80 mg, and was leaning towards making 40 mg the standard dose. But because of side effect concerns – impaired driving and others – the FDA has approved four dose levels – 5 mg, 10 mg, 15 mg, and 20 mg, with the 10 mg dose being standard. Merck scientists have expressed the view that the 10 mg dose would not be an effective anti-insomnia medication, but Merck is clearly taking what it can get and hoping to push the standard dose higher.

Suvorexant is the first orexin antagonist; certainly others are on the way. The advantages of employing that pathway to treat sleep problems are many, and the market for sleep aids is enormous. Suvorexant has the potential to be a dominant drug for Merck – I would even consider using the “B” word.

Other options

 

From Doc Gumshoe’s perspective, a first step in addressing sleep problems is to try to figure out just what it is that’s keeping you awake and try to deal with it. The W. C. Fields advice to insomniacs – “Try to get a lot of sleep” – is clearly counterproductive; the very act of trying keeps you awake. A boring book before turning out the light might help; or hot bush tea, perhaps with a spoonful of honey and a dollop of rum. But what prevents lots of people from sleeping soundly and long enough is that they aren’t able to put the brakes on their busy brains, which keep speeding along and exploring different paths. My personal view on this is that it’s useless to try to tell your brain what to do – that only makes it more obstinate and willful. Let it go along whatever pathways it wants to take, and before long it begins to drift and not make too much sense, and there you are, right where you want to be – in the arms of Morpheus.

* * * * * * *

As always, Doc Gumshoe welcomes your comments, and, in particular, would like to know what is tickling your curiosity these days. I have been doing some work on interesting doings in the pharmaceutical field – the development of a class of drugs called “biosimilars.” These might just have a profound effect on the treatment of lots of individuals, and also on the health-care system in general, as well as on the prospects of many pharmaceutical outfits. Look for a report in a future installment. Best to all, Michael Jorrin (aka Doc Gumshoe)


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DrKSSMDPhD
October 7, 2014 7:21 pm

Nice article Michael. I might add that Ambien has been highly prized over alternatives like Sonata and Lunesta because it really works….for sleep induction anyway. Lunesta and that bloody awful moth on its TV ads is an attempt at racemic reinvention of zopiclone, a lousy drug. In everyone except those with genetic inability to taste phenylthiocarbamazine, ie, certain Scots, the bitter aftertaste makes staying on it unsustainable.

Ambien’s shortfall is that it is lousy at sleep maintenance. It also leads to what I call white noise sleep, sleep in which no dreaming ever happens…sleep thus not truly restorative. It’s reasonable to mix in trazodone or doxepin.

I commonly see patients in whom sleep is literally something that happens no longer because some or another primary doctor has placed them on an SSRI or SNRI. People! If you are taking enough of an SSRI or SNRI to matter, you will NOT sleep and you need to be on a sleep agent! Insist on it!

Ambien has some misuse potential. I always give patients a speech: do NOT take it until you are in bed, TV off, books closed, not planning intercourse, etc and you are ready to go to sleep. You MUST take it on an empty stomach. One of the first scrips for it I wrote was in someone I would soon to realize was a bumbling idiot. He got the speech. At the next visit, he marveled at how after he’d taken the Ambien first dose, he’d decided to go grocery shopping, found himself in the left lane, then found himself driving up the sidewalk and then slamming into a fire hydrant. Did I think that-there Ambien had done that?

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sheldon
sheldon
Irregular
October 7, 2014 9:04 pm

I deal c insomnia both my addictions and geriatrics practices. Look up ‘sleep hygiene ‘ for suggestions on preparation for bedtime. This includes a routine -turning down lighting, turning screens off,taking a warm shower/bath,avoiding late meals,trying white noise to block extraneous sounds,warm milk etc. Trazodone starting at 25mg is my favourite soporific. Mirtazapine at 7.5-15mg is a favourite of geriatricians. Consider going to a sleep lab if apnea is a possibility. Dimen/diphenhydramine is habit-forming, as is zopiclone-abuse/addiction is a risk. Regular exercise-not too late in the day- is invaluable

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omcdac1
omcdac1
Member
October 7, 2014 9:08 pm

I had sleeping problem too.
What works for me –
– Hard workout and weightlifting. I run like 6 miles every day or 20 miles in a week at least.
– Meditation which works but very hard to get “Delta State” by just bare meditation practice, so i use mind machine.
There are several but i use personally – Laxman Light and Sound Mind Machine Innertainment System
There is one more – Mindplace Kasina Audio Visual Synthesizer
Both are available in AMAZON.COM
Some times i watch a special video which makes my mind kind of blank and i fall sleep.
I use this when i really have a lot of stress.
I don’t remember the name right now as i am in office but i can tell name and link of the program.
Any music which can create Delta waves works. I have several but i like “Brain Sync”
All these options are non medicated not additive and natural.
These works for me however they may not work for everyone.
Thanks
Om

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ScorpioRising
ScorpioRising
Irregular
October 7, 2014 11:27 pm

Thanks for the very informative article, Doc Gumshoe. I also have problems falling asleep a few times a week. I’ve taken Doc KSS’s advice previously and take some diphenhydramine an hour before bed and maybe 1/2 Ambien just before bed. That seems to do the trick. Dr. KSS has suggested Trazodone in other threads, so I was keen to read about it in your article. The next visit to my doctor, I’ll ask him about it..

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KennyG
KennyG
Irregular
Reply to  ScorpioRising
October 8, 2014 12:00 am

Whenever I have difficulty falling asleep I read Peter French’s press releases and it quickly puts me to sleep. But…it does give me nightmares.

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arch1
Member
Reply to  KennyG
October 8, 2014 1:07 am

I will have to try that,,,so far Speaker of the House Boehner’s utterances have worked well
for me. It is too cold at night for the frogs and crickets to serenade me now.

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jonken
jonken
Member
Reply to  KennyG
October 8, 2014 9:26 am

Hey Brother, are you saying your preferred method is TORTURE?
I slept like a newborn for three night after I dumped his stock several months ago 🙂
Blessings,
Ken

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ET
ET
Guest
Reply to  jonken
October 8, 2014 5:34 pm

Call me “old school” if you like but I find the best “Drug” is love. I always sleep like a baby after having sex. You can keep your Pharmaceuticals!

Lulu
Member
Reply to  ET
October 8, 2014 10:52 pm

Cucumbers R out of season now.

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