A patient emailed me recently: he was going to a few countries in Europe. Could he take his medications with him? He was on a schedule II stimulant.
I think it’s a good idea, before visiting a new country, to check out a few websites:
The first is the US State Department’s Alerts and Warnings Page to see if anything really dangerous is happening where you’re going. http://travel.state.gov/content/passports/english/alertswarnings.html
Then, on the same page, check out the information for the individual country you’re going to: http://travel.state.gov/content/passports/english/country.html
Finally, check out the Center for Disease Control Website to see if there are any medical concerns where you’re going.
http://wwwnc.cdc.gov/travel/destinations/list
It turns out that taking a prescribed stimulant to Europe is legal (keep the medication in the original prescription bottle).
But every country is different, and the laws in the United States are very different from those of other countries, in some surprising ways.
For example, taking a schedule II stimulant into Japan is illegal, with the exception of Concerta (the only schedule II stimulant allowed in Japan for the treatment of ADHD). Adderall, Vyvanse, dextroamphetamine, etc are illegal, even in the original bottle, with a copy of the prescription and a note from the prescribing physician. So are over the counter inhalers containing pseudoephedrine.
“However, it is illegal to bring into Japan some over-the-counter medicines commonly used in the United States, including inhalers and some allergy and sinus medications. Specifically, products that contain stimulants (medicines that contain pseudoephedrine, such as Actifed, Sudafed, and Vicks inhalers) or codeine are prohibited. You can generally bring up to one month’s supply of allowable prescription medicine into Japan. You must bring a copy of your doctor’s prescription as well as a letter stating the purpose of the drug. However, some U.S. prescription medications, such as Adderall, cannot be imported into Japan, even when accompanied by a customs declaration and a copy of the prescription.” (my emphasis)
http://travel.state.gov/content/passports/english/country/japan.html (under the heading: Local Laws and Special Circumstances, and sub-heading: Confiscation of Prescription Drugs and Other Medication
This is not a misprint. From another source:
Prescription Medications
“Heroin, cocaine, MDMA, opium, cannabis, stimulant drugs including some prescription medications such as Adderall, and including some medications available over-the-counter in the U.S. are prohibited in Japan. There are no exceptions in bringing these prohibited medications into Japan, even if the medication is legally obtained outside of Japan. The import of stimulant drugs such as methamphetamines and amphetamines in particular are strictly prohibited, even when accompanied by a customs declaration and a copy of the prescription. Japanese customs officials or police can detain travelers importing prohibited items. Japanese customs officials do not make on-the-spot “humanitarian” exceptions for medicines that are prohibited in Japan.”
http://japan.usembassy.gov/e/acs/tacs-medimport.html
And another:
“When bringing prescription medications to Japan you may have items inspected and cleared upon arrival by the Customs Agency, and avoid further processing if the following conditions apply:…
Items are not prohibited drugs in Japan such as stimulants (i.e. Adderall)
There are no exceptions in the case of (stimulants), even if the medication is legally obtained outside of Japan. The import of stimulants such as methamphetamines or amphetamines, as well as precursors such as ephedrine or pseudoephedrine exceeding a certain concentration level, is prohibited by the Stimulants Control Law.
http://www.seattle.us.emb-japan.go.jp/about/import_restrictions.html
Even more curiously, if one had the illusion that the world is rational, while one cannot bring legally prescribed Adderall or Vyvanse into Japan, one can bring in the following with no problem
“If you intend to import / export the psychotropics equal to or less than theamount indicated in the Table (excluding injection form), you don’t need a certificate written by your doctor nor the permission by authorities under the “Narcotics and Psychotropics Control Law”.
http://www.nco.go.jp/dl_data/keitai/keitai_guideh26.pdf
1. Secobarbital, up to 6 grams (a barbiturate, rarely used now due to narrow therapeutic index (too easy to overdose on)
2. Mecloqualone, up to 9 grams: per Wikipedia, “Mecloqualone is faster-acting but shorter-lasting than methaqualone and so was used only as a sleeping pill, in contrast to methaqualone, which was used as a general-purpose anxiolytic as well. Mecloqualone was never as widely used as methaqualone and is no longer prescribed because of concerns about its potential for abuse and overdose. In the United States it is a Schedule I non-narcotic (depressant) controlled substance with an ACSCN of 2572 and zero annual aggregate manufacturing quota. It is most often seen these days as a component in purported Quāāludes (resulting from incomplete synthesis of methaqualone) from underground labs.”
3. glutethimide, up to 15 grams: glutethimide is Doriden. Per Wikipedia, “Glutethimide is a hypnotic sedative that was introduced by Ciba in 1954 as a safe alternative to barbiturates to treat insomnia. Before long, however, it had become clear that glutethimide was just as likely to cause addiction and caused similarly severe withdrawal symptoms… Current production levels in the United States (the annual quota for manufacturing imposed by the DEA has been three grams, enough for six Doriden tablets, for a number of years) point to it only being used in small scale research.
So you’re allowed to bring 15 mg of this into Japan, with no problem: this is equivalent to 5 times the annual quota for the entire United States.
In overview, one is allowed to bring in a month of benzodiazepines (diazepam: 1200 mg (Valium), zolpidem (Ambien) 300 mg, and a variety of amphetamine like appetite suppressants (phendimetrazine 3.15 g, phentermine 1.125 g, benzfetamine 1.5 g)
Finally, meprobamate 18 grams: continuing our tour of pharmaceuticals popular in the Mad Men era, meprobamate (Miltown) was “launched in 1955 and rapidly became the first blockbuster psychotropic drug in American history, becoming popular in Hollywood and gaining notoriety for its seemingly miraculous effects” (Wikipedia) in relieving anxiety. Like glutethimide, it soon became apparent that it was as dangerous as the barbiturates. “By 1957, over 36 million prescriptions had been filled for meprobamate in the US alone, a billion pills had been manufactured, and it accounted for fully a third of all prescriptions written” (Wikipedia). In 1965, the Medical Letter reported meprobamate was addictive; in 1970, it became a controlled substance; in 2012, the European Union withdrew its marketing authorization; in 2013, Canada did the same.
But I digress. Back to Japan and Adderall, with an example of what happens when one brings prescribed stimulants into Japan:
Carrie Russell was a 26 year old college graduate, diagnosed with ADHD at the age of 7, whose mother, a physician, shipped her a 90 day supply of Adderall (prescribed by Carrie’s family practitioner), in a “care package”, when she was in South Korea. (Her mother removed her Adderall from the prescription bottle and put them in a Tylenol bottle, because she was worried they might be stolen if properly labeled). Carrie mailed the box to Nagoya, Japan, where she planned to teach English. “At 11 p.m. on Feb. 20, according to Russell’s Portland-area family, five plain-clothed police officers in black suits burst into a Tokyo restaurant where the 26-year-old American was dining with friends. They took her into custody. She was taken 275 miles west to Nagoya, where she was incarcerated in a women’s detention center outside the city.” She was released after 18 days in custody after the Caroline Kennedy, the Ambassador to Japan, intervened. She gave her Japanese prison experience a good review:
“Russell said that although her arrest was shocking, the detention center “was not anything terrifying,” Russell said. “The facility was clean. We had daily chores.” Inmates were served bento meals, Russell said, each with rice as a staple and small portions of noodles, potatoes, vegetables and other food. She said she learned some more Japanese language, such as, “How to say, ‘open,’ how to say, ‘refill my water,’” and, ‘I’m finished with my meal.’”
Interestingly, amphetamine abuse in Japan is quite common: “According to police officials, 2.6 million Japanese had used between 15 and 18 tons of amphetamines in the late 1990′s. This is more than the use of all other illegal drugs combined. Officials state that amphetamines are their biggest challenge. The drugs are popular amongst truck drivers, gang members, partiers, housewives, salary men, people wanting to lose weight, and the rich of Japan. Amphetamines are 10 times the cost in Japan than the United States, but still remain the most favorable drug of choice.” http://www.thecabinchiangmai.com/archive/statistics_of_japan___s_rising_drug_use#.VZbl3vlVikp
Apparently, the illegal amphetamine trade is controlled by criminal organizations, such as the Yakuza, whose profits might suffer if these medications could be legally prescribed by physicians, as is the case in the United States and the European Union. Thus economics helps us understand what appears irrational at first glance. Why would Japan allow in dangerous sedatives without restriction and forbid a medication commonly and safely used for ADHD in other countries? Apparently because it would interfere with the profits of the criminal elements who control the amphetamine market. Another factor is that mental illness is stigmatized in Japan.
Thinking about sleep: Maiken Nedergaard and the function of deep sleep
All animals sleep, even flies (research with the fruit fly Drosophila revealed the presence of clock genes). All mammals have REM (rapid eye movement) and non-REM sleep. Human infants sleep 16 hours/day (if their parents are lucky); adults sleep 8 hours/day; elderly adults 5.5 hours/day. (S Lockley and R Foster: Sleep: A Very Short Introduction, Oxford University Press, 2012, pages 48-49).
Continuous sleep deprivation kills rodents and flies within days to weeks.
But why do we sleep? It would seem to be an evolutionary disadvantage. We are more vulnerable to predators when asleep. We could be working instead of sleeping. Korean secondary-school students attend hagwons (private cram academies) for five hours after school, then go home at 10 PM to study until past midnight (The Economist, September 19-25, 2015). If they didn’t have to sleep, they could study all night.
So sleep must perform some very important functions. But what?
Maiken Nedergaard, a neuroscientist at the University of Rochester (more specifically, an astroglial biologist), appears to have answered the non-REM portion of this question, in her paper “Sleep Drives Metabolic Clearance from the Adult Brain” (Science Vol 342, 10/18/2013, p. 373-377) http://www.sciencemag.org/content/342/6156/373.long
Other bodily organs rid themselves of waste protein products by using bulk flow of fluid between cells to wash them into the blood or lymphatic system, which carry them to the liver, where they are metabolized.
The brain uses 20% of the body’s energy supply. Yet it has no lymphatic system. How does it get rid of its waste products, such as beta-amyloid (Alzheimer’s), alpha-synuclein (Parkinson’s disease, Lewy body dementia), and tau (Alzheimer’s), to name a few, all of which are present in the interstitial fluid surrounding brain cells.
This question becomes more interesting when one considers that “essentially all neurodegenerative diseases are associated with misaccumulation of cellular waste products. Of these, misfolded or hyperphosphorylated proteins are among the most difficult for the brain to dispose of. For example tau and beta-amyloid can accumulate as stable aggregates that are neurotoxic in conditions such as Alzheimer’s disease.” http://www.sciencemag.org/content/340/6140/1529
Nedergaard describes the glymphatic system, or, less politely, the “Garbage Truck of the Brain”. http://www.sciencemag.org/content/340/6140/1529
Astrocytes express a water channel, the aquaporin 4 water channel (AQP4). Penetrating arteries which end in the brain are covered by astrocytic endfeet which express AQP4. This perivascular space around the arteries is a “highway for fast influx”, which can be observed with radiolabeled tracer.
In a three-step process, first cerebrospinal fluid (CSF) passes from the para-arterial space, through the aquaporin 4 (AQP4) water channels, into the interstitial space, where “vectorial convective fluxes drive waste products away from the arteries and toward the veins”, and CSF exchanges with interstitial fluid (ISF). Then the ISF and its waste products enter the paravenous space, eventually reaching lymphatic vessels in the neck, and later the systemic circulation, where the proteins travel to the liver, where they are metabolized. The brain has better things to do than chopping up the garbage.
The AQP4 water channels in the astroglial endfeet are crucial to this process (AQP4- knockout mice have a 65% reduction in beta amyloid clearance). In traumatic brain injury and stroke, AQP4 gets “mislocated to the cell body of astrocytes or to astrocytic processes that do not abut the vasculature”, and protein clearance “declines substantially”.
The interstitial concentration of beta amyloid is higher in awake rodents and humans than it is in sleeping ones. One possibility is that “wakefulness is associated with increased beta amyloid production”.
Nedergaard tested “the alternative hypothesis that beta amyloid clearance is increased during sleep and that the sleep-wake cycle regulates glymphatic clearance”.
Her group found that CSF influx into the brain was decreased by 95% in awake mice, compared to sleeping mice or mice anaesthetized with ketamine/xylazine. (Ketamine has recently been discovered to be a very rapidly acting treatment for bipolar depression, but its antidepressant effect lasts only 1-2 weeks. One wonders if its short duration of action suggests that it clears the brain of garbage, which soon returns, leading to relapse.)
CSF influx into the brain is “in part driven by arterial pulse waves that propel the movement of CSF inward along periarterial spaces”.
“Convective glymphatic fluxes of cerebrospinal fluid (CSF) and interstitial fluid propel the waste products of neuronal metabolism (proteins, peptides, lactate, ammonia, amyloid) into the paravenous space from which they are directed into lymphatic vessels and ultimately returned to the general circulation for clearance by the kidney and the liver.” This is analogous to garbage removal by “street sweeping” with liquid.
To manipulate the glymphatic system (the garbage highway from the glial endfeet lining the arteries, through the extracellular space, to the paravenous spaces, and the lymph channels), 4 methods were employed, all of which decreased efflux:
1. AQP40 knockout mice: decreased fluid influx
2. Cisternotomy: this opening eliminated the low-pressure system
3. Acetazolamide: blocked CSF fluid production
4. Sleep deprivation
After traumatic brain injury, increased protein markers are noted in plasma; but all 4 of the above interventions blocked the increase.
(Footnote: This glymphatic process calls to mind both the first sentence of James Joyce’s novel of sleep, Finnegans Wake: “riverrun, past Eve and Adam’s, from swerve of shore to bend of bay, brings us by a commodius vicus of recirculation back to Howth Castle and Environs.”, and Steven Dedalus’s comment in Ulysses: “All Ireland is washed by the gulfstream.”)
Nedergaard points out that this process was first discovered by Patricia Grady in the early 1980’s, when she observed the movement of horseradish peroxidase into the brain. Attempts by others to replicate her work failed because the replicators used a “cranial window” cut into the skull, which destroyed the low pressure which drives the system. She left science and is now director of nursing at the NIH.
If pulse were the driving force behind the diurnal variation, one would expect to see greater influx during the day, when arterial blood pressure is higher than when asleep. Instead, one sees the opposite.
This system, Nedegaard reasoned, is like plumbing: all that matters is pressure and resistance. Pulse pressure is bigger when one is awake and alert. Yet influx is less. So therefore there must be less resistance while asleep.
“An alternative possibility is that the awake brain state is linked to a reduction in the volume of the interstitial space because a constricted interstitial space would increase resistance to convective fluid movement and suppress CSF influx”.
Nedegaard used techniques developed by Charles Nicholson to assess the volume and tortuosity of the interstitial space in awake, sleeping, and anaesthetized mice, and found that the interstitial space volume fraction averaged 23.4% in sleeping mice, and 14.1% in awake mice. Both sleeping and anaesthetized mice had higher levels of slow (delta) wave sleep. “Thus, the cortical interstitial volume fraction is 13 to 15% in the awake state as compared to 22 to 24% in sleeping or anaesthetized mice.” There was no change in tortuosity.
Interestingly, other studies have shown that the interstitial volume declines by 1/3 in aged mice compared to young mice. “The smaller space during wakefulness increases tissue resistance to interstitial fluid flux and inward movement of CSF.” The smaller space in aged animals (and humans) would make it harder to clear out the garbage/amyloid; neurodegenerative diseases are more common in the elderly.
Beta amyloid was cleared twice as fast in sleeping as in awake mice. Before the streets of the brain are swept, they are widened, not by removal of parked cars, as in Santa Monica, but by shrinkage of brain cells into their quiet, resting state.
Nedergaard next asked “what drives the brain state-dependent changes of the interstitial space volume?” Her observation that anesthesia increases glymphatic influx and efflux led her to hypothesize that it is not circadian rhythm but the sleep wake state itself.
Since noradrenergic neurons in the locus coeruleus drive cortical networks into the awake state, Nedergaard administered a cocktail of adrenergic antagonists (prazosin (α1 adrenergic receptor antagonist, which improves sleep in patients with PTSD), atipamezole (α2 adrenergic receptor antagonist), and propranolol (non-selective beta adrenergic receptor blocker) and found that they induced an increase in CSF tracer influx comparable to the sleep state, and increased the interstitial volume fraction from 14.3 to 22.6%. The antagonists also increased the prevalence of slow, delta waves. “Norepinephrine is the master regulator of ISS volume”, she notes.
Nedergaard can be seen talking about “The Nightlife of the Brain” at the National Institute of Health (2/11/2015) at the NIH website (534 views (http://videocast.nih.gov/summary.asp?Live=15718&bhcp=1 or, more efficiently, on YouTube (the NIH website frequently freezes; 821 views) https://www.youtube.com/watch?v=JmykxytFiGg
She also spoke at Cold Spring Harbor Laboratory on the Glymphatic System on 12/12/2014. https://www.youtube.com/watch?v=S-JXgPUmd3A . (1043 views).
So, clearance of brain garbage occurs primarily during slow wave, or deep (N3, formerly called stage 3-4) sleep.
Now, sleep problems occur very early in the course of Alzheimer’s disease (AD), even during mild cognitive impairment, often an Alzheimer’s precursor, with less slow wave sleep (SWS). (Ju, Lucey, Holtzman: Sleep and Alzheimer disease pathology-a bidirectional relationship. Nature Reviews Neurology 10: February 2014, 115-119; http://www.nature.com/nrneurol/journal/v10/n2/full/nrneurol.2013.269.html ). Alzheimer’s pathology begins 10-15 years before cognitive symptoms appear, when soluble beta amyloid becomes insoluble and aggregates into amyloid plaques. Amyloid accumulation disrupts sleep; disrupted sleep “increases the risk of beta amyloid accumulation in mice, as well as dementia due to Alzheimer’s disease in humans”.
While chronic sleep deprivation “accelerates beta amyloid deposition into insoluble amyloid plaques”, improving sleep “through treatment with an orexin inhibitor antagonist decreased beta amyloid plaque deposition” in mice. “One obvious approach is to investigate whether improving the quality of sleep in humans can either reduce the risk of AD or delay the progression of preclinical to symptomatic AD.”
In a more recent paper, Holtzman suggests that “considering the profound protective effect of almorexant on beta amyloid plaque burden in mice, the orexin system is a high priority target. The recent approval of suvorexant, the first Food and Drug Administration approved orexin receptor antagonist, provides an excellent opportunity to evaluate orexin-targeted therapeutics on Aβ dynamics and cognitive endpoints in early-stage or presymptomatic AD.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351409/
So, in summary: