Revised Drug Wheel

Know your chemicals.

The Losing Battle For Perpetual Reward

Or why you can't stay high forever.

The amphetamine high, like the cocaine high, is a marvel of biochemical efficiency. Stimulants work primarily by blocking the reuptake of dopamine molecules in the synaptic gap between nerve cells. Dopamine remains stalled in the gap, stimulating the receptors, resulting in higher dopamine concentrations and greater sensitivity to dopamine in general. Since dopamine is involved in moods and activities such as pleasure, alertness and movement, the primary results of using cocaine or speed—euphoria, a sense of well being, physical alertness, and increased energy—are easily understood. Even a layperson can tell when lab rats have been on a meth binge. The rapid movements, sniffing, and sudden rearing at minor stimuli are not that much different in principle from the outward signs of meth intoxication among higher primates.

Chemically, cocaine and amphetamine are very different compounds. Psychoactively, however, they are very much alike. Of all the addictive drugs, smoked cocaine and speed have the most direct and most devastatingly euphoric effect on the dopamine systems of the brain. Cocaine and amphetamine produce rapid classical conditioning in addicts, demonstrated by the intense cravings touched off by such stimuli as the sight of a building where the user used to buy or sell. Environmental impacts of this nature can produce marked blood flow increases to key limbic structures in abstinent addicts.

In clinical settings, cocaine users have a hard time distinguishing between equal doses of cocaine and Dexedrine, administered intravenously. As we know, it is the shape of the molecule that counts. The amphetamines are shaped like dopamine and norepinephrine, two of the three reward chemicals. Speed, then, is well suited to the task of artificially stimulating the limbic reward pathway. Molecules of amphetamine displace dopamine and norepinephrine in the storage vesicles, squeezing those two neurotransmitters into the synaptic gap and keeping them there. By mechanisms less well identified, cocaine accomplishes the same feat. Both drugs also interfere with the return of dopamine, norepinephrine, and serotonin molecules to their storage sacs, a procedure known as reuptake blocking. Cocaine works its effects primarily by blocking the reuptake of dopamine.

Amphetamine was once one of the most widely prescribed drugs in the pharmacological cornucopia. It exists in large part now as a recreational drug of choice, abuse, and addiction. The same is true of cocaine. It was replaced as a dental anesthetic long ago, in favor of non-addictive variants like Novocain. The same tragic list of statistical side effects that apply to abusers of alcohol, heroin and nicotine also apply to stimulant abusers: Increased risk of car accidents, homicides, heart attack, and strokes.

In the late 1990s, scientists at Johns Hopkins and NIDA showed that opiate receptors play a role in cocaine addiction as well. PET scans demonstrated that cocaine addicts showed increased binding activity at mu opiate receptors sites in the brain during active cocaine addiction. Take away the cocaine, and the brain must cope with too many empty dopamine and endorphin receptors. It is also easy to understand the typical symptoms of cocaine and amphetamine withdrawal: lethargy, depression, anger, and a heightened perception of pain. Both the cocaine high and the amphetamine high are easily augmented with cigarettes or heroin. These combinations result in “nucleus accumbens dopamine overflow,” a state of neurochemical super saturation similar to the results obtained with the notorious “speedball”—heroin plus cocaine.

With the arrival of smokable forms of cocaine and amphetamine, the race to pin down the biology of stimulation became even more urgent. Stimulants in smokable form—crack and ice—are even more rapidly addictive for addiction-prone users. “The reason has to do with the hydraulics of the blood supply,” a researcher at the University of Minnesota explained to me. “High concentrations are achieved with each inhalation, and sent right upstairs to the brain—but not all of the brain simultaneously. The target of the flow of blood is the limbic system, whereas the remainder of the brain is exposed to much milder concentrations.”

This extraordinarily concentrated jolt to the reward center is the reason why smokable cocaine and speed are able to pack such a wallop. The entire range of stimulative effects hits the ventral tegmental area and associated reward regions of the brain in seconds, and the focused nature of the impact yields an astonishingly pleasurable high.

But the long-term result is exactly the opposite. It may sound dour and religious, but the scientific fact of the matter is that continuous chemical pleasure extracts its fee in the end: The body’s natural stock of these neurotransmitters starts to fall as the brain, striving to compensate for the artificial flooding of the reward center, orders a general cutback in production. At the same time, the receptors for these neurotransmitters become excessively sensitive due to the frequent, often unremitting nature of the stimulation.

“It’s clear that cocaine causes depletion of dopamine, norepinephrine, serotonin—it is a general neurotransmitter depleter,” said my research source. “That may account for many of the effects we see after someone has stopped using cocaine. They’re tired, they’re lethargic, they sleep; they may be depressed, moody, and so on.” Continued abuse of stimulant drugs only makes the problem worse. One reason why cocaine and amphetamine addicts will continue to use, even in the face of rapidly diminishing returns, is simply to avoid the crushing onset of withdrawal. Even though the drugs may no longer be working as well as they once did, the alternative—the psychological cost of withdrawal—is even worse. In the jargon used by Alcoholics Anonymous, addicts generally have to get worse before they can get better.

When addicts talk about “chasing a high,” the metaphor can be extended to the losing battle of neurotransmitter levels.

[First published September 28, 2011]

Graphics Credit: http://www.keepcalm-o-matic.co.uk

Methamphetamine: An Excerpt

There’s more than one kind of monster.

Type and I pass the pipe.  The overhead light flickers and the wind picks up even more. It’s coming from the north because with each exhale, the smoke slips past my face, back toward the Twin Cities and my dead parents.
 
But for a brief moment, I’m not thinking about all that. I’m feeling the closest thing I can think of to God and he’s playing the samba inside of my body, his fingers gentle, as they press on the backs of my retinas, my spine, the tendons along my hip flexors. I’m thinking that I love drugs more than anything. That they are the one and only constant in my life. Yeah, they demand a lot of attention and effort, but their love is legendary, their compassion endless. I hold each hit for hours, exhale for decades. The determination that comes with the onset of a high rushes back and I’m all about conquering the world and making money and finding happiness in the form of a loving woman who knows when it’s time to brush the backs of her nails across my cheek and then I’m thinking about this being the same thing as what God is doing to me now.

I love it when my heart rattles against my uvula.

I love it when my vision is a camera shutter.

I love it when I know that someday, I will do great things.

I love it when methamphetamines make things okay.

But I don’t love it when I start to hallucinate because the line between knowing it’s only the drugs and knowing your psyche is about to snap the fuck apart like a high wire is oh so delicate....

—From Fiend, a novel by Peter Stenson

MDPV Turns Lab Rats Into "Window Lickers"

Popular bath salt drug shown to be highly addictive.

Researchers at the Scripps Research Institute (TSRI) in La Jolla, California, appear to have hammered the last nail into the coffin for the common “bath salt” drug known as MDPV. We can now say with a high degree of certainty that, based on animal models, we know that 3,4-methylenedioxypyrovalerone is addictive—perhaps more strongly addictive than methamphetamine, although such comparisons are always perilous. However, principal investigator Michael A. Taffe, an associate professor at TSRI, said in a prepared release that the research group “observed that rats will press a lever more often to get a single infusion of MPDV than they will for meth, across a fairly wide dose range.”

Like methamphetamine, MDPV works by stalling the uptake of dopamine, and it also has effects on noradrenaline and serotonin.  As cathinone derivatives, MPDV and mephedrone are related to the stimulant drug khat, which is used like cocaine in northeastern Africa.  In earlier research at Scripps under Dr. Taffe, investigators found that lab rats would intravenously self-administer mephedrone and behave in a manner similar to the effects produced when the rats were on methamphetamine. In a paper  for Drug and Alcohol Dependence, the Taffe Lab concluded that “the potential for compulsive use of mephedrone in humans is likely quite high, particularly in comparison with MDMA.”

Now the researchers have zeroed in on the effects of the dirty pharmacology represented by MDPV, the other primary ingredient in many bath salt mixtures. In a new study by Michael Taffe, Tobin J. Dickerson, Shawn M. Aarde, and others, to be published in the August issue of Neuropharmacology, the investigators found that MDPV was a more potent attraction than meth for rats allowed to self-administer the drugs. Very little lab data exists for MDPV, and this study was among the first to directly compare the effect of MDPV to methamphetamine in an animal experiment.

It took some time to tease out the behavioral clues—the cognitive, thermoregulatory, and potentially addictive effects of the drug—but MDPV’s strong affinities with speed can no longer be ignored. The researchers saw the same types of repetitive activities seen in animals on meth, such as excessive grooming, tooth grinding, and skin picking.  Lead author Shawn Aarde said in a prepared statement that “one stereotyped behavior that we often observed was a rat repeatedly licking the clear plastic walls of its operant chamber—a behavior that was sometimes uninterruptable.”

 MDPV, in the jargon of such experiments, had “greater reward value” than methamphetamine. Which is saying something, given the well-publicized addictive threat of speed. When the group boosted the number of lever presses needed for another infusion of MDPV or meth, “we observed that rats emitted about 60 presses on average for a dose of meth but up to about 600 for MDPV—some rats would even emit 3,000 lever presses for a single hit of MDPV,” said Aarde in a press release. “If you consider these lever presses a measure of how much a rat will work to get a drug infusion, then these rats worked more than 10 times harder to get MDPV.”

Excuse me, did he say as many as three thousand bar presses for another bump of intravenous MDPV? He did. Overall, the rats self-administered more MDPV than methamphetamine. In the paper itself, the authors write that “compared with meth, the effect of MDPV on drug-reinforced behavior was of greater potency (more responding under lowest dose under fixed-ratio schedule) and greater efficacy (more responding under optimal dose under a progressive ratio schedule)…”

The conclusion? MDPV’s “abuse liability” may be greater than that of standard methamphetamine. Which is another excellent piece of evidence for approaching the world of new synthetic psychoactives with great caution.

Aarde S.M., Huang P.K., Creehan K.M., Dickerson T.J. & Taffe M.A. (2013). The novel recreational drug 3,4-methylenedioxypyrovalerone (MDPV) is a potent psychomotor stimulant: Self-administration and locomotor activity in rats, Neuropharmacology, 71  130-140. DOI: 10.1016/j.neuropharm.2013.04.003

Khat: A Psychologist's Field Trip

Looking for a chew in London.
 
I ran across a great story by Vaughan Bell at Mind Hacks, about his stroll around London, looking for khat, the East African stimulant plant that is chewed much like coca leaves.

 Research psychologist Vaughan Bell is not your average armchair academician. Currently a Senior Research Fellow at the Institute of Psychiatry, King’s College, London, Bell is well known online for his contributions to the Mind Hacks blog, which covers unusual and intriguing findings in neuroscience and psychology. He recently taught clinical psychiatry at Hospital Universitario San Vicente de Paúl and the Universidad de Antioquia in Medellín, Colombia, where he remains an honorary professor. He has also worked for Médecins sans Frontières (Doctors Without Borders) as a mental health coordinator for Colombia. (See my interview with Bell last year).

Reprinted with permission:


Finding myself at a loose end yesterday I decided I’d try and track down one of London’s mafrishes – a type of cafe where people from the capital’s Ethiopian, Somali and Yemeni community chew the psychoactive plant khat.

I’d heard about a Somali cafe on Lewisham Way and thought that was as good a place as any to try. The cafe owner first looked a bit baffled when I walked in and asked about khat but he sat me down, gave me tea, and went out back to ask his associates.

“Sorry, there’s no khat in Lewishman. We have internet?” he suggested while gesturing towards the empty computers at the back. I kindly declined but in reply he suggested I go to Streatham. “There are lots of restaurants there,” he assured me.

Streatham is huge, so I arrived at one of the rail stations and just decided to walk south. Slowly I became aware that there were more Somali-looking faces around but there were no cafes to be seen.
Just through chance I noticed some Somali cafes off a side street and walked into the first one I saw. “There’s none here, but next door”, I was told. The people in the next cafe said the same, as did the next, and the next, until I came to an unmarked door.

“Just go in,” a cafe owner called to me from across the street, so I walked in.

The place was little dark but quite spacious. My fantasies of an East African cafe translocated to London quickly faded as my eyes adjusted to the trucker’s cafe decor. Inside, there were four guys watching the news on a wall-mounted TV.

The cafe owner greeted me as I entered. I asked my usual question about khat and he looked at me, a little puzzled.

“You know, khat, to chew?” I ventured. A furrowed brow. Thinking. “Oh, chat. Yes, we have bundles for three pounds and bundles for seven. Which do you want?”

“Give me one for seven” I said. “No problem” he replied cheerily. “Have a seat”.

This wasn’t the first time I had tried khat. Many years ago, when I was an undergraduate in the Midlands, I discovered khat in an alternative shop. It was sold as a natural curative soul lifting wonder plant from the fields of Africa.

I bought some, didn’t really know what to do with it, and just began to ‘gently chew’, as the leaflet advised, while walking through the streets of Nottingham.

So when my bundle of khat arrived, I just picked out some stems and began chomping on one end. “Wait, wait, stop!” they shouted in unison. “We’ll help you” said one and I was joined by the cafe owner and a friend. “Anyway, he said”, “you’re not allowed chew alone, it’s a social thing.”
I was given a bin to put beside my table, was shown how to strip off the stems and pick out the soft parts, and how to chew slowly. I was provided tea and water on the house and told to keep drinking fluids. Apparently, it can be a little strong on the stomach and the plant makes you go to the toilet a lot as, I was told, ‘it speeds up the body’.

I had the company of the cafe owner, a Somali Muslim, and his friend, an Ethiopian Christian.
Over the next two hours we chewed and talked. Ethiopian politics, football, living in another country, khat in Somalia, Haile Selassie, religion, languages, Mo Farah, stereotypes of Africa and family life in London.

People strolled in an out of the cafe. Some in jeans and t-shirt, others looking like they’d just walked in from the Somali desert. Everyone shook my hand. Some bought khat and left, others joined us, all the while chewing gently and drinking sweet tea. At one point I asked the Christian guy why he wore an Islamic cap. He whipped off his hat. “I’m bald” he said “and it’s the only cap you can wear inside” which sent me into fits of laughter.

Khat itself has a very tannin taste and it is exactly like you’d imagine how chewing on an indigestible bush would be. It’s bitty and it fills your mouth with green gunk. The sweet tea is there for a reason.
The effect of the khat came on gently but slowly intensified. It’s stimulating like coffee but is slightly more pleasurable. There’s no jitteriness.

It reminded me of the coca plant from South America both in its ‘mouth full of tree’ chewing experience and its persistent background stimulation. But while coca gave me caffeine-like focus that always turned into a feeling of anxiety, khat was gently euphoric.

My companions told me that it lifts the spirits and makes you talkative. They had a word, which for the life of me I can’t remember, which describes the point at which it ‘opens your mind’ to new ideas and debate.

The active ingredient in khat is cathinone which has become infamous as the basis of ‘bath salts’ legal highs which chemists have learnt to create synthetically and modify. But like coca, from which cocaine is made, the plant is not mental nitroglycerine. It has noticeable effects but they don’t dominate the psyche. It’s a lift rather than a launch.

The guys in the cafe were not unaware of its downsides though. “Don’t chew too often” they told me “it can become a habit for some”. I was also told it can have idiosyncratic effects on sexual performance. Some find it helps, others not so much.

Not everyone was there for khat. Some guys chewed regularly, some not at all, some had given up, some only on special occasions. Some just came to hang out, drink tea and watch the box.

Towards the end when I felt we had got to know each other a bit better I asked why the cafe was unmarked. The owner told me that while khat is legal they were aware of the scare stories and were worried about the backlash from less enlightened members of the community. ‘Immigrants sell foreign drug’ shifts more papers, it seems, than ‘guys chew leaves and watch football’.

Eventually, I said my goodbyes and decided I could use my buzz to go for a walk. I made London Bridge in a couple of hours. But I think my newfound energy came as much from the welcome as it did from the khat.


Popular “Bath Salt” Hooks Lab Rats

Mephedrone shows addictive properties in animal models.

Cathinones, like methedrine and other stimulants, are primarily dopamine-active drugs. Though they are now illegal in the U.S., they were formerly of primary interest only to pharmaceutical researchers. The best-known cathinone sold in the form of bath salts and plant food—mephedrone—has both dopamine and serotonin effects. It broke big in the UK a few years ago as a “legal” party drug alternative to MDMA. The idea was to get high without testing dirty, as the saying goes.

Behavioral clues about mephedrone have been teased out of rat studies. The Taffe Laboratory at Scripps Research Institute has been focusing on the cognitive, thermoregulatory, and potentially addictive effects of the cathinones, and mephedrone in particular. Scripps researchers have carried the investigation forward with a recent study in the journal Drug and Alcohol Dependence.

Now comes additional evidence, also from the Taffe Lab at Scripps, that mephedrone, or 4-MMC, looks like an addictive drug. In a paper accepted for publication by Addiction Biology, which Addiction Inbox was allowed to review in advance, Dr. Michael Taffe, along with lead author S.M. Aarde and coworkers, demonstrated in an animal study that lab rats will intravenously self-administer mephedrone under normal lab conditions—roughly analogous to shooting speed.

Without suitable strains of test animals, most genetic and neurobiological research would take centuries, and would involve ethical questions about human testing far stickier than the questions raised by work with animals. Animal models are one of the primary pathways of discovery available to neurobiologists and other researchers.

But it’s tricky. Establishing traditional rodent laboratory conditions is a Goldilocks endeavor: The environment must be not too hot, but not too cold, because this can effect rodent behavior. And the drug must be given at rates that are not too frequent and not too rare.

The curious thing about mephedrone is that it appears to combine the effects of prototypical stimulants like cocaine and methamphetamine, with the trippy, “entactogen” effects of MDMA, aka Ecstasy, in the bargain. The drug rapidly crosses the blood-brain barrier, reaching peak levels two minutes after injection, and full effects last about an hour. In one study, 76% of people who had snorted both cocaine and mephedrone reported that the quality of the mephedrone high was “similar to or better than” cocaine. But the paper also states that “human recreational users report 4-MMC to be subjectively similar to MDMA.”

The investigators ran a series of tests with various groups of rats, and found that 80-100% of the rats would happily reward-press a lever for an infusion of mephedrone. “Under these conditions,” writes Taffe, “methamphetamine and 4-MMC have about equal effect on rat self-administration although the 4-MMC is considerably less potent, requiring about 10 times the per-infusion dose for effect.” Although it wasn’t demonstrated directly in this paper, Ecstasy “is at best unevenly self-administered by rats,” and “despite an MDMA-like serotonin/dopamine neuropharmacological effect, mephedrone has a liability for repetitive intake more similar to the classical amphetamine-type stimulants such as methamphetamine.”

It’s a weaker type of stimulant, mephedrone, but it does the trick. It is highly reinforcing. Mephedrone chemically resembles speed, but also has Ecstasy-like effects. "Furthermore, neurochemical data suggest MDMA-like patterns of relatively greater serotonin versus dopamine accumulation in nucleus accumbens.” Even with its added Ecstasy-like effects, the scientists conclude that “the potential for compulsive use of mephedrone in humans is likely quite high, particularly in comparison with MDMA.”

Photo Credit: Creative Commons

The Triumph of Synthetics

Designer stimulants surpass heroin and cocaine.

A troubling report by the United Nations Office on Drugs and Crime (UNODC) shows that amphetamine-type stimulants (ATS) have, for the first time, become more popular around the world than heroin and cocaine. Marijuana remains the most popular illegal drug in the world, and the use of amphetamines has fallen sharply in the U.S., but the world trend represents the worldwide triumph of synthetic drug design over the plant-based “hard drugs” of the past.

The 2011 Global ATS Assessment estimates that in 2009, some 14 to 57 million people aged 15-64 took an amphetamine-type substance during the year.  The category includes methamphetamine, synthetic stimulants known as bath salts, and Ecstasy. For ecstasy, which is grouped with the ATS family because of its speed-like qualities, “global annual prevalence” stood at only 11-28 million past-year users in 2009, basically unchanged.  Not so for the use of the new synthetic methamphetamines—compounds such as mephedrone, 4-methylmethcathinone (4-MMC) and MDPV, which first took off in the UK, Canada, and New Zealand. In fact, bath salts in the form of mephedrone are competing with ecstasy as the club drug of the moment. (Ecstasy seizures are currently at a 5-year high in the United States, so the window for alternatives is currently wide open.) Meanwhile, recorded worldwide use of heroin, cocaine, and marijuana remained essentially steady from 2005 to 2009.

So what’s behind the global surge in production of amphetamine-type drugs? What advantages do these stimulants hold over time-tested drugs like heroin and coke?  And why is it happening now?

                                                      Emerging Markets

The seismic changes in worldwide drug production begin with geography. Amphetamine-type stimulants are spreading to new regions, and are now being manufactured in places previously off the radar—Iran, Malaysia, and West Africa, for starters. The UNODC report notes that synthetic stimulants “offer criminals a new entry into unexploited and fresh markets.” The locus of activity is no longer the opium fields of Afghanistan, or the coca plantations of Columbia. In absolute numbers, the report claims, “most ATS users live in Southeast Asia, the most populous subregion the world.”

The growing number of methamphetamine pills seized in Southeast Asia is staggering: “The 93.3 million methamphetamine pills seized in 2009 in China, Lao People’s Democratic Republic, Myanmar and Thailand represent a three-fold increase in comparison with 2008 figures,” the UN report alleges. “In 2010, total seizures surpassed 133 million pills.” Not since the Japanese amphetamine scourge of the post-World War II years has East Asia seen anything like this.

 The UN report singles out two new countries—Lao People’s Democratic Republic, and Malaysia—as nations reporting, for the first time, “the injecting use of crystalline methamphetamine in 2008 and 2009.” And a massive increase in production has been documented in northern Burma. Voice of America News reports that amphetamine-type drug seizures in Burma went from one million pills in 2008 to a mind-blowing 23 million pills a year later.

A regional representative for the UNODC in East Asia said that the seizures “reflect a dramatic increase in production in the Shan State” in Northern Burma. The production of methamphetamine is a primary source of income for the Shan, whose territory is near the borders of China and Thailand. “What we are worried about,” said the UNODC rep, “is the nexus of drugs, of weapons, of money that is moving around that region at a time when elections are pending and the political situation is quite fragile.” At the same time, Burma remains a major supplier of opiates, though competition with Afghanistan may have helped encourage the production of illegal stimulants. UNODC Executive Director Yury Fedotove explained that the market for synthetic stimulants “has evolved from a cottage-type industry typified by small-scale manufacturing operations to more of a cocaine or heroin-type market with a higher level of integration and organized crime groups involved throughout the production and supply chain.“

                                                    Homegrown vs. Manmade

Amphetamines, in all their synthetic forms, have several production advantages over plant-based addictive drugs like heroin and cocaine. In recent years, the U.S. and other countries have cracked down on amphetamine precursor drugs like ephedrine and pseudoephedrine. Once these tried and true compounds for amphetamine manufacture—found in cold and allergy medications—were registered and controlled, traffickers made the switch to different chemical approaches. New building blocks like phelylacetic acid and l-phenylacetylcarbinol (l-PAC) have been found in labs from Canada to Mexico. Growers of opium and coca have no such alternatives available to them. Pharmacologist David Kroll, Professor and Chair of Pharmaceutical Science at North Carolina Central University in Durham, who has been following the new synthetic drug products on his blog, Terra Sigillata, said that ome of the latest precursors have a problematic history. “Phenylacetate and phelylacetic acid have been investigated in clinical trials for cancer and in the treatment of sickle cell disease,” said Dr. Kroll. “But they didn’t fare well in large clinical trails because they required such high doses, and patients had side effects.”

While this is definitely not a reliable class of compounds from which to fashion new recreational stimulants, Dr. Kroll noted that rendering synthetic drugs illegal can sometimes play havoc with efforts to develop the same drugs for therapeutic purposes. “If these precursors become more strictly regulated, there might be an untoward effect on the prices of other drugs” that use the same compound as a building block, he said.

                                                               New Players

Drug lab seizures in Jordan, Syria, and the United Arab Emirates have also reached new highs—particularly the clandestine manufacture of a form of amphetamine called phenethylline, marketed under the brand name Captagon. Very little in the way of equipment or startup capital is required, which facilitates new players in this market. Captagon, said Dr. Kroll, “makes pretty good sense. The body can metabolize it to amphetamine itself—it’s an amphetamine pro-drug. The other metabolite of the drug is theophylline, the old asthma drug that also acts as a mild stimulant. But it’s potentially as dangerous as amphetamine, depending on how efficient one’s metabolism is.” This is, of course, a huge problem: One bath salts user might have an acceptable drug experience, while another might find that a few whiffs of the same synthetic stimulant will land him or her in the emergency room, with a dangerously elevated heart rate or other complications.

What drug designers, drug manufacturers, and drug suppliers have come to realize is that methamphetamine and other ATS drugs appear to fill the lifestyle void left by the uncertain supply and pricing situation associated with cocaine. Everywhere they land, synthetic stimulants—from biker crank to mephedrone—wreak instant havoc. They simply are not predictable compounds. One bath salts user compared the experience to “a shot of methamphetamine with a PCP chaser." From any kind of rational sociocultural point of view, these are not safe drugs. And it hardly needs repeating that they are highly addictive for many people. The legalization of amphetamine is not a cause likely to gain much momentum any time soon.

Even though the United States has a long history of dealing with amphetamine, this is manifestly not true of every country in the world. And now these untapped markets are fair game for cheaper, longer lasting amphetamine-type stimulants, which “seem to appeal to the needs of today’s societies and have become part of what is perceived to be a modern and dynamic lifestyle,” according to the UNODC report.

We don’t know with complete certainty that the drug data coming out of several key areas—Southeast Asia, Africa, and the Middle East in particular—is accurate. Authorities have captured and dismantled ATS labs in Central and South America as well. In all likelihood, drug production and use in all these regions is underreported. The UNODC document laments that “household and other surveys are lacking or are outdated in some countries in several of the most affected regions.” This is a particular problem in China and India, where no serious national survey of amphetamine-type stimulants has ever been undertaken.

We have a long way to go before we know the outcome of the current craze for synthetic stimulants. The historical wreckage caused by injected methedrine in the 60s and 70s, and smokable ice in the 90s and the aughts, is a grisly matter of public record. Now we are confronted with a baffling cornucopia of designer concoctions whose track record for safe recreation is, thus far, not so good. Amphetamine drugs have sent thousands to their deaths, and countless others to the emergency rooms. And now this deadly deck of stimulants has many more cards in it than it did just a few years ago. Pick a card, any card. First one’s free.

Photo Credit: http://teens.drugabuse.gov/

The Biology of Stimulants, or Why You Can’t Stay High Forever

An essay on the losing battle for perpetual reward.

The amphetamine high, like the cocaine high, is a marvel of biochemical efficiency. Stimulants work primarily by blocking the reuptake of dopamine molecules in the synaptic gap between nerve cells. Dopamine remains stalled in the gap, stimulating the receptors, resulting in higher dopamine concentrations and greater sensitivity to dopamine in general. Since dopamine is involved in moods and activities such as pleasure, alertness and movement, the primary results of using cocaine or speed—euphoria, a sense of well being, physical alertness, and increased energy—are easily understood. Even a layperson can tell when lab rats have been on a meth binge. The rapid movements, sniffing, and sudden rearing at minor stimuli are not that much different in principle from the outward signs of meth intoxication among higher primates.

Chemically, cocaine and amphetamine are very different compounds. Psychoactively, however, they are very much alike. Of all the addictive drugs, smoked cocaine and speed have the most direct and most devastatingly euphoric effect on the dopamine systems of the brain. Cocaine and amphetamine produce rapid classical conditioning in addicts, demonstrated by the intense cravings touched off by such stimuli as the sight of a building where the user used to buy or sell. Environmental impacts of this nature can produce marked blood flow increases to key limbic structures in abstinent addicts.

In clinical settings, cocaine users have a hard time distinguishing between equal doses of cocaine and Dexedrine, administered intravenously. As we know, it is the shape of the molecule that counts. The amphetamines are shaped like dopamine and norepinephrine, two of the three reward chemicals. Speed, then, is well suited to the task of artificially stimulating the limbic reward pathway. Molecules of amphetamine displace dopamine and norepinephrine in the storage vesicles, squeezing those two neurotransmitters into the synaptic gap and keeping them there. By mechanisms less well identified, cocaine accomplishes the same feat. Both drugs also interfere with the return of dopamine, norepinephrine, and serotonin molecules to their storage sacs, a procedure known as reuptake blocking. Cocaine works its effects primarily by blocking the reuptake of dopamine.

Amphetamine was once one of the most widely prescribed drugs in the pharmacological cornucopia. It exists in large part now as a recreational drug of choice, abuse, and addiction. The same is true of cocaine. It was replaced as a dental anesthetic long ago, in favor of non-addictive variants like Novocain. The same tragic list of statistical side effects that apply to abusers of alcohol, heroin and nicotine also apply to stimulant abusers: Increased risk of car accidents, homicides, heart attack, and strokes.

In the late 1990s, scientists at Johns Hopkins and NIDA showed that opiate receptors play a role in cocaine addiction as well. PET scans demonstrated that cocaine addicts showed increased binding activity at mu opiate receptors sites in the brain during active cocaine addiction. Take away the cocaine, and the brain must cope with too many empty dopamine and endorphin receptors. It is also easy to understand the typical symptoms of cocaine and amphetamine withdrawal: lethargy, depression, anger, and a heightened perception of pain. Both the cocaine high and the amphetamine high are easily augmented with cigarettes or heroin. These combinations result in “nucleus accumbens dopamine overflow,” a state of neurochemical super saturation similar to the results obtained with the notorious “speedball”—heroin plus cocaine.

With the arrival of smokable forms of cocaine and amphetamine, the race to pin down the biology of stimulation became even more urgent. Stimulants in smokable form—crack and ice—are even more rapidly addictive for addiction-prone users. “The reason has to do with the hydraulics of the blood supply,” a researcher at the University of Minnesota explained to me. “High concentrations are achieved with each inhalation, and sent right upstairs to the brain—but not all of the brain simultaneously. The target of the flow of blood is the limbic system, whereas the remainder of the brain is exposed to much milder concentrations.”

This extraordinarily concentrated jolt to the reward center is the reason why smokable cocaine and speed are able to pack such a wallop. The entire range of stimulative effects hits the ventral tegmental area and associated reward regions of the brain in seconds, and the focused nature of the impact yields an astonishingly pleasurable high.

But the long-term result is exactly the opposite. It may sound dour and religious, but the scientific fact of the matter is that continuous chemical pleasure extracts its fee in the end: The body’s natural stock of these neurotransmitters starts to fall as the brain, striving to compensate for the artificial flooding of the reward center, orders a general cutback in production. At the same time, the receptors for these neurotransmitters become excessively sensitive due to the frequent, often unremitting nature of the stimulation.

“It’s clear that cocaine causes depletion of dopamine, norepinephrine, serotonin—it is a general neurotransmitter depleter,” said my research source. “That may account for many of the effects we see after someone has stopped using cocaine. They’re tired, they’re lethargic, they sleep; they may be depressed, moody, and so on.” Continued abuse of stimulant drugs only makes the problem worse. One reason why cocaine and amphetamine addicts will continue to use, even in the face of rapidly diminishing returns, is simply to avoid the crushing onset of withdrawal. Even though the drugs may no longer be working as well as they once did, the alternative—the psychological cost of withdrawal—is even worse. In the jargon used by Alcoholics Anonymous, addicts generally have to get worse before they can get better.

When addicts talk about “chasing a high,” the metaphor can be extended to the losing battle of neurotransmitter levels.

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