One man, convinced he was being followed by a murderous mob, used his fists and a rock to try to smash his way into a Ft. Lauderdale police station. Another, also under the delusion of imminent attack, tried to scale the same station’s fence, so desperately that he ended up impaling himself. Yet another was arrested after running naked through traffic—again to evade people (the same ones who had stolen his clothes). Still another climbed naked onto a roof, brandished a handgun, and claimed a Haitian gang was after him. And then there was the fellow who was arrested performing a lewd act with a tree—and calling himself Thor for some reason. When tasered by police, “Thor” simply pulled out the shock-delivering electrodes, twice.
The men in all these cases—all since late 2014—were high on a new recreational drug called flakka, or gravel, which clearly in certain users, at high enough doses, has serious adverse effects on the brain and behavior. Strong paranoid psychosis, physical hyperactivity, dangerous overheating, and a weird insensitivity to pain and fatigue—resulting in seemingly “superhuman” powers—seem to be the key features of flakka overdose. Such symptoms have been seen with other stimulants, but flakka seems able to cause them with relative ease.
“This is an incredibly potent drug,” says Michael H. Baumann, of the Designer Drug Research Unit at the National Institute on Drug Abuse (NIDA).
The origins of α-PVP
Flakka’s formal name is α-pyrrolidinopentiophenone, or α-PVP. It’s a synthetic stimulant, a “designer drug” like Ecstasy (MDMA), although the World Health Organization, the US Drug Enforcement Administration (DEA), and other agencies are starting to use the alternative term “new psychoactive substances” (NPS) to describe these lab-made stimulants.
Apparently α-PVP and its chemical cousins are made almost entirely in laboratories in mainland China, where they remain legal, and may be legally shipped out of that country—often mixed with weaker or inert compounds. They are derived from stimulants developed as potential weight loss drugs by the pharmaceutical industry in the 1960s—compounds whose chemical recipes are easily available online.
These synthetic stimulants also happen to be closely related to the natural stimulant cathinone, the active ingredient in the khat leaves chewed throughout Ethiopia, Somalia, and the Middle East. Thus they are sometimes called “synthetic cathinones.”
One of the first drugs in this class to make a major impact among recreational users in the US was 3,4-methylenedioxypyrovalerone (MDPV). It was legal for a time, was inexpensive, and—to prolong its legality—was often misleadingly labeled as “bath salts: not for human consumption.”
The DEA effectively made MDPV illegal in the US in 2011. Shortly thereafter, labs that had been producing it started shipping a new drug: α-PVP, which was only moderately different in its chemical structure—but different enough to lie outside the ban on MDPV.
Although α-PVP too is now illegal in the US, it continues to circulate, in part because it is so powerful and so cheap—one of its nicknames is “five dollar insanity.”
The mechanisms of action
Like MDPV, α-PVP appears to exert its effects mostly by blocking the activity of two key nervous system proteins: the dopamine transporter and the norepinephrine transporter. These transporters are situated in the synaptic terminals of dopamine and norepinephrine neurons, respectively. By transporting neurotransmitter molecules out of the synapse and back into the neuron, they keep the signaling activity at the synapse within a narrow, safe range.
“They’re like little vacuum cleaners,” says Baumann. “If you get a release of dopamine, for example, the dopamine transporter quickly vacuums it up and brings it back into the cell.”
That’s what’s supposed to happen, anyway. But when a drug such as MDPV or α-PVP blocks the function of these important regulators of synaptic activity, the neuronal reuptake of dopamine and norepinephrine drops sharply. “It’s like sticking a sock in the vacuum cleaner,” says Baumann.
In such a situation, neurotransmitter molecules keep being released into synapses, to activate neighboring neurons, but their usual reuptake into the releasing neuron is greatly reduced, leading to an abnormal synaptic buildup—and potentially a state of “hyper” dopamine and norepinephine signaling.
“You can show in rats that for ordinary rewards like food and sex, the elevations of extracellular dopamine, for example, are on the order of a doubling,” says Baumann. By comparison these drugs are pushing it many times higher—“far above what could happen in a natural circumstance,” he notes.
As dramatic as that may seem, it is in line with what stimulants generally do. Cocaine, a plant-derived stimulant, is also a dopamine and norepinephrine transporter blocker, but it blocks the serotonin transporter too, and thus has somewhat more complicated effects. Methamphetamine isn’t a transporter blocker per se, but a sort of Trojan Horse molecule that enters dopamine, norepinephrine and serotonin neurons via their transporters, and triggers a complex chain of events that includes the reversal of normal transporter flow—so that transporters now flush their neurotransmitters from the neuronal interior back out into synapses.
What really set MDPV apart from other stimulants, when it appeared in the US, was the magnitude of its effect on users—which soon gave rise to horror storiesvery much like those now being reported for α-PVP.
In a 2013 paper, Mike Taffe, Tobin Dickerson, and colleagues at The Scripps Research Institute showed that MDPV, compared to methamphetamine, is active at lower doses, and causes rats—once hooked—to work much harder to get it. Meth had been considered one of the world’s most addicting drugs, but the data suggested that MDPV is even worse in this regard.
More recent studies involving α-PVP suggest that It, too, is worse than meth and other “old” stimulants—and about as bad as MDPV.
“We recently showed that α-PVP blocks uptake at the dopamine transporter at a concentration of only about 12 nanomolar, compared to 200 nanomolar for cocaine,” says Baumann.
Taffe and colleagues also recently compared α-PVP’s and MDPV’s abilities to bring about classic stimulant effects in rats—including a desire for more drug that, in this case, led the animals to press levers hundreds of times just to get a single extra dose. “The α-PVP and MDPV self-administration data in rats shows nearly identical potency and effect for these two,” says Taffe.
The odd behaviors and physiological changes of α-PVP users while under the influence—such as physical hyperactivity, hyperthermia, and paranoia—aren’t yet fully understood, but they generally have been seen with other stimulants.
The boost in physical—“locomotor”—activity that comes with the use of α-PVP and other stimulants is generally considered to be an effect of greater dopamine signaling in the brain. Stimulants also are well known to cause disturbances in metabolism and thermoregulation, possibly via both increased dopamine and norepinephrine signaling. An overheating user will often tear off his clothes in an attempt to cool down.
“There are also cardiovascular stimulation effects including increases in heart rate and blood pressure, and those are probably more related to elevations in norepinephrine” says Baumann. Norepinephrine signaling activity, he notes, occurs in the brain but also in the heart, for example.
The paranoid psychosis that sometimes emerges with stimulant use—especially after multiple sleepless nights—has long been of special interest to researchers, in part because it is responsible for the more bizarre and often criminal behaviors of users. It also closely mimics the psychosis of schizophrenia, which hints that studying it might yield key insights into the origins of schizophrenia—though it doesn’t appear to have done so, yet.
“You normally have to get into the higher dose ranges and repeated doses to start seeing these psychiatric side effects such as paranoia,” says Baumann. “In the worst case scenario this excited delirium goes into another realm where [the user] is completely out of touch with reality.” Because drugs such as α-PVP are so selective for dopamine and norepinephrine transporters, he adds, “I’d be willing to go out on a limb and say that this is probably [due to] a hyperdopaminergic state, or a hypernoradrenergic state.”
The research continues, as groups including Baumann’s and Taffe’s try to keep pace with the flow of new designer stimulants from overseas laboratories to illicit US markets. And that research may be about to get more complex. “As the government keeps declaring these drugs illegal, at some point the producers are going to run out of new cathinone analogs to make,” Baumann says. “They’re seeing this in Europe, for example—new stimulants that are not cathinone-related.”
For now in America, though, α-PVP remains dominant in the designer stimulant market as it burns its way through the user population. “It still looks pretty bad,” says Baumann.