11/16/15

A Blood Test for Addiction?

© Judith Flacke | 123rf.com

© Judith Flacke | 123rf.com

A research team with the Scripps Research Institute has published the results of a study that shows how a specific protein molecule controls the mu-opioid receptor (MOR) in a small group of brain cells. The mu-opioid receptor is the main one activated by morphine. When study animals lacking a specific protein called RGS7 were given morphine, they had an increased reward response, increased pain relief, delayed tolerance and a heightened withdrawal response. “In other words, without the protein, the animals were predisposed to morphine addiction.”

Several news outlets, including The Fix and HCP Live described the research and its implications. The research team hypothesized that RGS7 may regulate morphine behavior through neurons located in the nucleus accumbens, part of the neural circuitry that seems to be involved in the development of addiction. Kirll Martemyanov, who led the research team, said: “The mu opioid receptor acts as a conductor of the drug’s effects, while RGS7 acts as a brake on the signal.” Laurie Sutton, one of the researchers and the lead author of the published study, said that RGS7 could be a potential target for future drug development. “Pharmacological intervention at the level of RGS7 may reduce some of the detrimental side-effects associated with opiates.”

Martemyanov also sees where their research findings have a potential future in diagnosis. There are also some implications for why certain individuals have a difficult time with opioid addiction, while others are not so susceptible. In addition to drug craving, the animals lacking RGS7 also worked harder for a food reward, suggesting RGS7 may be a more general regulator of reward behavior beyond just drug-induced euphoria.

If our findings hold true for human patients, you could look specifically for RGS7 levels for any disabling mutation with a simple blood test. . . . Mutations could indicate a strong reaction to a drug such as morphine—people carrying a deficient copy of the RGS7 gene might need much lower doses of opioids and could be cautioned to be extra careful with these substances.

Martemyanov is currently a tenured Associate Professor for the Department of Neuroscience for the Scripps Research Institute in Jupiter Florida. He has done extensive past research into the potential role of the RGS protein. Here are links to abstract for two of his previous research studies: “A Role of RGS Proteins in Drug Addiction” and “The R7 RGS Protein Family.” Here is a link to the study discussed here: “Regulator of G-Protein Signaling 7.”

Keri Blakinger for The Fix is getting a bit ahead of the research in saying it could mean a near-future genetic test for opiate addiction. Martemyanov clearly said that IF their findings held true for humans (the study was done on animals) a simple blood test for people with a deficient RGS7 gene could be done. As explained above, this would indicate a predisposition to opiate addiction because of the dysregulation that occurs with the mu receptor. A defective RGS7 gene would reinforce the euphoria and pain relief experienced with opiates, while heightening the withdrawal when the levels drop. Chasing the high or pain relief of opiates coupled with a desire to avoid the pain and discomfort of withdrawal is the classic dynamic in opiate addiction.

If the research holds true for humans, individuals with a deficient RGS7 gene could be treated with lower doses of opioids and cautioned to be careful with opioids of all kinds. Drug development that targets RGS7 would need to explore how other mechanisms are effected by the RGS7 gene. Remember that it may be a more general regulator of reward behavior beyond drug-induced euphoria. “Fixing” the addiction problem may cause another neurochemical one. Another important research question I see is whether or not the abuse of opiates leads to a dysregulation of the mu receptor similar to what Martemyanov found with a defective RGS7 gene.

Let’s see where this research takes us. It is exciting, basic research. But don’t run ahead of it, trying to anticipate where it will lead.

09/14/15

High on Flakka

P14296870603635738mFlakka continues to make the news and it seems to be spreading beyond its popularity in South Florida. A Fusion article showed that while 48% of the confirmed cases of flakka in the first half of 2014 were from Southern states, 27% were in the North East and 23% in the Midwest. “In 2015, individuals have been arrested for dealing Flakka in Illinois, Iowa, New York, and Minnesota.”

But the largest epicenter outside of Florida may be southern Ohio around the town of Ironton. In January of 2015, two brothers, residents of Ironton, were arrested and charged with trafficking in alpha-PVP (flakka). Detective Joe Ross said they were having a lot of complaints from citizens about the sale of Alpha-PVP.  “It’s been a big problem here in the city and in the county.”

In Broward County, Florida, flakka accounted for 34% of their crime lab reports. In the ten months prior to August 2015, 33 people died from flakka-related overdoses in Broward County alone. Hospitals in Broward County reported seeing up to 20 flakka-related patients a day. Two men in Broward County pleaded guilty in August 2015 to importing more than 24 pounds of the main ingredient in flakka from China. Also see “Flack from Flakka” and this article by McCarton Ackerman on The Fix.

Flakka is more than just fodder for crazy news stories about naked people running around saying they are Satan, or trying to break into police stations to avoid get away from 20 cars chasing them and trying to kill them. It has also caught the attention of respected addiction professionals—Terence Gorski and researchers at The Scripps Research Institute.

Scientists at The Scripps Research Institute (TSRI) have found that flakka (alpha-PVP) seems to be equivalent to MDPV (bath salts). The study was a classic animal pressing a drug-delivery lever study; and the rats increased their lever pressing for the drug as the 20 daily sessions progressed. “When the researchers increased the number of lever presses required to get one dose, the animals kept pressing—for up to hundreds of presses per dose.” Those rats must have REALLY like their flakka. Head-to-head tests of flakka and bath salts showed an almost identical potency for inducing lever presses. This suggested to the researchers that the horror stories about flakka may have been overblown. An abstract for the 2015 study discussed by Aarde et al., is here.

They noted how a 2013 study, also by Aarde et al., found that bath salts induced far more drug-seeking lever presses among rats than crystal meth. In a TSRI News & Views report of the 2013 study, researchers said the rats worked more than ten times harder to get bath salts instead of crystal meth. “Animals will self-administer MDPV like no drug I have ever seen.” Where rats would emit about 60 presses on average for a dose of meth, they would emit around 600 for bath salts. “Some rats would emit 3,000 lever presses for a single hit of bath salts.”

Another study, Aarde et al. (2015b), found that bath salts could induce rats to forgo other rewarding behaviors. Rats will almost always respond more to food and tasty flavors than drugs. In this study, wheel running, a normally rewarding activity for rats, declined significantly as they self-administered more bath salts. A subset of the rats didn’t gradually increase their intake of bath salts. Rather, they went from occasional sampling to binging on as much as they could get during a session. “That was when they stopped using the wheel—that very day they binged.” An abstract of the Aarde et al. (2015b) binge study is here.

Terence Gorski wrote an informative summary about flakka on his blog: “Flakka: What You Need to Know.” He said it can cause extreme behavioral reactions and there have been reports of long-lasting neurological damage. “It is definitely a dangerous drug that is rapidly entering the drug-using culture.” Citing Jacob Sullim on reason.com, he suggested his readers read his blog to get a balanced view on flakka. Here is a link to Sullum’s article.

Gorski noted how flakka was a relatively new drug, initially available in South Florida in the spring of 2015. It’s a variation of bath salts (MDPV). The active ingredient, alpha-PVP, is a synthetic cathinone, the active ingredient in the khat shrub. Flakka is a stimulant and induces paranoia, psychosis and aggression. In high doses, it leads to “excited delirium,” with high body temperatures rising up to 107F. This leads to many users stripping off their clothes because they feel like they are on fire. When restrained, individuals on flakka scream, flail and struggle to free themselves. The struggling causes high core body temperatures, called hyperthermia, which needs immediate medical treatment to prevent disability and death. The struggling can also cause dehydration.

Flakka can be injected, swallowed, smoked or snorted. Especially when smoked or vaped, individuals can overdose on flakka. Remember the overdose deaths in Broward County noted above. It looks like a white or pink crystal; and smells like sweaty socks. Flakka users can become very agitated, making them verbally aggressive and irrational. Muscle tissue begins to break down, releasing proteins and other cellular products into the bloodstream, a condition referred to as rhabomolysis. It can lead to complications such as renal (kidney) failure and in rare cases, death. Gorski also provided this link to the Drudge Report Archives, which tracks news stories on flakka.

If understanding the danger from this drug hasn’t gone from your head to your gut yet, watch a few of these YouTube videos of people on flakka: “Flakka drug effects;” “High on Flakka;” Crazy! Woman High on “Flakka;” “Woman in Florida on Flakka.” Here is a 6 minute video from Fusion: “We spent 24 hours living through Florida’s flakka crisis.”

10/13/14

Russian Roulette with Heroin?

Some of the most intriguing research into addiction treatment being done today is with vaccines. The idea is rather simple. Drugs of abuse pass through the blood-brain barrier because they are too small, too simple to be targeted by the immune system. So researchers have designed vaccines that take key fragments of the drug molecules and attach them to larger, more immune-provoking carriers (such as a cholera toxin or a tetanus toxin). The antibodies produced by this work-around will attack the drug and prevent it from passing through the blood-brain barrier and reaching the reward pathway in the brain. In other words, you can ingest the drug BUT WON’T GET HIGH!

Vaccines are being developed for drugs of abuse like alcohol, marijuana, heroin, methamphetamine, nicotine, and cocaine. A previous blog post, “Raising the Stakes in the War on Cocaine Addiction,” looked at the attempts to develop a cocaine vaccine by Thomas Kosten. His research has developed to the stage of clinical trials with humans, but a concern was discovered. Some of the human participants used tem times as much cocaine while attempting to override the blocking action of the cocaine vaccine. That trick could kill an individual who tried it with heroin.

Heroin has been a moving target for vaccine research because it quickly degrades into 6-acetylmorphine (6AM) and morphine. Kim Janda and his team of researchers associated with The Scripps Research Institute have developed a “dynamic vaccine” that creates antibodies against heroin and its psychoactive metabolites. You can read the academic journal article on their work found in the Proceedings of the National Academy of Sciences here or a summary of their research on The Scripps Research Institute website here or here.

There are positives and negatives to Janda’s dynamic heroin vaccine. First, while it will attach to heroin and its metabolites, it won’t work with oxycodone (OxyContin) or hydrocodone (Vicodin, Zohydro); or any other opioid. This is a trade-off because of the above-mentioned rapid degradation of heroin into its psychoactive metabolites. Second, this means the dynamic vaccine also won’t work with methadone or buprenorphine (Suboxone, Subutex), which are both opioids. So it can be used in conjunction with opioid maintenance therapy.

Although Janda’s research suggested that his vaccine helped limit heroin seeking behavior and halted the progression of compulsive heroin taking with rats, there are easy work-arounds for human beings. A human addict could ingest oxycodone or hydrocodone while taking the heroin vaccine to get high. They could even take a benzodiazepine along with their methadone or Suboxone for a nice, heroin-like buzz while taking the Janda vaccine. These limitations were acknowledged by Janda’s research team: “Although the dynamic heroin vaccine is not targeted to treat the ‘addicted’ brain, it represents a robust tool in the continuous blockade of all heroin activity.” In the concluding paragraph of the journal article, the research team said:

The prospect of heroin vaccine use in the treatment of addiction presents a high-payoff, low-risk opportunity. Drug vaccination requires minimal medical monitoring and compliance to maintain opiate resistance, allowing for greater potential worldwide accessibility. Furthermore … drug vaccines represent a low risk for long-term side effects. . . . Although it may not be a “magic bullet” against all aspects of drug addiction, the dynamic nature of our heroin vaccine represents a promising and innovative adjunct therapy in the treatment of heroin addiction.

But Janda’s research is stalled because it ran out of funding. In an interview with The Fix, he said: “We are not anywhere near human trials because nobody wants to pay for them.” Earlier funding was obtained by the Scripps Research Institute, the Pearson Center for Alcoholism and Addiction Research and the National Institute of Health (NIH). Janda and others have approached the NIH for additional funding, but so far have been unsuccessful.

Pharmaceutical companies aren’t interested either. Janda commented: “I have talked to many different companies and not one has shown any interest whatsoever. They don’t feel there is value for their company.” He doesn’t understand this from the standpoint of the greater good of society, but will attempt the route of applying for more research grants from the government. “I think we’ll probably just have to keep going it alone.”

I have mixed feelings about this vaccine, not because of the research, but because of what I know about how some addicts think. The research from the cocaine vaccine clinical trails discussed above noted how some addicts tried to test the vaccine with ten times as much cocaine as they usually ingested to get high. If heroin addicts test Janda’s heroin vaccine in a similar way, they will be risking their lives. It will be like playing Russian roulette with heroin.

There is also an “addiction” to the ritual of getting high (tying off, cooking the heroin, etc) for some addicts that the vaccine will not touch. I’ve known heroin addicts under the influence of this kind of obsession who compulsively “shoot up” water attempting to satisfy this urge. As Janda himself said, while it will blockade all heroin activity, it is not targeted to treat the “addicted brain.”