SR-17018: Great Promise; A Grave Warning

There is an odd, promising opioid called SR-17018 that is being hailed in addict / underground chemistry circles as a potential miracle cure for opioid addiction. The hype is justified, but the dangers and drawbacks are largely unknown at the moment.

SR-17018: The hope, the myth, the legend. Kind of a cute little chemical structure, as opioids go.

Q: What is SR-17018?

A: SR-17018 (from here, "SR") is a biased mu opioid receptor agonist. Basically, what that means is that it produces some of the effects of traditional opioids but not others.

To simplify the science, it's helpful to understand that classical opioids trigger two different pathways.

The G-protein-coupled receptor (GPCR) pathway provides pain relief, euphoria, calm, warmth, etc., while the β-arrestin pathway leads to respiratory depression / overdose, tolerance, constipation, and other undesirable side effects.

It is the β-arrestin pathway that leads to receptor desensitization / internalization*, which causes opioid tolerance.

*A sort of deactivation or benching of a mu opioid receptor, which occurs when the body senses that the receptor system is being overstimulated and consequently decreases the number of available receptors to maintain physiologic balance (homeostasis); this is why people dependent on classical opioids require ever-increasing doses to maintain the same level of opioid effect.

Put simply, SR initiates the GPCR effects without triggering the β-arrestin pathway, which means that it produces the desirable, painkilling effects without leading to tolerance through downregulation of the mu opioid receptor system. In fact, there is some evidence that SR actually causes decreases in opioid tolerance along a fairly rapid timescale when administered to animals that are dependent upon traditional opioids.

Q: Why do these properties matter?

A: This is game-changing stuff. Not only because a whole new generation of pain patients might be able to use opioids without worrying about overdose, tolerance, and potentially dangerous side effects like severe constipation, but also because currently opioid-addicted patients might be able to use SR to get off of their opioid of choice without experiencing nearly as much pain as this has traditionally entailed.

Q: How much do we know about SR?

A: Not nearly enough. I have read several peer-reviewed research articles on SR, and I would summarize them as the scientific equivalent of "WTF!?" It feels like every time one research group notes a novel property and proposes a mechanism that explains it, another group comes out with a discrepant finding / contradictory result. Add to that the fact that there is just not much research to go on, and you have a very confusing information landscape.

The receptor dynamics being discussed are some of the most complex that I have ever come across in scientific / medical literature. I studied cellular biology for years and am generally able to read and understand relevant research, but some of these papers have been a stretch for me.

All of this is complicated by the fact that we don't have any evidence of how SR works in humans except for what's available on Reddit, where brave, I-volunteer-as-tribute guinea pigs have already been dosing themselves with SR using various protocols to try to taper off of other opioids.

Q: How have these early self-experimentations by opioid addicts gone?

A: People have self-reported promising results, but there are huge questions that remain.

You can check out the SR-17018 subreddit here if you want to read about these experiences yourself.

The results have been promising, but I have a great deal of hesitation about SR. Specifically:

1. Some of SR's properties resemble those of buprenorphine, a partial agonist that I've written about extensively on this blog. It's possible, perhaps even likely, that there is a ceiling effect to SR and that it could therefore put someone who is dependent on a high dose of a full agonist (fentanyl, oxy, hydrocodone, methadone) into precipitated withdrawal.

   
   

2. In connection with point (1), many of the users sharing their SR experiences are dependent on relatively low doses of strong opioids or higher doses of weaker opioids (for example, kratom). Again, for this reason, it's not clear that they're having an easier time tapering off of their opioid of choice using SR than they would, for example, using buprenorphine or methadone or even their opioid of choice itself.

   
   

3. The mental component of withdrawal is enormous, and these people's belief in SR - evidenced by comments hailing it as a magic solution throughout the subreddit - could be creating a massive placebo effect.

   
   

   Many of these SR users report significant withdrawal symptoms, including severe insomnia, while using SR, but they seem to process those experiences differently due to their expectations and beliefs (for example, they label it "excitement" or "renewed motivation" rather than just withdrawal-related insomnia).

   
   

4. Many of the users who get off of their opioid of choice using SR relapse almost immediately thereafter. If it is true that SR decreases opioid tolerance very quickly, this could put them at immense risk of overdose when they resume use.

   
   

5. SR is currently available, as far as I know, exclusively from chemical suppliers who are not adhering to the standards usually applied to pharmaceuticals intended for human consumption. That means that - even if SR is a best-case-scenario solution - there are significant concerns about proper dosage, contamination, fraud, and more.

   
   

6. Opioid tolerance, addiction, and withdrawal are not solely mediated by the mu opioid receptor system. Depending on your opioid of choice, there are other opioid receptors (kappa and delta), as well as non-opioid receptors involved.

   
   

   Withdrawal is a complex biochemical and physiological process, and it is hard for me to believe that any substance could simply take away the adjustment pains that result from it. Withdrawal is physiologic work being accomplished, and - while some substances may be able to attenuate the pain and speed the process - it's unlikely that there will be a true, complete "magic bullet" fix.

Q: What's your preliminary verdict on SR?

A: First, the obligatory IANAD.

Beyond that, for the reasons outlined above, I caution against using SR at this time. If you are ready to get off of your opioid of choice, a long, slow taper using buprenorphine, methadone, or another agent is probably your best bet. This blog is full of resources for planning and executing a taper, and I am glad to answer any further questions, as well.

We need human trials for SR. There is certainly scientific evidence that it could be a paradigm-shifter, but without randomized trials using standardized dosages and withdrawal measurement scales, we are fumbling around in the dark. People are likely to get hurt.

Q: Do you know anyone who has used SR to get off of opioids?

A: Yes. Er; sort of. I was contacted by a regular reader, a man in his 40s who has used opioids and benzos for years. Recently, he used SR to get off of full-agonist opioids that he had been taking at fairly high doses for an extended time.

He used a several-day taper protocol based on the one featured on the SR subreddit, beginning with a small, test dose to make sure that he wasn't allergic and that the SR didn't precipitate withdrawal. Like many of the SR users who have shared their experiences on the subreddit, he used occasional doses of benzos and Soma to help him through the process - another confounding factor in evaluating the efficacy of SR, which I neglected to mention above.

He was initially very optimistic about the results of the SR taper, but he eventually found it necessary to take a small dose of buprenorphine each day to stave off the significant withdrawal symptoms that he was experiencing even after the SR taper was concluded. Restless Legs Syndrome was the most prominent lingering withdrawal symptom, for what that's worth.

Be careful, please. More to come on this one.