Pre-clinical study: A step forward in search for non-addictive painkillers

Over 97 million Americans took prescription painkillers in 2015, with over 2 million reporting problems with the drugs. Drug overdoses are the No. 1 cause of death for Americans under 50, outranking guns and car accidents and outpacing the HIV epidemic at its peak.

Medical researchers are increasingly studying positive allosteric modulators because they target secondary drug receptor sites in the body. By contrast, "orthosteric" drugs -- including cannabinoids such as delta-9-tetrahydrocannabinol (THC) and opioids such as morphine -- influence primary binding sites, which means their effects may "spill over" to other processes in the body, causing dangerous or unwanted side effects. Rather than acting as an on/off switch, PAMs act like an amplifier, enhancing only the effects of the brain's own natural painkillers, thereby selectively altering biological processes in the body that naturally suppress pain.

A pre-clinical study led by Indiana University scientists reports a promising step forward in the search for pain relief methods without the addictive side effects behind the country's current opioid addiction crisis.

The research, which appears in the journal Biological Psychiatry, finds that the use of compounds called positive allosteric modulators, or PAMs, enhances the effect of pain-relief chemicals naturally produced by the body in response to stress or injury. This study also significantly strengthens preliminary evidence about the effectiveness of these compounds first reported at the 2016 Society for Neuroscience Conference in San Diego, California.

"Our study shows that a PAM enhances the effects of these pain-killing chemicals without producing tolerance or decreased effectiveness over time, both of which contribute to addiction in people who use opioid-based pain medications," said Andrea G. Hohmann, a Linda and Jack Gill Chair of Neuroscience and professor in the IU Bloomington College of Arts and Sciences' Department of Psychological and Brain Sciences, who led the study. "We see this research as an important step forward in the search for new, non-addictive methods to reduce pain."

Medical researchers are increasingly studying positive allosteric modulators because they target secondary drug receptor sites in the body. By contrast, "orthosteric" drugs -- including cannabinoids such as delta-9-tetrahydrocannabinol (THC) and opioids such as morphine -- influence primary binding sites, which means their effects may "spill over" to other processes in the body, causing dangerous or unwanted side effects. Rather than acting as an on/off switch, PAMs act like an amplifier, enhancing only the effects of the brain's own natural painkillers, thereby selectively altering biological processes in the body that naturally suppress pain.

 

The PAM used in the IU-led study worked by amplifying two brain compounds -- anandamide and 2-arachidonoylglycerol -- commonly called "endocannabinoids" because they act upon the CB1 receptor in the brain that responds to THC, the major psychoactive ingredient in cannabis.

Although the PAM compound enhanced the effects of the endocannabinoids the study found that it did not cause unwanted side effects associated with cannabis -- such as impaired motor functions or lowered body temperature -- because its effect is highly targeted in the brain. The pain relief was also stronger and longer-lasting than drugs that block an enzyme that breaks down and metabolizes the brain's own cannabis-like compounds. The PAM alone causes the natural painkillers to target only the right part of the brain at the right time, as opposed to drugs that bind to every receptor site throughout the body.

The PAMs also presented strong advantages over the other alternative pain-relief compounds tested in the study: a synthetic cannabinoid and a metabolic inhibitor. The analysis' results suggested these other compounds' remained likely to produce addiction or diminish in effectiveness over time.

While the IU-led research was conducted in mice, Hohmann said it's been shown that endocannabinoids are also released by the human body in response to inflammation or pain due to nerve injury. The compounds may also play a role in the temporary pain relief that occurs after a major injury.

"These results are exciting because you don't need a whole cocktail of other drugs to fully reverse the pathological pain in the animals," Hohmann said. "We also don't see unwanted signs of physical dependence or tolerance found with delta-9-tetrahydrocannabinol or opioid-based drugs. If these effects could be replicated in people, it would be a major step forward in the search for new, non-addictive forms of pain relief."

Q: What is D-8 THC?

A: It is an analog of tetrahydrocannabinol. It is a natural cannabinoid with neuroprotective properties. It binds to cannabinoid receptor CB1 in the central nervous system for its activity. 

Delta-8 is considered a cousin of Delta-9, as it resembles its structure. D-9 is the primary form of the cannabinoid found in plants, and Delta-8 is less potent and psychoactive. Both D-8 and D-9 differ slightly in their structures, with a few bonds displaced. 

Delta-8 exists in trace amounts only, and scientists produce them through selective breeding.  

Q: Can I get high after consuming Delta-8?

A: Delta-8 is much less potent than Delta-9. As such, it may have psychotropic effects and make you feel relaxed. The buzz you get after consuming delta-8 is not extreme, and you may get mild euphoric feelings but without getting stoned.

Q: How is D-8 different from Delta-9?

A: Both D-8 and D-9 are said to be cousins because Delta-8 is derived from Delta-9. The main difference between D-8 and D-9 is the chemical bonding.

D-8 will give you a milder euphoric effect, whereas D-9 is more potent and gets you stoned.

Also, Delta-9 is federally illegal, while Delta-8 is legal in many states.

Q: Is Delta-8 safe to use? 

A: Delta-8 THC is safe to use and does not have any severe side effects. But take precautions before using any product to avoid serious health problems. 

You must consult your doctor before using Delta-8 for medical diagnosis. 

Q: Can I get a positive drug screening test after I have consumed D-8 products?

A: You may fail a drug screening test after consuming Delta-8 THC.

Q: Is Delta-8 THC legal?

A: Yes! Delta-8, unlike Delta-9 THC, is considered legal to use.

For your information, Delta-9 THC is illegal, but THC itself is not.

Q: At what age can I buy Delta-8 THC?

A: There are no federal regulations regarding the age to buy Delta-8 THC. But several states made it mandatory for a person to be at least 21 years old to buy Delta-8 THC. 

Q: Is Delta-8 psychoactive?

A: Yes! Delta-8 is psychoactive but not very potent.

It produces very mild effects of euphoria, which will uplift you without making you anxious or sleepy.

Q: Is D-8 natural?

A: Yes! Delta-8 is an organic, natural compound. But it is found in plants in trace amounts. Therefore, scientists grow Delta-8 through selective breeding.

Q: Does D-8 impart any side effects?

A: The existing scientific research does not observe any adverse effects of Delta-8 THC. 

Delta-9, which is present in weed, produces effects like confusion and sleepiness in adults. 

Anyhow, it is always best to consult a doctor before consuming any such products. If you have an allergic reaction or observe any side effects, you must discontinue using Delta-8 immediately.

Q: How strong is Delta 8?

A: According to most estimates, Delta-8 is 40% less psychoactive than its cousin, Delta-9.

Q: How long will it take to feel the effects of Delta 8?

A: If the effects do not appear, do not take more at that time. Wait for results, or try a higher dosage the next day. 

Too large a dosage can lead to stronger psychoactive effects. Here are some guidelines to follow. 

  • Do not intake Delta-8 on an empty stomach.
  • Edible THC can take 1-1.5 hours to show its effect.
  • Sublingual THC shows its best results if kept under the tongue for 60 seconds. Effects should begin within 45 minutes.
  • Vaping can show its effect almost instantly.

Q: Why Is Delta-8 legal when Delta-9 is not?

A: If a product contains less than 0.3% Delta 9, it is considered legal. But those products containing 0.3% or more of it are considered marijuana. 

Different states have different regulations regarding marijuana. In some states, it is only legal if used for medical purposes. And in other states, it may be completely illegal.

On the other hand, Delta-8 is milder than Delta-9 and is not considered marijuana. So, Delta-8 is legal federally.

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