research on schedule 1 drugs

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Inside the tightly controlled world of Schedule 1 drug research

The pharmacy vault where Schedule 1 narcotics and other drugs are stored exceeds DEA requirements. (Liz Reid/for WHYY)

At the Behavioral Biology Research Center at Johns Hopkins University in Baltimore, there’s a special room set up for smoking. Inside is a ventilated chamber made of plexi-glass and steel that is nearly the size of the room itself. And inside that chamber sits a young man, who is about to do something that in most circumstances would be against federal law.

He stands up when I come in, shakes my hand, and introduces himself as “Number 15.” He’s using his study identification number rather than his name because he doesn’t want the world to know he’s smoking weed in the name of science.

It’s 8:45 a.m. and Number 15 looks like he just rolled out of bed. He’s wearing a t-shirt and gym shorts, and his thick brown hair sticks out wildly in every direction. He sits back down in the chair, picks up a lighter and a small metal pipe, and gets to work.

The pipe is covered with a metal cap, so neither Number 15 nor research assistant Muhammad Waraq knows whether it’s a placebo or active marijuana inside. Number 15 has to continually tap the sides of the pipe with the light, to make sure all the weed falls to the middle of the bowl. It’s important that he smokes everything.

Each participant in the study has 10 minutes to finish the pipe full of weed. If it’s a high dose today, it will contain 10 milligrams of delta-9-tetrahydrocannabinol, more commonly known as THC, the psychoactive compound in marijuana. Number 15 isn’t wasting any time. Every exhale is followed almost immediately by another hit on the pipe. He finishes in seven minutes.

Number 15 is part of a study funded by the federal Substance Abuse and Mental Health Services Administration, or SAMHSA. Associate Professor of Psychiatry and Behavioral Sciences Ryan Vandrey is running the study, at JHU’s Behavioral Pharmacology Research Unit.

“There’s been a couple of studies comparing drug effects and blood pharmacokinetics for smoking and vaporization, but no study has done all three, blood, urine and saliva,” he said. “There’s also been very little evaluation of different doses on drug effects and cognitive performance.”

The three-story brick building where this research takes place wouldn’t look out of place on any college campus. The inside is equally unremarkable. There are narrow, winding hallways with offices and small rooms. I get a peek inside a staff kitchen, which looks like any other office kitchen.

But this place is remarkable, because scientists here study all kinds of drugs, from caffeine and nicotine to heroin and LSD. Security is tight. After Number 15 is done smoking, Waraq takes the pipe he used to the pharmacy to make sure all the marijuana is gone.

“One thing you should know is that this building is a maze. When I started working here it took me a good two months to realize which door I should go into,” Waraq says. “Every door has a key card entry, you can’t pass through it unless you work here and you have a badge.”

There are security guards at the building 24 hours a day and cameras all over the place. You have to have a badge just to get inside, and some doors, like the pharmacy, won’t open for just anybody, including Waraq. The pharmacist has to buzz him in.

I’m not allowed in the pharmacy so I have to wait outside. A few people pass me in the narrow hallway, giving me quizzical looks. It’s not the kind of place you typically see reporters. It took months of planning to get inside.

When Waraq comes back out, he tells me that the pharmacist has confirmed that Number 15 successfully smoked all the weed in the pipe. He’ll be happy to hear that.

As we round the corner on our way back to the smoking room, we see Number 15 sitting on the ground with his head between his legs. Another research assistant stands next to him with a clipboard, looking worried.

“You good?” asks Waraq.

“Very light-headed,” says Number 15.

The other research assistant helps him up and takes him to another room, where he’ll fill out a questionnaire so researchers can get a handle on how this strong drug effect feels for him. He’ll fill out the same questionnaire about a dozen times over the course of the next eight hours. He’ll also have blood drawn, saliva sampled, urine collected and vitals measured, and will complete cognitive tasks on the computer.

All this happens in what they call the “session room,” which looks like the central hangout area in a college dormitory. There are TVs and couches, a kitchen and even a pool table.

Each participant in the study will go through the whole day-long process six different times: three times smoking and three times vaporizing, with placebo, high dose and low dose weed.

Later on, after securing the right permissions, Vandrey takes me inside the pharmacy and introduces me to pharmacist Olivia Han. Han handles storage, accountability, preparation and dispensation of the drugs, which are stored in a large vault that takes up nearly one whole wall of the small pharmacy.

Only Han and a handful of other Johns Hopkins pharmacists are allowed inside the vault. Even Vandrey’s never been in there. Han hesitates when I ask if I can take a look, but eventually she opens the wide, heavy door – for about 15 seconds.

The vault is mostly empty except for a couple of refrigerated steel cabinets in the corner. Inside one of those cabinets is the 20 grams of marijuana Vandrey needs for his study, an amount that would fit in a sandwich bag.

The Drug Enforcement Administration requires that even small amounts of Schedule 1 drugs –those considered to have a high potential for abuse and no medical purpose – be stored in safes that weigh more than 750 pounds or are bolted or cemented to the floor. This vault exceeds those requirements, but Han says the DEA still comes to inspect the vault every time a new study starts just to make sure.

Storing the drugs is at the tail end of a long process of paperwork and permissions. For his study, Vandrey had to go through a university ethics review and get approval from the Food and Drug administration and the DEA. Then, there’s a whole other mess of red tape to deal with to actually get the marijuana.

Vandrey says it took about nine months to get the study off the ground. Given all the permissions, bureaucracy and strict storage and security requirements, I imagine the drugs being delivered in some sort of armored vehicle, so I ask him, “It’s not like UPS right?”

Vandrey gives me a nod. “FedEx,” he says.

This is just one of many contradictions inherent in marijuana research. Nearly half of U.S. states have legalized the drug specifically for medical uses, yet according to the FDA, there are no medical uses for cannabis. Here’s Vandrey again.

“The DEA has no motivation to unschedule cannabis and they’re sticking with their no established medical benefit, I think because the FDA hasn’t approved it. And nobody’s funding the trials that the FDA would need to see to approve it, and so it’s a quagmire,” Vandrey says. “It’s a horrible state of affairs and it’s highly driven by politics I think. It’s driven more by emotion than it is by science.”

While the DEA has once again rejected a request to reschedule marijuana, it is making one key change that could impact the pace of research. Currently, all the marijuana that Vandrey and other scientists use in their research comes from just one farm at the University of Mississippi. The agency says it will soon begin licensing other farms to grow marijuana for academic and medical research, though it hasn’t said when or how many.

Meanwhile, the march of states legalizing marijuana for medical purposes continues, at a pace far faster than scientists can prove that it actually works as medicine.

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• Published: 12 June 2013

Effects of Schedule I drug laws on neuroscience research and treatment innovation

• David J. Nutt 1 ,
• Leslie A. King 2 &
• David E. Nichols 3  

Nature Reviews Neuroscience volume  14 ,  pages 577–585 ( 2013 ) Cite this article

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Many psychoactive drugs are used recreationally, particularly by young people. This use and its perceived dangers have led to many different classes of drugs being banned under national laws and international conventions. Indeed, the possession of cannabis, 3,4-methylenedioxy- N -methylamphetamine (MDMA; also known as ecstasy) and psychedelics is stringently regulated. An important and unfortunate outcome of the controls placed on these and other psychoactive drugs is that they make research into their mechanisms of action and potential therapeutic uses — for example, in depression and post-traumatic stress disorder — difficult and in many cases almost impossible.

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Acknowledgements

We thank V. Curran, R. Carhart-Harris and R. Doblin for helpful comments.

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Leslie A. King was previously at the Drugs Intelligence Unit, Forensic Science Service, 109 Lambeth Road, London SE1 7LP, UK.,

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David E. Nichols is at the Eschelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27514 USA.,

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Effects of Schedule I drug laws on neuroscience research and treatment innovation

Affiliation.

• 1 Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College, London, W12 0NN, UK. [email protected]
• PMID: 23756634
• DOI: 10.1038/nrn3530

Many psychoactive drugs are used recreationally, particularly by young people. This use and its perceived dangers have led to many different classes of drugs being banned under national laws and international conventions. Indeed, the possession of cannabis, 3,4-methylenedioxy-N-methylamphetamine (MDMA; also known as ecstasy) and psychedelics is stringently regulated. An important and unfortunate outcome of the controls placed on these and other psychoactive drugs is that they make research into their mechanisms of action and potential therapeutic uses - for example, in depression and post-traumatic stress disorder - difficult and in many cases almost impossible.

PubMed Disclaimer

• Controlled substances and innovation of biomedicine: a preclinical perspective. Stewart AM, Kalueff AV. Stewart AM, et al. Nat Rev Neurosci. 2013 Dec;14(12):877. doi: 10.1038/nrn3530-c1. Epub 2013 Oct 23. Nat Rev Neurosci. 2013. PMID: 24149185 No abstract available.
• New victims of current drug laws. Nutt DJ, King LA, Nichols DE. Nutt DJ, et al. Nat Rev Neurosci. 2013 Dec;14(12):877. doi: 10.1038/nrn3530-c2. Epub 2013 Oct 23. Nat Rev Neurosci. 2013. PMID: 24149187 No abstract available.

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• Brain dynamics predictive of response to psilocybin for treatment-resistant depression. Vohryzek J, Cabral J, Lord LD, Fernandes HM, Roseman L, Nutt DJ, Carhart-Harris RL, Deco G, Kringelbach ML. Vohryzek J, et al. Brain Commun. 2024 Feb 15;6(2):fcae049. doi: 10.1093/braincomms/fcae049. eCollection 2024. Brain Commun. 2024. PMID: 38515439 Free PMC article.
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HHS Recommends Cannabis Move From Schedule 1 to Schedule 3, the Result Will Impact Opportunities for Drug Research

Moving cannabis to Schedule 3 will make it easier to research, resulting in the development and creation of new cannabinoid-based pharmaceuticals, with notable potential in oncology.

Pharmacy Times interviewed Kris Krane, the director of cannabis development for KCSA Strategic Communications, and former President of 4Front Ventures, discusses the recent HHS letter to the DEA making a formal recommendation that cannabis be moved from Schedule 1 of the Controlled Substances Act into Schedule 3. Krane discusses the likelihood of the DEA making this update and the potential roadblocks that may be ahead.

Pharmacy Times : What have been the recent updates around rescheduling cannabis to a lower-risk category, and what is that lower-risk category expected to be at this time?

Kris Krane: At this stage, the HHS has made a formal recommendation that cannabis be moved from Schedule 1 of the Controlled Substances Act into Schedule 3 of the Controlled Substances Act, so that is a less restrictive class. The main difference there is that Schedule 1 substances are recognized as substances that have a high potential for abuse and no recognized medicinal value. Schedule 3 recognizes the medicinal value of the substances, recognizes that it has a low potential for abuse, and would allow it to be more easily—in theory—prescribed, or at least more easily researched, for the creation of prescription medications. It is also going to have a real-world impact on existing state legal cannabis businesses, both medical and adult use businesses. In particular, it would eliminate the 280E provision of the IRS tax code in terms of no longer applying to state-licensed cannabis businesses, which is right now the biggest drain on the bottom line for these businesses.

Pharmacy Times : What are other substances currently scheduled for Schedule 3—would ketamine be an example?

Krane: Ketamine, codeine, and vicodin, I believe, is Schedule 3. A lot of the weaker opiates, for example, have fallen to Schedule 3. It's quite a robust category, a lot of drugs fall into Schedule 3.

Pharmacy Times : Will there be 1 government agency leading this rescheduling process, or would it be a multi-agency endeavor?

Krane: This will be a multi-agency endeavor. So, it'll involve primarily the HHS, the FDA, and the Department of Justice, particularly the Drug Enforcement Agency (DEA).

Pharmacy Times : What will rescheduling cannabis mean for small business owners and larger businesses working in the cannabis industry across the country?

Krane: Some of this is still to be determined. The interesting part of this is right now, all these state licensed businesses are illegal under federal law. Changing this from Schedule 1 to Schedule 3 doesn't change that, these businesses will continue to be illegal under federal law. None of these businesses will be distributing Schedule 3 substances with a DEA license, and essentially dispensing prescribed medication which is typically what happens with the Schedule 3. However, 1 of the biggest problems in the cannabis industry and cannabis businesses right now is the 280 E provision of the IRS tax code, which says that if you're deriving your income from the sale of an illegal product, that you are not allowed to claim any standard business deductions—other than your cost of goods sold—that any other business owner is allowed to claim. That bumps the tax rate for these cannabis businesses up to a much higher tax rate to the point where it essentially makes it nearly impossible for cannabis businesses to turn a profit. 280E only applies to Schedule 1 and 2 substances, so moving it to Schedule 3 eliminates that 280E tax provision from applying to state-licensed cannabis businesses, which is a really big deal. That will allow these businesses to have higher margins, it'll allow them to actually turn profits, it will likely allow them to take on lending that's currently unavailable to them, in part because lenders are hesitant to lend to cannabis businesses because they don't have the free cash flow to service the debt and pay back the loan because of 280E. So this will free up new cash flow for the businesses, allow them to take on loans—likely lower interest loans that are currently available to the cannabis industry—as more and more open up, and allow businesses to reinvest that new free cash flow into expanding their businesses, into making their businesses better, to put money back into the businesses that's currently not available to them because it's all eaten up by this 280E tax provision.

Pharmacy Times : How might rescheduling impact pharmacy’s ability to potentially dispense cannabis by prescription from a provider?

Krane: As far as the cannabis side of it goes, I think in the short term, it shouldn't really have any impact. In the longer term, there may be a bit of an impact. I think it's extremely unlikely—if not impossible—that cannabis itself, or cannabis flour, or even most cannabis edibles or concentrates…The products that are currently sold in dispensaries, those products are not going to go through a 3-phase clinical trial with the FDA which would allow them to be prescribed by a doctor and then dispensed out of a pharmacy. Pharmacists don't dispense whole plant medicine for basically anything. It's impossible to meet the production standards and the standardization standards that are required to pass 3-phase clinical trials for botanical medicine like cannabis. So, it actually prescribed cannabis buds, but I don't think that's ever going to happen, even though it's moved into Schedule 3. So, in the near-term, I don't expect pharmacies to all of a sudden start dispensing cannabis, or edibles, or concentrates, or all of the products that are sold out of dispensaries today.

Where it may impact pharmacists—and most likely will—is a few years down the road. Moving this to Schedule 3 makes cannabis much easier to research, and so, what this will likely lead to is over the course of the next few years, the research and creation of new cannabinoid-based pharmaceuticals. So actual pharmaceutical drugs, pills, topicals, sublinguals, any number of forms that are cannabis-derived, they're created from cannabinoids extracted from or derived from the cannabis plant, or even potentially synthetics. Right now, as a Schedule 1, that research is very difficult for pharmaceutical companies or researchers to gain access to. As a Schedule 3, that's going to become a lot easier, and so, I think it will lead to the creation of essentially a new category of cannabinoid-derived pharmaceutical drugs. That's likely where you would see an impact on the pharmacies, but that's probably a few years away because it takes years to go through phase 3 trials and get approval from the FDA. But that process is likely going to start pretty quickly after this has moved from Schedule 1 to Schedule 3.

As a Schedule 3, that's going to become a lot easier, and so, I think it will lead to the creation of essentially a new category of cannabinoid-derived pharmaceutical drugs. Image Credit: Adobe Stock - Tsareva.pro

Pharmacy Times : With expected FDA approval of MDMA likely to come in 2024 or 2025, is this rescheduling somewhat preparatory around the likely rescheduling that will occur for other medicines within the psychedelic medicine space, as they come onto the PFD docket for review—likely MDMA first, and then psilocybin following?

Krane: I think one doesn't really have anything to do with the other. This is a different substance that's being moved into Schedule 3. Psilocybin and MDMA—which is probably a year to 2 years away—they've already been going through their clinical trials. I know MDMA is on the back end of their phase 3 trials, so that's a process that's happening on its own track. I don't think 1 really has anything to do with the other.

Pharmacy Times: What have been some of the concerns around rescheduling cannabis outside of concerns around its medicinal value?

Krane: I don't see a whole lot of concern. I think there are some folks that are concerned that it'll make it more widely available, I think those concerns are unfounded. Schedule 3 drugs are still controlled substances, so I don't see any issue there. I think the biggest concern from the cannabis industry's perspective is that this may get the FDA more involved in their day-to-day business, that you might start seeing businesses fined by the FDA for distributing a Schedule 3 substance without a DEA license. I don't think that there's a whole lot to actually be concerned about there, the FDA has that enforcement power currently against these businesses that are that are distributing a Schedule 1 substance without a license to do. I don't think moving into Schedule 3 really changes that. You may see some impact where businesses may be making medical claims about the cannabis and cannabinoids that they're selling, you may see the FDA start coming down on them. But again, they have the ability to do that currently, and they have done that in some cases where companies are making actual medical claims without medical approval from the FDA. But I don't think that we're looking at a situation where the FDA is going to basically fine the industry out of existence because they're now all of a sudden distributing Schedule 3 substances without a DEA license when they haven't done so for them distributing a far more restrictive Schedule 1 substance without a DEA license. But that is the 1 major concern that I've seen out of folks in the industry, that this is going to bring the FDA into their businesses and put more hoops in front of them and potentially enforce these rules and sort of fining them out of existence, but it's not something that—being in the cannabis industry myself—would keep me up at night.

Pharmacy Times : What could block or hinder this rescheduling, and do you see that happening?

Krane: The DEA, that's the concern right now. HHS has made their recommendation, the DEA has to approve it, and start the rescheduling process. The DEA has traditionally not been very friendly to cannabis and to its reform. It's possible that they say no, it's possible that they say, “We looked at the evidence ourselves and we'd rather go to Schedule 2,” which does nothing to help the cannabis industry, 280E stays in place if it goes from [Schedule] 1 to 2. I think there is likely a lot of political pressure on the DEA to accept HHS recommendation. This is something that was called for by the President of the United States. It seems quite likely that the President and his political staff—and probably campaign staff—wants this to happen in advance of the 2024 election. I think they see this as something that could potentially motivate or energize young voters who aren't particularly riled up to vote for an 81-year-old candidate for president. And so, I think there's likely a lot of political pressure on the DEA to accept the HHS’s recommendation, but they don't have to do so. I think if there is 1 roadblock to this happening, that's the most likely.

If the DEA comes out and approves it and says that they will move towards Schedule 3, at that point, I don't see very much that could stop it because at that point, it's an administrative process. It does not need approval of Congress, so you couldn't have a Republican-controlled House kill it, unless they were to pass a bill but even then, it would have to pass through the Democratic-controlled Senate and that would be DOA in the Senate. As long as the DEA says yes, then that's the next step in this process. I don't know if it's in a week, or in a month, or in 4 months…but once the DEA has given the thumbs up if they do, then I think it's really a matter of time and making sure that the administration is able to get through the rescheduling process before the end of next year. I think the only other potential roadblock would be if the DEA drags their feet, they approve it sometime [during] Q2 of next year, and they're not able to get through the full administrative process, because there's the public hearing process, there's a whole process that has to happen before rescheduling happens. If they're not able to get that finished by the end of next year and there's a new presidential administration, if the current president loses and you're at a new Trump administration, or a DeSantis administration, or whatever, they could stop the process and kill it if it hasn't been finalized by that point.

So, I think those are the 2 potential roadblocks or potential areas that it could die. It would be the DEA choosing to ignore HHS’s recommendation, or the process not being finished in time for a new administration who may be more hostile to take over in 2025.

Pharmacy Times : Any closing thoughts?

Krane: Sort of reiterating something I mentioned before, moving cannabis’s classification on the Schedule 3, it really does make it easier for pharmaceutical companies and researchers to create a new classification of cannabinoid-based pharmaceuticals, and I think that's really important. I think there are a number of treatments that that are currently prescribed that may well be replaced over the course of the next 5 to 10 years by cannabinoid-based medication. Potentially, some fairly profound ones, there's some early research that [shows] highly concentrated cannabinoid therapy could wind up being a replacement for something like chemotherapy. For traumatic brain injuries, if administered immediately after an accident, it could be more efficacious than our current treatments for traumatic brain injuries. Right on the spot type of things. There's a whole number of areas that cannabinoids in very early phase trials have shown tremendous potential and that it's been really hard for companies to get the approvals that they need at the federal level, to go through the full clinical trials. Now those roadblocks should largely open up, and I think we are potentially looking at an environment where if we look 10 years down the road, there may be a whole classification of cannabinoid-based pharmaceuticals, some of which can have a really profound impact on patients and effectively replace some of the medications that pharmacists and pharmacies are accustomed to dispensing today.

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Clinical research and schedule 1 drugs: is the issue about legal barriers or poor quality?

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Remove barriers to clinical research for schedule 1 drugs with therapeutic potential

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Rapid Response:

Dear Editor

Certainly, legal barriers to clinical research for schedule 1 drugs with therapeutic potential must be removed as pledged by King and colleagues.(1) However, we are concerned that the reviewers allowed them to claim “the misuse of controlled drugs intended for clinical use is extremely rare”.(1) How to ignore that fentanyl and other opioids fuel the worst drug crisis in the history of the United States? England is not spared (2) and opioids are only one among many misused medicines, an old, frequent and growing but unsettled issue yet, as with benzodiazepines.(3)

Similarly, the claim that “the placement of psilocybin in schedule 1 over 50 years ago was based on scant scientific evidence” (1) is a smokescreen: The federal government classified psilocybin as schedule I substances in 1971, after the Controlled Substance Act was signed into law by President Richard Nixon on October 27, 1970; this is several years after Sandoz Pharmaceutical’s wise decision to stop its production and dispensation, under the brand name indocybin®, in 1965. Indeed, harms are not limited to headaches or nausea, psilocybin is a hallucinogen, producing effects similar to LSD, reliably and dose-dependently inducing hallucinations, delusions and even psychosis.(5) In 1965 Sandoz also gave up LSD, discovered by Hoffman in 1943, 15 years before psilocybin.

In our opinion, the real challenge is about raising the bar of the quality of clinical research. Indeed, robust evidence for benefits and harms on clinically relevant outcomes vs appropriate comparators is needed. Presently, this is not the case yet, not to account for the numerous small trials of highly selected patients in particularly secure settings with little attention to safety issues and the lack of double blinding. The latter issue will need an innovative design.

1 King LA, Nutt DJ, Nichols DE. Remove barriers to clinical research for schedule 1 drugs with therapeutic potential. BMJ. 2023;381:p981. doi:10.1136/bmj.p981

2 Mahase E. Opioid related hospital admissions in England increased by nearly 50% in 10 years. BMJ. 2022;376:o299. doi:10.1136/bmj.o299

3 Hayhoe B, Lee-Davey J. Tackling benzodiazepine misuse. BMJ. 2018;362:k3208. doi:10.1136/bmj.k3208

4 Geiger HA, Wurst MG, Daniels RN. DARK Classics in Chemical Neuroscience: Psilocybin. ACS Chem Neurosci. 2018;9:2438-2447. doi:10.1021/acschemneuro.8b00186

5 Benjamin C. Persistent psychiatric symptoms after eating psilocybin mushrooms. BMJ. 1979;1:1319-1320. doi:10.1136/bmj.1.6174.1319

Competing interests: No competing interests

Should cannabis still be a Schedule I drug?

The Drug Enforcement Agency received a recommendation to reclassify cannabis as a Schedule III drug, a move that would be a boon to research and patient care.

Comprehensive Pain and Addiction Center researchers say reclassifying cannabis as a Schedule III substance would loosen the restraints on research into possible benefits, as well as any potential negative side effects, of medical marijuana.

It all starts with a license application. There are background checks to pass, not only for the person applying, but also for their colleagues and employees. Then, federal agents show up on site to confirm that a lockable safe is securely bolted to the concrete floor of a lockable room. When work begins, the safe can only be opened by someone on the Drug Enforcement Agency approved persons list. Everything about the contents must be dutifully recorded, including where it came from, when it was removed from the safe, how it was used, and when it was returned to the safe or disposed of.

Todd Vanderah, PhD, director of the Comprehensive Pain and Addiction Center at the University of Arizona Health Sciences, has spent two decades studying cannabinoids, including their potential as a treatment for metastatic cancer-related bone pain.

It might sound like a system used to safeguard priceless antiquities, but it isn’t. Instead, it is a fact of life for researchers who want to conduct experiments using cannabis. Nothing about studying cannabis is easy, but the reason for the high security is simple – cannabis is a Schedule I drug, alongside heroin, LSD and ecstasy.

“The federal government says that anything that comes from the medical marijuana plant is a Schedule I drug, which is any drug that has no medicinal purpose,” said Todd Vanderah, PhD , director of the University of Arizona Health Sciences Comprehensive Center for Pain and Addiction . “But there is not a lot of research to know what the benefits and harms are that come along with cannabis or medical marijuana.”

Vanderah has been researching cannabinoids – naturally occurring compounds found in the Cannabis sativa plant – for nearly 20 years and is currently a professor and head of the Department of Pharmacology at the UArizona College of Medicine – Tucson. He believes cannabis more correctly fits under Schedule III, alongside products containing less than 90 milligrams of codeine per dose – Tylenol with codeine, for example – ketamine, anabolic steroids and testosterone.

He is not alone. Cannabis’ Schedule I classification has been challenged several times, most recently by Rachel Levine, assistant secretary for health at the U.S. Department of Health and Human Services, after President Joe Biden requested a scientific and medical review. The Health and Human Services’ recommendation, sent to DEA head Anne Milgram in late August, is to reclassify cannabis as a Schedule III drug.

Schedule I drugs, substances, or chemicals are defined as drugs with no currently accepted medical use and a high potential for abuse.

Cannabis policy, then and now

Dronabinol, marketed under the brand names Marinol or Syndros, is an FDA-approved synthetic form of THC used to treat nausea and vomiting caused by cancer chemotherapy, as well as loss of appetite and weight loss in people who have acquired immunodeficiency syndrome. (Credit: Steffen Geyer/CC BY-NC 2.0 DEED)

Cannabis and the United States government have a long history together. In 1860, when cannabis was legal in the U.S., the first federal commission to study cannabis was created due to concerns about potential negative side effects.

Over the next century, regulations around cannabis sales and use increased: federal drug policies were enacted; cannabis possession was deemed illegal by many states; the Marijuana Tax Act was imposed; and cannabis was included in the Federal Narcotics Control Act. None were as impactful, though, as the Controlled Substances Act of 1970. It categorized all substances regulated under federal law into one of five classifications based upon the drug’s medical use, potential for abuse, and safety or dependence liability. Cannabis was classified as a Schedule 1 drug, where it has remained ever since.

As time went on, researchers studying the two most well-known cannabinoids – THC and CBD – identified medical uses for both that led the Food and Drug Administration to approve four cannabis-derived or -related medications:

• Epidiolex, which contains CBD and is used to treat two rare and serious forms of epilepsy;
• Marinol and Syndros, which contain a synthetic form of THC called dronabinol and are used to treat loss of appetite and weight loss in AIDS patients; and,
• Cesamet, which contains a synthetic compound with a chemical structure similar to THC called nabilone and is used to treat nausea and vomiting associated with cancer chemotherapy.

The dichotomy between the FDA’s approval of those drugs and the DEA’s Schedule I definition is clear – science has shown that some parts of the Cannabis sativa plant have medicinal value.

Opening the doors for research

Lowering cannabis to Schedule III would loosen the restraints on research into other possible benefits, as well as any potential negative side effects.

The Cannabis sativa plant researchers currently have access to has significantly lower percentages of THC than many of the products being sold in states where medical or recreational marijuana is legal. Vanderah believes higher levels of THC may be causing more extreme side effects, but he cannot test that hypothesis until cannabis is removed from the Schedule I list.

“If cannabis wasn’t a Schedule I drug, there would be more scientists doing research, which means more interest in this area and more research funding,” Vanderah said. “We would have many more unique cannabinoid compounds to use as tools to understand the different types of receptors and their functions. Right now, a lot of that is unknown – we are still stuck with THC and CBD.”

Research into opiates, by comparison, has flourished over the last 50 years. Scientists have uncovered the benefits, risks and negative effects of a variety of opioid compounds, ranging from loperamide, which does not cross the blood-brain barrier and is commonly used to treat diarrhea, to codeine and fentanyl. Recent research into kappa opioids has resulted in compounds that may be helpful for conditions such as depression, as well as medication-assisted treatments.

Hydrocodone, oxycodone, cocaine, methamphetamine and fentanyl are all classified as Schedule II drugs, making them easier to research than cannabis.  

Schedule III drugs, substances, or chemicals are defined as drugs with a moderate to low potential for physical and psychological dependence.

Additionally, scientists who hope to study cannabinoids cannot simply walk down to the nearest dispensary and buy some CBD or medical marijuana. Only cannabis from federally approved growers can be used in published research studies, even though the THC levels often fall far below what is being sold in dispensaries in states where marijuana is legal for recreational or medical use. 

“The other reason there is not a lot of cannabis research is because there is still a stigma around the fact that you are studying something that is federally illegal and has a reputation as a gateway drug that is going to cause more addiction,” Vanderah said. “Making cannabis a Schedule III drug would open the doors to say, ‘Hey, this is relevant. We should have more people doing this.’ It would reduce the stigma that we’ve had for many, many years on doing research on cannabis.”

Giving doctors another tool to combat pain

One of the most challenging areas of research when it comes to Schedule I drugs is clinical trials. Vanderah believes a Schedule III classification for cannabis would make it much easier to transition basic science findings into human studies, which could be good news for pain management physicians including Mohab Ibrahim, MD, PhD , associate director of medical affairs for the Comprehensive Centerfor  Pain and Addiction. Ibrahim sees patients at the Banner – University Medical Center Chronic Pain Management Clinic and is a professor of anesthesiology at the College of Medicine – Tucson.

Mohab Ibrahim, MD, PhD, associate director of medical affairs for the Comprehensive Pain and Addiction Center, is a pain management physician who did his doctoral research on cannabinoids. He says reclassifying cannabis as a Schedule III drug could reduce the hesitancy of some physicians to prescribe medical marijuana and make patients feel less stigmatized about its use.

“From a physician standpoint, recategorizing cannabis as a Schedule III drug would have huge implications,” Ibrahim said. “When something is Schedule I, meaning it has a very high potential for abuse and probably no medical benefit, many physicians are very hesitant to even consider it. The transition from Schedule I to Schedule III will encourage physicians who see benefits for medical marijuana to be able to prescribe it or at least recommend it.”

Ibrahim also believes a Schedule III classification for cannabis would make medical marijuana more acceptable from a societal standpoint, which should make patients feel less stigmatized and more willing to try it. Several studies have shown that when states legalize recreational or medical marijuana, the overall use of opioids for pain decreases.

Additionally, patients should find it easier to travel between states with a doctor’s prescription for a Schedule III drug. Currently, it is not legal to cross state lines with cannabis, even when traveling between two states that have similar marijuana laws.

“At the end of the day, it’s a medication, and just like any other medication, it can still be misused and mis-prescribed. But that applies to almost every medication in the market, from the most addictive opioid to the least harmful, benign antacid that you can get over the counter,” Ibrahim said. “The positive part is that physicians will have an additional tool to manage chronic conditions, and one that potentially has fewer side effects than many of the medications on the market right now. But just like any medication, physicians need to understand the indications and contraindications for medical marijuana.”

While recategorizing cannabis as a Schedule III drug would create tangible benefits for research and patient care, the Health and Human Services’ recommendation could face an uphill battle with the Drug Enforcement Agency. Since 1981, multiple proposals to remove cannabis from the Schedule I category have been introduced and failed, with the most recent in 2016. Still, in 1999 the DEA acted on the HHS’ advice when reclassifying Marinol as a Schedule III drug, and in 2017 it classified Syndros as a Schedule II substance.

“It all comes back to the plant. The plant itself is like a little compounding pharmacy. I believe that what we are seeing from the medical marijuana plant is a synergistic effect of several compounds,” Vanderah said, reiterating the need for more research and the Schedule III reclassification that could make it all possible. “What compounds can we remove that would make it less toxic or addictive, removing some of the unwanted side effects of cannabis? What are the five chemicals that, when combined, produce a very nice pain relief that's not only inhibiting pain but also decreasing inflammation, and maybe having an effect in the central nervous system so that a person is not worried, stressed or depressed about their pain? Those are the kinds of questions we need to answer with research.”

Pain Relief Research: Clearing the Smoke Surrounding Cannabis

Uncovering a Connection Between Cannabinoids and Migraine

Finding Better Paths to Treat Pain and Prevent Addiction

Physician-Scientist Finds Purpose in a Life Devoted to Pain

Our Experts

Todd Vanderah, PhD Director, Comprehensive Center for Pain and Addiction  Regents Professor, Department of Pharmacology, College of Medicine – Tucson Department Head, Department of Pharmacology, College of Medicine – Tucson Co-Director, MD/PhD Dual Degree Program Assistant Vice President, Research and Innovation, Global MD Program Professor, Department of Anesthesiology, College of Medicine – Tucson Professor, Department of Neurology, College of Medicine – Tucson Member, BIO5 Institute Member, Cancer Biology Program, UArizona Cancer Center

Mohab Ibrahim, MD, PhD Associate Director of Medical Affairs, Comprehensive Center for Pain and Addiction  Director, Banner Health Chronic Pain Management Clinic Professor, Department of Anesthesiology, College of Medicine – Tucson Program Director, Pain Medicine Fellowship Member, Clinical and Translational Oncology Program, UArizona Cancer Center

Stacy Pigott UArizona Health Sciences Office of Communications 520-539-4152, [email protected]

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After 50 Years, U.S. Opens The Door To More Cannabis Crops For Scientists

More than 30 states have medical marijuana programs — yet scientists are only allowed to use cannabis plants from one U.S. source for their research. That's set to change, as the federal government begins to add more growers to the mix. Drew Angerer/Getty Images hide caption

More than 30 states have medical marijuana programs — yet scientists are only allowed to use cannabis plants from one U.S. source for their research. That's set to change, as the federal government begins to add more growers to the mix.

After more than 50 years, the federal government is lifting a roadblock to cannabis research that scientists and advocates say has hindered rigorous studies of the plant and possible drug development.

Since 1968, U.S. researchers have been allowed to use cannabis from only one domestic source : a facility based at the University of Mississippi, through a contract with the National Institute on Drug Abuse (NIDA).

That changed earlier this month, when the Drug Enforcement Administration announced it's in the process of registering several additional American companies to produce cannabis for medical and scientific purposes.

It's a move that promises to accelerate understanding of the plant's health effects and possible therapies for treating conditions — chronic pain, the side effects of chemotherapy, multiple sclerosis and mental illness, among many others — that are yet to be well studied .

Shots - Health News

How one boy's fight with epilepsy led to the first marijuana-derived pharmaceutical.

"This is a momentous decision," says Rick Doblin, executive director of the Multidisciplinary Association for Psychedelic Studies (MAPS), which has spearheaded research into other Schedule 1 drugs — the most restrictive class of controlled substance, which the federal government defines as "drugs with no currently accepted medical use."

"This is the last political obstruction of research with Schedule 1 drugs," he says.

About one-third of Americans currently live in a state where recreational marijuana is legal — and more than 30 states have medical marijuana programs . Yet scientists still aren't allowed to simply use the cannabis sold at state-licensed dispensaries for their clinical research because cannabis remains illegal under federal law.

Medical Marijuana's 'Catch-22': Limits On Research Hinder Patient Relief

"It is a big disconnect," says Dr. Igor Grant , a psychiatry professor and director of the Center for Medicinal Cannabis Research at University of California, San Diego.

The new DEA decision doesn't resolve the conflict between federal and state laws, but it does offer researchers a new, federally sanctioned pipeline for more products and strains of cannabis.

"We'll see a decade or more of explosive cannabis research and potential new therapies," says Dr. Steve Groff, founder and chairman of Groff North America , one of three companies that has publicly announced it has preliminary approval from the federal government to cultivate cannabis for research.

A long-running fight to overturn federal "monopoly"

Despite their efforts, scientists have encountered administrative and legal hurdles to growing pharmaceutical-grade cannabis for decades.

In 2001, Dr. Lyle Craker, a prominent plant biologist, first applied for a license to cultivate marijuana for research — only to encounter years of delay that kicked off a prolonged court battle with the DEA, which has to greenlight research into Schedule 1 drugs like cannabis.

"There's thousands of different cannabis varieties that all have unique chemical profiles and produce unique clinical effects, but we didn't have access to that normal diversity," says Dr. Sue Sisley , a cannabis researcher and president of the Scottsdale Research Institute, which also received preliminary DEA approval to produce cannabis for research.

Only in 2016 did the federal government signal a change in policy that would open the door for new growers, but applications to do so languished for years. Craker and others ended up suing the federal government over the delay.

Psychiatrist Explores Possible Benefits Of Treating PTSD With Ecstasy Or Cannabis

Sisley has long taken issue with the supply of cannabis coming from the NIDA facility in Mississippi — in particular, how it's processed. She used cannabis produced there in her recently published clinical trial on treating PTSD in military veterans.

She describes the product as an "anemic" greenish powder.

"It's very difficult to overcome the placebo effect when you have something that diluted," she says.

The 76-person study, which took 10 years to complete, concluded that smoked cannabis was generally well tolerated and did not lead to deleterious effects in this group. But it also did not find any statistically significant difference in abating the symptoms of PTSD when compared to a placebo.

For Grant of UCSD, the problem with the long-standing supply of cannabis isn't so much the quality, but the lack of different products like edibles and oils and of cannabis strains with varying concentrations of CBD and THC, the plant's main psychoactive ingredient.

"We don't have enough research on the kind of marijuana products that people in the real world are using," he says.

As CBD Oils Become More Popular, The FDA Considers Whether To Set New Rules

Because of the limited domestic supply, some researchers have resorted to importing cannabis from outside the U.S. — a legal but wildly counterintuitive arrangement that is "arduous" and prone to hiccups, says Sisley.

The constraints on research cannabis also has impeded the pathway to drug development because the NIDA facility's cannabis could only be used for academic research, not for prescription drug development . A drug studied in phase 3 clinical trials — what's required before submitting for approval from the Food and Drug Administration — must be the same as what's later marketed.

"The NIDA monopoly has primarily been why we have medical marijuana in the states, but we don't have medical marijuana through the FDA," says Doblin of MAPS. "It's a fundamental change that we can now have drug development with domestic supplies."

A few barriers still remain

The few companies that will soon land DEA spots to cultivate cannabis have an eager marketplace of researchers who are "clamoring" for the chance to study the scientific properties and medical potential of the plant, says Groff, whose company is up for DEA approval and who also has an FDA project to study the antimicrobial properties of cannabis for killing dangerous bacteria like MRSA .

By the end of next year, Groff anticipates his company will be producing up to 5,000 pounds of marijuana per year, offering researchers a "full menu of customizable options."

Biopharmaceutical Research Company — a third company that will soon cultivate cannabis with a DEA license — already has dozens of agreements in place with U.S. researchers and is hearing from more academic institutions, drugmakers and biotech companies in the wake of the change in policy, says CEO George Hodgin.

"Now there's a very clear, approved and legal path for them to legally enter the cannabis space in the United States," says Hodgin.

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Washington State University's Center for Cannabis Policy, Research and Outreach is one of the places that expects to eventually procure cannabis from Hodgin's business.

"It's definitely a big step in the right direction because the industry is moving much faster than we are in research," says Michael McDonell , an associate professor of medicine and director of the university's cannabis center.

But he also points out that even with more growers coming online, it's still by no means easy to study cannabis, because researchers need a special license when working with a Schedule 1 drug and grants to conduct these studies are hard to come by.

Despite the widespread use of marijuana in the U.S., research into the medical potential of other Schedule 1 drugs like MDMA (ecstasy) is much further along than cannabis .

UCSD's Grant says the biggest leap forward for research would come from moving cannabis out of the Schedule 1 drug classification. "If that were to happen," he says, "that would solve a lot of these problems that we've been talking about."

• medical marijuana
• medical cannabis

Do LSD and Magic Mushrooms Have a Place In Medicine?

LSD and magic mushrooms are illegal for recreational use, but some medical experts see major benefits from the drugs. In a commentary published in the journal The BMJ on Tuesday, a London-based psychiatrist argues in favor of legally reclassifying the drugs so that they can more easily be used in medical research.

In his paper, James Rucker, a psychiatrist and honorary lecturer at the Institute of Psychiatry, Psychology and Neuroscience at King’s College London, argues that psychedelic drugs like LSD are less harmful and addictive than other controlled drugs like cocaine or heroin. But strict restrictions on the drugs make it difficult to conduct medical trials, he says.

Rucker writes that psychedelic drugs were frequently used in clinical research until they became classified as schedule 1 drugs—considered the most dangerous, and which aren’t used medically—in the UK in the late 1960s. “Hundreds of papers, involving tens of thousands of patients, presented evidence for their use as psychotherapeutic catalysts of mentally beneficial change in many psychiatric disorders, problems of personality development, recidivistic behavior, and existential anxiety,” Rucker writes.

It’s now challenging for researchers to conduct research on the drugs, largely due to stigma, cost and reluctance of funders to back such research. “These restrictions, and the accompanying bureaucracy, mean that the cost of clinical research using psychedelics is 5-10 times that of research into less restricted (but more harmful) drugs such as heroin—with no prospect that the benefits can be translated into wider medical practice,” argues Rucker.

Though Rucker is based in the UK, the United States has similar restrictions. According to the Atlantic , the world of research has in recent years seen a revival of interest in studying these drugs, but there’s currently no legislation to reclassify LSD and psilocybin, the main ingredient in magic mushrooms, for medical purposes.

Rucker says that in controlled settings like research laboratories, there’s little evidence to suggest that these can be harmful. But such drugs can be abused, and there’s some evidence to suggest that they can lead to health consequences that range from increased heart rate and nausea to memory loss among people who have abused the drugs for a long time.

“Importantly, and unlike most other drugs, the effects of hallucinogens are highly variable and unreliable, producing different effects in different people at different times,” the National Institutes of Health writes on its website. “Because of their unpredictable nature, the use of hallucinogens can be particularly dangerous.”

More research is needed to determine the safety and medical potential of psychedelic drugs —but in the UK, only four hospitals hold the expensive license necessary to conduct research on schedule 1 drugs, Rucker says.

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The federal drug scheduling system, explained

by German Lopez

The Drug Enforcement Administration (DEA) has announced its decision: It will keep marijuana in the same legal, regulatory category as heroin — schedule 1.

To many people, this is outrageous. Obviously, marijuana is nowhere as dangerous as heroin. And it’s not more dangerous than schedule 2 drugs like cocaine and meth. So why the hell is pot schedule 1?

But the classification doesn’t mean that the federal government thinks of marijuana and heroin as equally dangerous drugs. The schedule reflects a more complicated system — one that accounts for a drug’s medical value as much as a drug’s potential for abuse.

A harsh schedule also does not mean a drug is totally illegal. Criminal laws , while guided by the scheduling system, often take other factors into account. For pot, they do — leaving it as one of the less-punished illicit drugs at the federal level, even though it’s schedule 1. And opioid painkillers, as one example, are schedule 2 but legal for medical purposes.

Still, a drug’s schedule is an important policy guide. A stricter schedule lets the DEA more stringently limit access to a drug and its supply, which can make a drug more difficult to research — as has happened for marijuana, limiting researchers’ ability to study the drug for its medical value. (As a result, advocacy and medical groups have long contended that pot’s schedule is out of step with the available scientific evidence.)

So what is the scheduling system, how does it work, and what would it take to reschedule a drug? Here’s what you need to know.

How does the US classify illicit drugs like marijuana?

Under the Controlled Substances Act , the federal government — which has largely relegated the regulation of drugs to the Drug Enforcement Administration (DEA) — puts each drug into a classification, known as a schedule, based on its medical value and potential for abuse.

To initiate a schedule, the DEA first asks if a drug can be abused. If the answer is yes, then it’s put on a schedule. If no, the drug is left out. After that, the drug’s medical value and relative potential for abuse are evaluated to decide where on the scale it lands.

Congress did not clearly define abuse under the Controlled Substances Act

The two big issues, then, are a drug’s potential for abuse and its medical value. Congress did not clearly define abuse under the Controlled Substances Act. But for federal agencies responsible for classifying drugs, abuse is when individuals take a substance recreationally and develop personal health hazards or pose other risks to society as a whole. To find medical value, a drug must have large-scale clinical trials to back it up — similar to what the Food and Drug Administration (FDA) would expect from any other drug entering the market. Schedule 1 drugs have no medical value and high potential for abuse, while schedule 2 through 5 substances all have some medical value but differ in ranking depending on their potential for abuse (from high to low).

Some examples of the drugs that are on each schedule:

• Schedule 1: marijuana, heroin, LSD, ecstasy, and magic mushrooms
• Schedule 2: cocaine, meth, oxycodone, Adderall, Ritalin, and Vicodin
• Schedule 3: Tylenol with codeine, ketamine, anabolic steroids, and testosterone
• Schedule 4: Xanax, Soma, Darvocet, Valium, and Ambien
• Schedule 5: Robitussin AC, Lomotil, Motofen, Lyrica, and Parepectolin

In general, schedule 1 and 2 drugs have the most regulatory restrictions on research, supply, and access, and schedule 5 drugs have the least.

Does the federal government really consider marijuana more dangerous than cocaine?

To many people, one of the more bewildering aspects of the scheduling system is that marijuana is schedule 1 — the same category as heroin — while cocaine and meth are schedule 2.

But that doesn’t necessarily mean the federal government views marijuana and heroin as equally dangerous drugs, or that it considers marijuana to be more dangerous than meth or cocaine. Schedule 1 and 2 drugs are both described as having “a high potential for abuse” — a vague description that doesn’t rank drugs in the two categories as equal or different.

The big distinction between schedule 1 and 2 substances, instead, is whether the federal government thinks a drug has medical value. The DEA says schedule 2 substances have some medical value and schedule 1 substances do not, so the latter receive more regulatory scrutiny even though they may not be more dangerous.

The war on drugs was initiated when much of the nation was in hysterics about what drugs would do to the moral fabric of the country

It may be helpful to think of the scheduling system as made up of two distinct groups: nonmedical and medical. The nonmedical group comprises the schedule 1 drugs, which are considered to have no medical value and high potential for abuse. The medical group comprises the schedule 2 to 5 drugs, which have some medical value and are numerically ranked based on abuse potential.

There are some cultural considerations to the scheduling system, as well. The war on drugs was initiated at a time when much of the nation was in hysterics about what drugs like marijuana and LSD would do to the moral fabric of the country. Marijuana was seen as dangerous not necessarily because of its direct health effects, but because of the perception — partially rooted in racial prejudices — that pot makes people immoral, lazy, and even violent. This perception persists among many supporters of the war on drugs to this day, and it’s still reflected in America’s drug scheduling.

Beyond the scheduling system, the federal government imposes criminal trafficking penalties for drugs that don’t always align with their scheduling. For instance, marijuana trafficking is generally punished less severely than cocaine. And state governments can set up their own criminal penalties and schedules for drugs as well.

Why does a drug’s schedule matter?

A drug’s schedule sets the groundwork for the federal regulation of a controlled substance.

Schedule 1 and 2 drugs face the strictest regulations. Schedule 1 drugs are effectively illegal for anything outside of research, and schedule 2 drugs can be used for limited medical purposes with the DEA’s approval — for example, through a license for prescriptions.

The DEA even sets strict limits on the production of schedule 1 and 2 drugs, although the limits vary from drug to drug. Only one place in the US — a University of Mississippi farm — is currently allowed to grow marijuana under federal regulations, and the pot is limited to research purposes. By comparison, several private companies produce oxycodone, a schedule 2 substance, and use the drug for prescription painkillers.

A drug's schedule can interfere with state laws

A drug’s schedule can interfere with state laws . Marijuana’s schedule 1 status is one reason banks are reluctant to open accounts for pot shops and growers in Colorado and Washington, even though the businesses are legal under state law.

Federal tax law also prohibits businesses from deducting many expenses related to the trafficking of schedule 1 and 2 drugs, which can cause state-legal marijuana businesses’ effective income tax rates to soar as high as 90 percent.

The DEA sometimes uses marijuana’s classification to pressure physicians, hospitals, and pharmacies into not working with medical marijuana operations that are compliant with state law. If these medical providers don’t comply, the DEA threatens to take back licensing that lets doctors prescribe drugs, such as prescription painkillers with oxycodone, that contain scheduled substances.

What does it take to reschedule a drug?

Congress could pass a law that changes or restricts a drug's schedule. But Congress mostly leaves scheduling to federal agencies like the DEA. (One exception: Congress previously passed the Hillory J. Farias and Samantha Reid Date-Rape Prevention Act of 2000 and added gamma hydroxybutyric acid, a date rape drug, to the scheduling system.)

The US attorney general can also initiate a review process that would look at the available evidence and potentially change a drug’s schedule. The review includes several steps :

• The DEA, US Department of Health and Human Services, or public petition initiate a review.
• The DEA requests HHS to review the medical and scientific evidence regarding a drug’s schedule.
• HHS, through the FDA, evaluates the drug and its schedule through an analysis based on eight factors. Among the factors: a drug’s potential for abuse, the scientific evidence for a drug’s pharmacological effects, and the scientific evidence for a drug’s medical use.
• HHS recommends a schedule based on the scientific evidence.
• The DEA conducts its own review, with the HHS’s determination in mind, and sets the final schedule.

Although very rigorous, this process has been successfully carried out in the past. For example, the DEA in 2014 announced it had rescheduled hydrocodone combination products, or opioid-based prescription painkillers, from schedule 3 to schedule 2.

“Almost 7 million Americans abuse controlled-substance prescription medications, including opioid painkillers, resulting in more deaths from prescription drug overdoses than auto accidents,” former DEA head Michele Leonhart said in a 2014 statement . “Today’s action recognizes that these products are some of the most addictive and potentially dangerous prescription medications available.”

Can a drug be unscheduled?

It’s possible, but it’s much more difficult than simply rescheduling a drug.

One big hurdle is international treaties . The US is party to international agreements that effectively require some drugs, including marijuana, to remain within the scheduling system — and possibly schedule 1 or 2.

Proving that a drug has no potential for abuse is also very difficult, if not impossible. An American Scientist analysis , for instance, found even relatively safe marijuana has some potential for dependence; it’s less addictive than heroin, meth, cocaine, nicotine, and alcohol, but more addictive than hallucinogens such as LSD, which doesn’t cause much, if any, dependence. And since pot is widely used recreationally, that makes it a sure lock-in for “high potential for abuse.”

The two major recreational drugs not on the scheduling system — alcohol and tobacco — required a specific exemption in the Controlled Substances Act. Mark Kleiman, a drug policy expert, argues both would be marked schedule 1 if they were evaluated today, since they’re widely used recreationally, addictive, detrimental to one’s health and society, and deadly .

Why is marijuana still schedule 1?

When marijuana’s classification comes under review, its schedule 1 status is consistently maintained due to insufficient scientific evidence of its medical value.

Specifically, the scientific evidence available for marijuana doesn’t pass the threshold required by federal agencies to acknowledge a drug’s potential as medicine. No studies proved the drug’s medical efficacy in controlled, large-scale clinical environments. No studies established adequate safety protocols for marijuana. And marijuana’s full chemical structure has never been characterized and analyzed.

There have been some studies showing marijuana has medical benefits, particularly for pain and muscle stiffness. But these studies haven’t been large enough to meet the threshold the DEA and other federal agencies, such as the FDA, require to prove a drug has medical value — by proving its worth in controlled, large-scale clinical trials.

Changing marijuana's schedule is a bit of a Catch-22

But one reason there isn’t enough scientific evidence to change marijuana’s schedule 1 status might be, in fact, the drug’s schedule 1 status. The DEA restricts how much marijuana can go to research. To obtain legal marijuana supplies for studies, researchers must get their studies approved by HHS, the FDA, and the DEA.

Changing marijuana’s schedule, in other words, is a bit of a Catch-22. There needs to be a certain level of scientific research that proves marijuana has medical value, but the federal government’s restrictions make it difficult to conduct that research.

To address those issues, the DEA hopes to allow much more research into pot in other ways. For one, it’s increased the amount of pot grown for research over the past few years, and it plans to continue doing so. Crucially, it also plans to let more people and facilities grow marijuana for studies — aside from University of Mississippi, the only federally legal grower right now.

That could significantly open up research access to pot — including potentially higher-quality marijuana and different strains of the drug, which the University of Mississippi doesn’t currently meet demands for. But the effects of the changes remain to be seen.

While a reclassification would be a symbolic win for legalization advocates, Kleiman says it wouldn’t have much practical effect. Schedule 2 substances typically require a prescription to be distributed, and the state-legal marijuana dispensaries and retail outlets don’t work through traditional prescriptions (they distribute “recommendations” for medical marijuana) — so even rescheduling may not open up access. (Cocaine and meth are schedule 2, and they’re definitely not easily legally available, after all.)

Still, if the federal government acknowledged pot’s medical value through a schedule 2 classification, advocates hoped it would make federal agencies far more receptive to paying for and approving medical research into pot. But the DEA hopes its other steps will unlock far more research instead.

There would be some effects on policy, such as allowing state-legal marijuana business to deduct certain taxes , if marijuana was reclassified to schedule 3 or lower. But that’s extremely unlikely: Schedule 3 and lower drugs need to have some medical value and not meet criteria for “high potential for abuse.” Since marijuana is widely used recreationally, it’s a lock-in for “high potential for abuse,” keeping it at schedule 1 or 2.

Is there an alternative to the scheduling system?

Kleiman has proposed moving to a scheduling system that looks only at a drug’s potential for abuse without considering whether it has medical value. The regime would control all intoxicating drugs, including alcohol, to try to prevent problematic drug use, based on the scientific definition of drug abuse disorders. Whether a drug has medical value would be addressed by a different set of policies focused on medical drug production and health care.

“Whether something is medication is a separate set of issues,” Kleiman said. His ideal system “would classify drugs by dangerousness, with a penalties for dealing ramping up with more dangerous drugs.”

"The current prohibition system has generated many bad side effects"

One of the problems with the current scheduling system, Kleiman argued, is it tries to lump drugs with completely different effects and risks into a few categories. “There are lots of different drugs in the world, and we have to figure out what to do with each of them,” Kleiman said. “Some categorization is helpful, but it’s not as if the drugs neatly break down.”

Kleiman, who supports decriminalizing illicit drug use and legalizing marijuana, said an ideal replacement to the current scheduling system would also come with less stringent criminal penalties.

“The current prohibition system has generated many bad side effects,” Kleiman said. “We should try to develop new policies that duplicate the success of preventing the development of more drugs that are as big a problem as alcohol, but with fewer of the costs.”

Watch: America’s opioid epidemic, explained

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• Marijuana Legalization
• War on Drugs

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What Are Schedule I Drugs?

• The Schedules
• Schedule I Drugs
• Cannabis/Medical Marijuana
• Historical Context
• Comparisons
• Legal Ramifications

Frequently Asked Questions

The U.S. Drug Enforcement Administration (DEA) sets national standards for controlled substances per the Title 21 U.S. Code (USC) Controlled Substances Act (CSA). Controlled substances are subjected to high levels of government regulation.

The DEA maintains a list of controlled medications and illicit substances categorized from Schedules I to V (1 to 5), depending on the medication's medical use and potential for dependency and abuse. This law provides government oversight over the manufacturing and distribution of these substances.

Prescribers and dispensers must have a DEA license to supply these drugs. Schedule I drugs have the highest risk, while Schedule V drugs have the least potential for abuse.

Schedule I drugs include heroin , LSD (lysergic acid diethylamide ), and cannabis (marijuana) , among others. These drugs have the most potential for abuse, with the highest levels of dependency, and must not be used when not needed.

This article will provide a detailed analysis of the different categories of controlled substances and discuss the different drugs that comprise these sections.

Icy Macload / Getty Images

Understanding Drug Schedules

Drugs, substances, or chemicals used to make medicines are classified into five distinct categories or schedules. Such categories are based on the drug's acceptable medical use, its potential for abuse or dependency, and its tendency to create physical or psychological dependence.

The five schedules, I to V, range from maximum (Schedule I) to least potential for abuse (Schedule V).

The content below defines each category of controlled substances and lists common drugs that comprise each category:

Schedule I drugs have no accepted medical use and safety under medical supervision in the United States, with a high potential for abuse and/or addiction.

Cannabis, for example, is legal in some states but is still classified as a Schedule I drug at the federal level.

In addition to cannabis, Schedule I drugs include heroin, LSD, and Ecstasy (3,4-methylenedioxymethamphetamine) .

Schedule II

Schedule II drugs have some medically acceptable uses but a high potential for abuse and/or addiction. They are prescribed to treat severe pain, anxiety,  insomnia , and attention deficit hyperactivity disorder (ADHD) .

Examples of Schedule II narcotics include Dilaudid (hydromorphone) , Percocet (oxycodone/acetaminophen) , Demerol (meperidine), OxyContin (oxycodone) , and Sublimaze (fentanyl).

Other Schedule II narcotics include codeine, morphine , and opium.

Examples of Schedule II stimulants include Adderall (amphetamine/dextroamphetamine) , Desoxyn (methamphetamine), and Ritalin (methylphenidate) .

Schedule III

Schedule III drugs have low to moderate potential for abuse and psychological addiction compared to Schedule I or II.

Medications in this category are often used for pain management , anesthesia , or appetite suppression . These drugs are available only on prescription and are generally unavailable over-the-counter (OTC).

Schedule III contains no more than 90 milligrams (mg) of codeine per dosage unit, such as Tylenol #3 (acetaminophen and codeine) and Suboxone (buprenorphine) .

Examples of Schedule III nonnarcotics include benzphetamine, Ketalar (ketamine) , and anabolic steroids , such as Depo-Testosterone (testosterone cypionate).

Schedule IV

Schedule IV drugs have viable medical use and low potential for use or misuse.

Examples of Schedule IV substances include: Xanax (alprazolam) , Soma (carisoprodol), Klonopin (clonazepam) , Tranxene (clorazepate) , Valium (diazepam) , Restoril (temazepam), and Halcion (triazolam).

Schedule V drugs possess lower abuse potential than Schedule IV drugs and above. They consist primarily of preparations containing limited quantities of certain narcotics.

Schedule V substances include cough preparations containing no more than 200 mg of codeine per 100 milliliters (mL) or 100 grams (g), such as Robitussin AC (guaifenesin and codeine) and promethazine with codeine.

Schedule I Drugs: Recreational and Medical Use

It is very challenging to regulate the use of Schedule I drugs.

One reason for this is that many of these drugs have proven health benefits, such as cannabis in the form of medical marijuana, as well as LSD. However, these drugs, while common, are often misused.

Nonetheless, legal restrictions are placed on the recreational use of controlled drugs to prevent drug misuse. For example, prescription drugs labeled as Schedule I, such as methaqualone (commonly known as quaaludes ), are abused.

This drug has effects similar to heroin. Research data suggests that 4% to 6% of people who misuse prescription opioids switch to heroin.

What Are Designer Drugs?

A controlled substance analog (also called a "designer drug" or "legal high") is a substance intended for human consumption and is similar to a controlled drug.

A designer drug is a structural or functional analog of a controlled substance. It is made by altering the chemical structure to mimic the effects of the parent compound.

It is structurally or pharmacologically similar to or characterized as being similar to a controlled (Schedule I or Schedule II) substance. Also, it is not an approved medication in the United States.

Medical Marijuana

Cannabis, a Schedule I drug, is derived from the plant Cannabis sativa . However, as of August 2023, the Joe Biden administration has recommended that cannabis be reclassified from a Schedule I substance to Schedule III.

The term "medical marijuana" refers to the role of cannabis in treating medical conditions. In the United States, over one-half of the states have legalized marijuana for medical use.

In states where medical marijuana is legal, a healthcare provider gives a written statement to get the drug. It includes the explanation for using cannabis for a specific condition, with your name, to acquire it from an authorized seller.

Cannabis is sometimes prescribed to treat chronic pain, including nerve damage , nausea, and vomiting caused by chemotherapy for cancer , eating disorders , and human immunodeficiency virus (HIV)/AIDS .

Some studies show that cannabis relieves symptoms of multiple sclerosis (MS) , Crohn's disease , inflammatory bowel disease (IBD) , glaucoma , and epilepsy .

The Food and Drug Administration (FDA) has approved two artificial derivatives of cannabis, e.g., Marinol (dronabinol) and Cesamet (nabilone). They are available on prescription to treat medical conditions.

Know, however, that laws differ across states for the recreational use of cannabis.

Health Benefits of LSD

The Schedule I drug LSD has been used to treat anxiety , depression , psychosomatic diseases (physical illness caused by stress) , and addiction .

However, most of the studies do not meet contemporary standards. It has taken several decades to revive interest in LSD research and its therapeutic potential for psychiatry.

New studies conforming to modern standards are necessary to strengthen the research regarding its use.

Historical Context of Schedule I Drugs

The Controlled Substances Act (CSA) established a federal policy that allowed the federal government to regulate the manufacture, distribution, import, export, and use of regulated substances.

The 91st U.S. Congress legislated the CSA in 1970, and it was signed into law by President Richard Nixon.

This law was an effort to combine all previous federal drug laws. It allows federal law enforcement of controlled substances and serves as the legal foundation in the fight against drug abuse.

The CSA also gives the DEA and the FDA the authority to control which substances are added or removed from drug schedules.

The United States has been striving for the safe and effective use of controlled drugs since the Pure Food and Drug Act of 1906, which required manufacturers to label any product containing dangerous substances such as alcohol, morphine, opium, and cannabis.

The Pure Food and Drug Act of 1906 has been amended several times over the following six decades, but the most significant change occurred in the early 1970s with the adoption of the CSA.

The cornerstone of the CSA is its classification system to regulate controlled substances. 

Furthermore, the CSA ensures that a controlled substance prescription must meet several criteria, such as being issued by a healthcare practitioner for a legitimate medical purpose.

The CSA also requires drug prescribers to list their DEA-issued registration number on each controlled substance prescription.

Comparison With Other Drug Schedule

While the drug schedules mainly refer to a drug's medical value and the likelihood of substance misuse, they also classify drugs by their chemical makeup and how they interact with the brain and body, as follows:

• Schedule I contains drugs with little or no therapeutic value and is subjected to the most restrictive control. These drugs cannot be lawfully possessed or prescribed.
• Healthcare practitioners can prescribe drugs in Schedules II and III. These drugs can be legally possessed and supplied lawfully by anyone with a prescription (note that Schedule II drugs cannot be refilled). These are medically acceptable in particular cases for treating chronic pain or addiction. However, it is an offense contrary to the 1971 Act to keep any Schedule II or III drugs without a prescription or lawful authority.
• Substances in Schedule IV have a low potential for abuse relative to drugs in Schedules II and III. These drugs can only be lawfully possessed under prescription.
• Schedule V includes drugs with a limited amount of controlled drugs (narcotics) and are rarely available as OTC medicines. 

Sometimes, a drug can be reclassified depending on its change in therapeutic uses. For example, in 2014, the DEA reclassified hydrocodone from Schedule III to Schedule II. However, reclassification is relatively rare.

Potential Legal Ramifications

It is illegal to prescribe, trade, sell, use, or possess Schedule I drugs. These are federally controlled substances under the CSA. There are strict penalties regarding the illegal possession of these drugs. Heavy fines and even jail are the consequences.

A detailed view of the legal penalties for possessing controlled substances from different schedules can be found on the DEA's official website.

The CSA drug scheduling information applies to drugs or substances regulated under federal law. There may be differences in laws between individual states and among state laws and federal law.

For example, there are drugs, specifically cannabis, that fall into Schedule I but have been legalized in many states for recreational or medical use. 

The DEA sets national controlled substance standards and lists the drugs in five schedules. These schedules have been outlined in the Federal Comprehensive Drug Abuse Prevention and Control Act of 1970 guidelines. The legal restrictions on using controlled drugs are to prevent drug misuse.

The drugs are listed into five schedules depending on the drug's acceptable medical use and potential for abuse or dependency. Schedule I contains medications with no medical value and maximum potential for abuse, and Schedule V contains drugs with the least potential for abuse.

Schedule I contains heroin, LSD, cannabis, peyote, and Ecstasy. Certain derivatives of these drugs are FDA-approved for various medical conditions.

Always use the prescribed drug in the recommended dosage to avoid adverse side effects and to lower the risk of dependence on these drugs.

Hospitals, clinics, and organizations using controlled substances must have policies and procedures to dispose of these substances and avoid potential drug diversion and environmental pollution.

Clinics and facilities using controlled substances must maintain adequate and detailed records, but individual healthcare systems impose specific requirements.

Return unused or expired medicines to the community-medicine return-back program or ask your pharmacist.

If you have an addiction or dependence on a controlled drug or need additional information on the controlled drugs, visit government websites for up-to-date, reliable information, including the U.S. Department of Justice/Diversion Control Division for a list of controlled substances.

United States Drug Enforcement Administration. The Controlled Substances Act .

United States Drug Enforcement Administration. Drug scheduling .

United States Drug Enforcement Administration. Mid-level practitioners authorization by state .

United States Department of Justice. Controlled substances - alphabetical order .

Department of Justice/Drug Enforcement Agency. Drug fact sheet: marijuana/cannabis .

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By Ayesha Gulzar, PharmD Ayesha Gulzar is a clinical pharmacist interested in medical research, pharmacy practice, and medication therapy management. Dr. Gulzar has been working in medical communications, writing medical and clinical research for patients and health professionals in the United Kingdom.

• News Releases

Cancer drug could treat early-stage Alzheimer’s disease, study shows

Researchers discovered that by blocking a specific enzyme called indoleamine-2,3-dioxygenase 1, or IDO1 for short, they could rescue memory and brain function in models that mimic Alzheimer’s disease. Pictured from right to left: Melanie Reynolds, Penn State’s Dorothy Foehr Huck and J. Lloyd Huck Early Career Chair in Biochemistry and Molecular Biology, Praveena Prasad, doctoral candidate at Penn State, Brenita Jenkins, lab manager and research scientist at Penn State. 

Credit: Michelle Bixby/Penn State

UNIVERSITY PARK, Pa. — A type of drug developed for treating cancer holds promise as a new treatment for neurodegenerative diseases such as Alzheimer’s, according to a recent study by researchers at Penn State, Stanford University and an international team of collaborators.

The researchers discovered that by blocking a specific enzyme called indoleamine-2,3-dioxygenase 1, or IDO1 for short, they could rescue memory and brain function in models that mimic Alzheimer’s disease. The findings, published today (Aug. 22) in the journal Science, suggest that IDO1 inhibitors currently being developed as a treatment for many types of cancer, including melanoma, leukemia and breast cancer, could be repurposed to treat the early stages of neurodegenerative diseases — a first for the chronic conditions that lack preventative treatments.

“We’re showing that there is high potential for IDO1 inhibitors, which are already within the repertoire of drugs being developed for cancer treatments, to target and treat Alzheimer's,” said  Melanie McReynolds , the Dorothy Foehr Huck and J. Lloyd Huck Early Career Chair in Biochemistry and Molecular Biology at Penn State and co-author on the paper. “In the broader context of aging, neurological decline is one of the biggest co-factors of being unable to age healthier. The benefits of understanding and treating metabolic decline in neurological disorders will impact not just those who are diagnosed, but our families, our society, our entire economy.”

Alzheimer’s disease is the most common type of dementia, an umbrella term that refers to all age-associated neurodegenerative disorders, McReynolds explained. In 2023, as many as 6.7 million Americans were living with Alzheimer’s disease, according to the  Centers for Disease Control and Prevention , and its prevalence is expected to triple by 2060.

“Inhibiting this enzyme, particularly with compounds that have been previously investigated in human clinical trials for cancer, could be a big step forward in finding ways to protect our brains from the damage caused by aging and neurodegeneration,” said  Katrin Andreasson , the Edward F. and Irene Pimley Professor of Neurology and Neurological Sciences at the Stanford University School of Medicine and the study’s senior author.

Alzheimer’s disease affects the parts of the brain that control thought, memory and language, the result of progressive and irreversible loss of synapses and neural circuitry. As the disease progresses, symptoms can increase from mild memory loss to losing the ability to communicate and respond to the environment. Current treatments for the disease are focused on managing symptoms and slowing progression, through targeting the build-up of amyloid and tau plaques in the brain, but there are no approved treatments for combating the onset of the disease, McReynolds said.

“Scientists have been targeting the downstream effects of what we identify as an issue with the way the brain powers itself,” said  Praveena Prasad , doctoral student at Penn State and co-author on the paper. “The therapies that are currently available are working to remove peptides that are likely the result of a bigger issue we can target before those peptides can start forming plaques. We’re demonstrating that by targeting the brain’s metabolism, we can not only slow, but reverse the progression of this disease.”

Using preclinical models — in vitro cellular models with amyloid and tau proteins, in vivo mouse models and in vitro human cells from Alzheimer’s patients — the researchers demonstrated that stopping IDO1 helps restore healthy glucose metabolism in astrocytes, the star-shaped brain cells that provide metabolic support to neurons.

IDO1 is an enzyme that breaks down tryptophan, the same molecule in turkey that can make you sleepy, into a compound called kynurenine. The body’s production of kynurenine is the first part of a chain reaction known as the kynurenine pathway, or KP, which plays a critical role in how the body provides cellular energy to the brain. The researchers found that when IDO1 generated too much kynurenine, it reduced glucose metabolism in astrocytes that was required to power neurons. With IDO1 suppressed, metabolic support for neurons increased and restored their ability to function.

The researchers conducted the study in several models of Alzheimer’s pathology, namely amyloid or tau accumulation and found that the protective effects of blocking IDO1 cut across these two different pathologies. Their findings suggest that IDO1 may also be relevant in diseases with other types of pathology, such as Parkinson’s disease dementia as well as the broad spectrum of progressive neurodegenerative disorders known as tauopathies, explained Paras Minhas, current resident at Memorial Sloan Kettering Cancer Center who earned a combined medical and doctoral degree in neuroscience at Stanford School of Medicine and is first author on the paper

“The brain is very dependent on glucose to fuel many processes, so losing the ability to effectively use glucose for metabolism and energy production can trigger metabolic decline and, in particular, cognitive decline,” Minhas said. “Through this collaboration we were able to visualize precisely how the brain’s metabolism is impacted with neurodegeneration.”

The other Penn State author is lab manager Brenita Jenkins. Other co-authors are Amira Latif-Hernandez, Aarooran S. Durairaj, Qian Wang, Siddhita D. Mhatre, Travis Conley, Hannah Ennerfelt, Yoo Jin Jung, Edward N. Wilson, Frank M. Longo, Takeshi Uenaka and Marius Wernig of Stanford University; Jeffrey R. Jones, Ryan Goodman, Traci Newmeyer, Kelly Heard, Austin Kang and Fred H. Gage of The Salk Institute for Biological Studies; Yuki Sugiura and Makoto Suematsu of Keio University; Ling Liu and Joshua D. Rabinowitz of Princeton University; Erik M. Ullian of the University of California San Francisco; Geidy E. Serrano and Thomas G. Beach of the Banner Sun Health Research Institute.

The Howard Hughes Medical Institute Hanna H. Gray Fellows Program Faculty Phase and the Burroughs Welcome Fund PDEP Transition to Faculty funded the Penn State aspects of this work.

10.1126/science.abm6131

Method of Research

Experimental study

Subject of Research

Article title.

Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies

Article Publication Date

22-Aug-2024

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Original Source

How AI drug discovery is identifying TBK1 inhibitors

August 23, 2024

The pace of innovation in the medical field is constantly accelerating, which means a greater understanding of human health conditions and the possibility of more effective treatments. However, identifying a condition, molecule, or therapeutic target doesn’t automatically mean we can cure a disease. The human body is complex, and each new discovery reveals more questions about how to develop the right therapies.

Fortunately, technology can support faster identification of scientific breakthroughs. At CAS, we applied machine learning algorithms to develop predictive models that can assist in finding effective new drugs to treat many diseases including cancer, viral infections, and inflammatory disorders. We focused on TBK1 (TANK-binding kinase 1), an enzyme with kinase activity that plays a crucial role in multiple biological processes. Targeting TBK1 has the potential to drive new therapies for life-threatening diseases, yet its complexity presents research challenges.

We analyzed the CAS Content Collection TM , the largest human-curated repository of scientific information, and found that journal publications on TBK1 have nearly doubled between 2020 and 2023. This suggests extensive interest in the research community, but the low growth we’ve seen in patent publications speaks to the potential difficulties in targeting TBK1.

Because TBK1 plays a critical role in immune and cellular responses, it’s a very promising target for new drug therapies, and researchers need tools to overcome the complexities related to this kinase and find breakthroughs faster. Our computer modeling approach shows how it can be done.

TBK1 plays a role in cancer, autoimmune diseases, and more

Kinases are enzymes that catalyze the transfer of a phosphate group from a high-energy molecule, such as ATP, to a specific substrate molecule, typically a protein, lipid, or carbohydrate. Kinases are essential for transmitting signals within cells and external stimuli. They’re involved in many physiological processes. As an important kinase, TBK1 is:

• A key regulator of the innate immune response to viral and bacterial infections.
• Involved in the regulation of inflammatory responses.
• Important for the regulation of autophagy, a cellular process involved in the degradation and recycling of damaged organelles and proteins.
• A contributor to cell survival and proliferation in various contexts.
• Involved in the regulation of metabolic processes, including glucose metabolism and lipid homeostasis.
• Implicated in the cellular response to DNA damage.

Because of its importance in so many biological processes, TBK1 has been implicated in various diseases. In our analysis of the CAS Content Collection, we visualized the co-occurrences of TBK1 with other proteins and diseases in scientific literature over the last 20 years (see Figure 1). Notable disease co-occurrences include:

• Autoimmune diseases such as lupus, multiple sclerosis, and irritable bowel syndrome.
• Neurodegenerative disorders like ALS and frontotemporal dementia.
• Cancer development and progression, where TBK1 can enhance cell proliferation, inhibit apoptosis, and modulate the tumor microenvironment in ways that cause tumor progression.
• Viral infections, which may be impacted by TBK1 dysregulation affecting the immune system’s response to viruses.
• Metabolic disorders, but the precise mechanisms are still being explored.

Researchers are pursuing TBK1 inhibitors that can selectively block this kinase’s activity. Targeting TBK1 in conditions where it’s dysregulated or overactive could result in significant clinical breakthroughs, including for cancer treatment. Despite promising preclinical results, the development of TBK1 inhibitors faces several challenges, including achieving sufficient selectivity to minimize off-target effects, optimizing pharmacokinetic properties for effective delivery and distribution in the body, and ensuring safety and tolerability in clinical settings.

QSAR modeling identifies potential therapies based on IC50 values

When developing an inhibitor drug, researchers examine the IC50 (half-maximal inhibitory concentration) value. IC50 is a measure that quantifies the potency of an inhibitor, particularly in enzyme inhibition studies. It represents the concentration of an inhibitor required to inhibit 50% of the activity of a biological or biochemical target, such as an enzyme or a cellular process. IC50 is the most widely used and informative measure of a drug's efficacy.

In computer-aided drug design, predicting the IC50 values of potential drug candidates is crucial for assessing their potency in inhibiting the target enzyme or protein. Quantitative structure-activity relationship (QSAR) models are useful for making these predictions because they relate the chemical structure of compounds to their biological activity, including IC50 values. By analyzing a dataset of known inhibitors with experimental IC50 values, QSAR models can predict the IC50 values of new compounds.

To accomplish this, we used the CAS Content Collection to extract all available data on IC50, pIC50, and TBK1. After some data scrubbing, we arrived at a training set of 1,183 compounds. About 40% (475) of them were represented with exact measurements of IC50, which is suitable for developing regression models. The rest of the data was represented as binary (active/inactive) at two different breakpoints: IC50=1uM and IC50=0.1uM. These were suitable for developing binary distribution and three-category classifier models.

Because scientists and regulatory agencies have different needs for predictive capabilities, we chose to build these three different model types.

Fragment-functional analysis descriptors drive the best results

When developing our models, we used three different sets of molecular descriptors: proprietary CAS Fingerprint, available descriptors in RdKit , and fragment-functional analysis. 

Of these, we found that the best overall predictive models were derived from the fragment-functional analysis descriptors (see Figure 2). For this analysis, over 66,000 single fragments were generated after splitting the chemical structures of the training set into sub-fragments. We performed this analysis on all three model types (regression, binary distribution, and three-category classifiers).

We then utilized machine learning algorithms to determine the importance of particular molecular descriptors (see Table 1). Feature selection is a critical part of any machine learning technique. It aims to extract the most informative features and remove noise as well as irrelevant and redundant attributes. Table 1 shows the top active molecular descriptors from the fragment-functional analysis that are mainly present in the most potent TBK1 inhibitors.

The predictions for new molecules obtained from a QSAR model are acceptable only if the new molecules fall inside its applicability domain (the chemical space defined by all molecular descriptors used to build the model). Figure 3 shows the Williams plot that represents the applicability domain as a plot of Leverage (h) vs. Standardized Residuals (σ). The applicability domain of our model is defined within ±3σ and a warning leverage threshold h* = 0.25.

This analysis demonstrates that machine learning tools and computer modeling can indeed help researchers identify promising drug therapies from complex data sets. By applying various modeling approaches, we can identify potential targets for TBK1, which can drive the development of drugs to treat cancer, neurodegenerative diseases, autoimmune conditions, and more conditions as medical discoveries continue. 

Analyzing vast amounts of data and accounting for the complexity of compounds and molecules is possible. By using cutting-edge technology to synthesize that data into predictions, we can reach  new breakthroughs in drug discovery.

To learn more about the exciting and dynamic field of anti-aging research, read our latest journal manuscript here .

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