Dennis McKenna: Matthew Metcalf, also known as Matt, is a neuroscientist with a background in the medicinal chemistry and pharmacology of opioids and cannabinoids as analgesic drugs. He is an assistant professor of medicinal chemistry at the Massachusetts College of Pharmacy and Health Sciences University School of Pharmacy in Worcester, Massachusetts. His current research focuses on the development of new approach methodologies, abbreviated NAMs, sometimes called non-animal models, which are drug tests designed to limit the use of animals in drug testing. His current work focuses on the use of living plants as biological organisms to replace animal models. Outside of his research, he is passionate about auroras and time-lapse photography.

Matthew, welcome to the Brainforest Café.

Matt Metcalf: Thank you so much for having me, Dennis. I’m really very honored to be here and excited to talk to you tonight.

Dennis McKenna: Well, I am extremely honored to have you, Matt. I love your office. I have a fake background because my office is so chaotic—you don’t want to see it. Yours is a typical academic’s office: very chaotic and stuffed with books, which is great. I think people’s offices are insights into their minds; mine is very cluttered, and so is yours.

Matt Metcalf: Yeah, but not a lot going on.

Dennis McKenna: So we met at the University of Minnesota a number of years ago. I think it was in the mid-2000s. Do you remember the year? It was probably 2008.

Matt Metcalf: I think 2008. Yeah, and I snuck into your class because I couldn’t officially take it. I was post-docking there at Phil’s lab. I snuck into the back, and you do this great thing when you start off your classes: you have everybody introduce themselves and talk. I’ve actually stolen that approach when I’m doing elective classes.

When you got to me, I thought I was being clever, but I wasn’t. I was like, “Oh, I’m undercover,” because I heard somebody say that once. Then everybody was like, “Wait, who is this guy?” You asked, “Is this after class?” Considering what we were talking about, I can understand why people might be alarmed—like, is this guy a narc or what?

Dennis McKenna: I know, right? Although, you know, it was still permitted to talk about drugs. We weren’t handing them out, but we were doing a lot of talking because, hey, it was ethnopharmacology, right?

Matt Metcalf: Yeah.

Dennis McKenna: And I always enjoyed your participation in that class. I always like it when people who know a lot more than I do about a topic join. You certainly understand chemistry and medicinal chemistry vastly more than I would ever pretend to. When people with that kind of expertise join my class, it really enriches the process because I’m kind of a cheerleader to try to bring people’s expertise to the forefront. So, I hope it was ethnopharmacology that you took, right?

Matt Metcalf: I took three of your classes, and I missed one and always regretted not taking it. I forget what the first one was. Was it Drugs and Society or something? Class, culture, drugs, and society.

Dennis McKenna: Yeah, I taught that in 2008, and they only let me teach it for one semester. They were actually quite appalled. At the University of Minnesota, you can propose a course, which I did, and they let you teach it for a semester. If they don’t like it, the graduate committee reviews it to decide whether they’ll make it an actual numbered course. But that course was too controversial for their taste, so they wouldn’t let me teach it past that one semester.

It was a pity because many of the people who signed up for it, including you, had pretty extensive backgrounds and it was actually a great course, but they were nervous about it. So I only got to do it once. But you took ethnopharmacology and you took botanical medicines.

Matt Metcalf: That was the one I missed—botanical medicines. I regret it; it was at a time when I needed to work or something, so I couldn’t get to that class.

But I remember one of your students came and gave a presentation in the other class I was in because she missed it for the main class. It was on fennel as birth control in ancient Greece, and they drove the plant extinct because they used it so much and it worked so well. I was like, “Whoa.” Did you assign topics in that class to students, or was it very loose?

Dennis McKenna: I didn’t assign topics. I gave them a list of possibilities to present, and many of them were very creative. I didn’t want to be top-down; I wanted people to present on stuff they were genuinely interested in. Do you happen to remember what you presented in that class?

Matt Metcalf: I don’t think that was a presentation class. I presented in the Drugs and Society class. I think glutamate was my neurotransmitter system. We had groups and we assigned neurotransmitter systems, right?

Dennis McKenna: Which was a great class, too. We met in that big open room—the atrium over in the academic center. That was a good place for it.

I had wonderful students. We had some very bright students in that class, and many of them I’m still in touch with. You know how it is—certain students stand out and you keep in touch. I regret that you and I have not kept in touch as much as we should have.

Matt Metcalf: Yeah.

Dennis McKenna: Let me ask you an obvious question. At the time, you were a postdoc in pharmacy, right?

Matt Metcalf: Yeah, I was at the pharmacy school post-docking for Phil Portoghese. He was the editor-in-chief of the Journal of Medicinal Chemistry. He published hundreds of papers, was one of ISI’s most highly cited researchers, and was the guy who discovered opioid receptor subtypes. He also found the selective ligands to discriminate between Kappa and Delta.

Dennis McKenna: So, what was his name again?

Matt Metcalf: Phil Portoghese.

Dennis McKenna: Right, right. Phil Portoghese. Sorry. To those who know opiates, this guy was a legend in pharmacy and opioids—a major, major figure. You were very fortunate to be able to work with him.

And did that get you interested in opiates, which in turn got you interested in what you’re working on now—these non-animal methodologies for testing drugs? How did you settle on this? What led you to the idea that plants would be a good substitute for animal models? This is kind of the holy grail of pharmacology. They’ve been looking for that for a long time. Of course, they use receptor bioassays and other types of in vitro assays, but this idea of testing plants—which are whole systems—gives you a much better picture than just a cell isolate in a petri dish. How did you stumble on this?

Matt Metcalf: That’s a great question. It was a number of different things. I had a lingering question: I wanted to know why the opium poppy made opioids. I scoured the literature and couldn’t find anything that made sense to me. There’s literature suggesting they’re used to make the opium latex stickier or for wound defense. Exopheromone theories are always prevalent, but I wanted to know what was going on inside the plant because it takes a tremendous amount of biochemical energy to produce these compounds. The shortest plant synthesis I’ve seen published is about eight steps, but it can go up to 13 or 15 different reactions to get to morphine and codeine in the plant.

I was trying to figure that out, and since the University of Minnesota is a tier-one research institution, they get great speakers. We had a speaker come in talking about the ethics of animal research and IACUC protocols—which stands for Institutional Animal Care and Use Committee. Everybody who works with animals has to go through these committees to ensure experiments are done ethically. There’s a rule stating that if animal alternatives can be developed, they should be, but nobody ever does it. They just say, “Well, we have to use the mice, there’s nothing else we can do.”

I started thinking, maybe I should come up with one of those alternatives. I wondered if I could figure out how opioids work in the plant and then develop a plant-based assay. If it worked really well, maybe I could get an antagonist to show it’s selective. I started some initial tests, but the opioids did nothing in the plants I was testing. I had to go to the osmotic point where all the water gets sucked out of the plant root and kills it, just like loading it up with sugar. The osmotic balance was off, but they didn’t do anything else.

So, I started digging into the literature. I couldn’t find anyone doing plant drug testing, so I looked more selectively and found two researchers: Applewhite in the ’70s, and David Macht. Macht fascinated me. I found him through a classic textbook, The Principles of Humane Experimental Technique by Russell and Burch. It’s the classic text on how medical experimentation is done and how we can avoid using animals. They outlined three principles for non-animal models: reduction, refinement, and replacement—known as the Three Rs of animal research.

The most valuable one is replacement, where we take an animal drug assay and completely replace it with another, such as cellular assays or in silico computer simulations. They had a line in the book stating that plants represent a nearly untapped source of potential, and the leading historical researcher was David Macht. I started trying to find his papers, which were all from the 1920s and ’30s. He developed assays using porridge seeds and plants. At the time, readers might be familiar with Digoxin, a drug used in heart failure and rhythm control. Up until the ’50s, it wasn’t easy to purify from the plant, so classic pharmacy used plant extracts and tinctures of digitalis. These always had to be standardized because plants vary.

The way they tested for standardization back then was through cat lethality tests, frog lethality tests, and pigeon head droop tests—all of which killed the animals. Macht developed a drug assay using porridge seeds to show bioequivalence with the animal drug assay. Even though the mechanisms of action were different, he could get standard curves that matched the animal assay. It was much more statistically robust because you can test with any number of seedlings, whereas with animals, the Three Rs dictate you must reduce numbers as much as possible.

Coincidentally, Macht was also an opioid researcher of his time. He believed that opioids acted at the nerve endings, which was contrary to the popular belief of the era that they did not.

Matt Metcalf: Sorry, I cut you off. He thought they acted at the synapses. And they do, just like other neurotransmitters.

But what do opioids do in the plant? Plants don’t have a nervous system. Although Mimosa pudica has an osmotic response that is kind of like an action potential.

Dennis McKenna: Yeah, definitely. That sort of thing goes on. On the surface, it doesn’t seem to make sense because plant physiology is so different from mammalian physiology. So, the simple question is: what do opioids do in the plant? What do they do for it, and what do they do to it?

Matt Metcalf: I am still searching for the answer to that question. It’s what got me into this. I’ve switched to a different drug class now, but I still want to find the answer.

Do you remember your 2011 paper in Journal of Pharmacology? You told me that you had to raise the threshold for specific binding because almost all of your extracts were binding to mu and delta opioid receptors.

Dennis McKenna: Yes, many of them did. I was very surprised by that.

Matt Metcalf: Yeah, and you were going after, presumably, serotonin agents, right?

Dennis McKenna: Yes, that’s right.

Matt Metcalf: I just have this feeling that there is something opioids are doing in plants. It’s more widely spread than we currently realize. I think we need to get an evolutionary biologist on this. Do you know who Bret Weinstein is?

Dennis McKenna: Uh, no.

Matt Metcalf: He runs the DarkHorse Podcast. He’s an academic heretic like us. I think he would be a great person to talk to about what this could be doing.

There are too many compounds in your paper that bind selectively to opioids. I still think there is an undiscovered system that opioids are targeting in plants. Since opioid receptors are so highly conserved, we find them in organisms all the way down to C. elegans. It makes sense that they are activated and serve a function in plants, and even in fungi. Fungi produce some of the wildest peptide-based opioids you can find. There is some integrated system in life that opioids are serving a function for, and we just haven’t elucidated it yet in plants and fungi.

Dennis McKenna: There are opioids in fungi? This is news to me.

Matt Metcalf: Oh, yeah. Some of the most interesting peptides in nature that target opioid receptors are found in fungi.

Dennis McKenna: Amazing. Well, never underestimate the fungi. Biochemically, they are much closer to animals than plants phylogenetically.

Matt Metcalf: And I would be surprised if people weren’t working with fungi to develop these non-animal bioassays, because they’re another obvious set of organisms to use.

Dennis McKenna: In a broader sense, the question becomes: why do plants make this vast variety of “secondary” products? There is nothing secondary about them. They are only called “secondary” because they are not universally distributed or part of primary metabolism; they are specific to certain families. But they are anything but secondary. The usual trope is that they are messenger molecules—acting as repellents, toxins, or attractants at an ecological level.

Matt Metcalf: Plants and fungi expend a vast amount of metabolic energy to build these compounds that don’t serve any obvious external functions. So, the thinking is they are messenger molecules. My take has always been that plants use them to mediate. There is a famous botanist who once said, “plants substitute biosynthesis for behavior.” Humans respond to environmental threats through behavior, like the fight-or-flight response. But plants are stuck in one place. They have had to rely on chemistry to deal with threats or to form symbiosis. All of these are chemically mediated processes. So this is a very rich area to look into.

Matt Metcalf: I completely agree. An obvious question people ask when I talk about testing analgesics is, “Do plants feel pain?” It’s a complicated answer—not in the way mammals do, but they do experience inflammation. They use salicylic acid to mediate that.

Salicin is intracellular, salicylic acid is intercellular (within the plant), and methyl salicylate (the methylated version) is pumped out through the stoma to signal damage to adjacent leaves. So they act as chemical messengers.

Dennis McKenna: That is very interesting. What does inflammation look like in a plant?

Matt Metcalf: That’s a great question, and I need to delve deeper into it. I was just thinking about one of my lectures for my pharmacy students where I talk about salicylates.

Opioids actually have a very similar relationship. Morphine-6-glucuronide mimics salicin (which is glycosylated salicylic acid). Morphine mimics salicylic acid, and codeine mimics methylated salicylate. I wonder if plants are using opioids in a similar way—something intracellular, something that travels between cells, and something that travels through the air to signal to different parts of the plant.

Dennis McKenna: That is extremely interesting. I think it’s fascinating that you chose mimosa as one of your subjects. Anyone who has touched a sensitive plant knows there is an immediate response, which is unusual because we usually think plants don’t move. But mimosa puts the lie to that. With the right stimulants, they do move, and there is an action potential that can be measured.

There is an interesting researcher, Monica Gagliano, who has been looking into plant intelligence. She devised a clever assay using mimosa. It’s a bit of a sidetrack, but—

Matt Metcalf: Oh, no. Please go on.

Dennis McKenna: If you take a potted mimosa and drop it a few inches using a sling, the leaves will close, right? She wanted to see if she could use this to induce a Pavlovian response. She repeatedly exposed hundreds of mimosa plants to this dropping sensation. At first, they all folded their leaves, but after a while, they began to ignore the stimulus because they realized it wasn’t a threat. They adapted and stopped folding. She concluded that the plants were developing a memory. I thought it was a very simple and elegant assay, showing that mimosa is an ideal subject for this work.

Matt Metcalf: Yeah, that is really interesting. Do you want me to put up my slides on my mimosa assay?

Dennis McKenna: I think that would be a good idea.

Matt Metcalf: I should note that I could not present any of this without my students. MCPHS at Worcester is an accelerated pharmacy program. We compress the normal PharmD program down into three years. It’s challenging enough at four years, but at three, it is extremely intense.

I don’t have graduate students or postdocs; I have my PharmD researchers, and they give me their precious time. I am incredibly grateful to them. This specific work was conducted by Songyun Liu (known as Leo) and Megan. I want to shout them out before I go through this.

Dennis McKenna: Every investigator depends on their team to make them look good.

Matt Metcalf: They make me look very, very good; it’s completely impossible without them.

So, I am not just looking at one organism. With plant drug assays, aside from a few low-hanging fruit systems, you have to find a specific assay for each drug class per plant. With a mouse, you can inject whatever you want—it’s a general model for humans. With plants, you have to find specific systems to target.

I was looking at mimosa because a researcher named Applewhite in the ’70s tested a couple of human-use drugs on it, but it was never followed up. My student, Leo, wanted to pick that up. The folding response in mimosa is called thigmonasty—rapid plant movement in response to touch.

Dennis McKenna: That’s a new term for me. How do you say it?

Matt Metcalf: I say “thigmonasty.”

Dennis McKenna: Thigmonasty—a rapid response in a plant.

Matt Metcalf: Yes, nastic movements are rapid plant movements. Some are in response to light, some to touch, and some to chemicals (which is chemonasty). Mimosa exhibits multiple types. In addition to touch, they fold their leaves at night when there isn’t enough light, and they also respond to chemical signals. One of those signals looks a bit like a glycosylated opioid, which is what drew me to this.

This slide shows the anatomy of the plant. This video shows Leo demonstrating the folding response. We grow them new each year. We plant them in February, and we have viable plants by July. They are very ephemeral. They fold their leaves, and they also fold down their petioles at the base where they connect to the stem, which drops the whole branch.

These are some of the proposed mechanisms involving ion channels and action potentials.

Dennis McKenna: So of course, Matt, I have to ask you—what happens when you put hallucinogens into these assays? I’m thinking specifically of dimethyltryptamine (DMT), which is structurally close to indoleacetic acid and other plant hormones. Tryptophan is pictured here as a leaf-opening substance. What happens when you apply DMT?

Matt Metcalf: I would love to know the answer. I do not have a Schedule I license, and they are incredibly tricky to get. So, I don’t know. I suspect it would perform similarly to tryptophan.

I would love to run that in the assay Monica Gagliano conducted. Testing various tryptamines to see if they influence behavior, speed up, or slow down the learning response would be wild.

Dennis McKenna: Yeah, that would be very interesting to see. So, here you are showing a variety of compounds that elicit this leaf-closing response.

Matt Metcalf: Yes, they are thought to be the chemical signals causing the response. We haven’t gone too deep into that yet; we basically created these drug assays out of thin air based on a few initial reports. We had to start from scratch.

This is what they look like when they are very young before they get leaves. We also looked at another plant, Chamaecrista.

Dennis McKenna: Yeah. Okay.

Matt Metcalf: It’s a type of sensitive pea plant that grows in my local area. When I was taking my daughter to scouts, I was like, “Wow, those look like mimosa. They look a lot like it. I wonder if they close.” And I touched them, and they didn’t close. But when I came back out to the parking lot later, they had all folded closed. I realized their folding response is just very slow—taking minutes, whereas Mimosa pudica folds in seconds. I took a video of it.

Dennis McKenna: Right.

Matt Metcalf: It is well-reported in the literature, but I thought we could use a local state plant rather than tropical plants like Mimosa pudica. Unfortunately, we just could not get them to grow indoors.

Dennis McKenna: But this raises the question: how widespread is this thigmonasty or depolarization response in the plant kingdom? Is it rare?

Matt Metcalf: In my opinion, it’s fairly common and widespread in the plant kingdom, even if not every plant does it. For example, there is a type of shamrock that folds its leaves closed at night and opens them during the day. Morphologically, Chamaecrista looks a bit like mimosa, which is how I noticed it. I bought some seed packets to study them, but I haven’t had enough time to grow them yet.

Dennis McKenna: Have you ever exposed the mimosa plants to volatile essential oils?

Matt Metcalf: I have not, but that’s a great idea to see if it elicits a response.

Dennis McKenna: Absolutely. Yeah.

Matt Metcalf: Let me explain the actual assay we do, because we don’t do this in the whole plant. Dr. Applewhite’s research involved removing the leaves. We started clipping off the petioles, which worked better, and we placed them immediately into water or a liquid growth solution called Shive solution. Shive solution is just a very dilute liquid fertilizer.

This video shows them opening back up at 16x speed. After about 20 minutes, the leaves open up and we incubate them. The petioles survive and maintain an intact folding response for about seven days before they fall apart, allowing us to do repeated testing. Different drugs will inhibit or delay this leaf-opening behavior.

Dennis McKenna: Right, right.

Matt Metcalf: Then we conduct the folding response test by stimulating them with a monofilament. When exposed to our drug test, they show either a delayed or completely inhibited ability to fold their leaves closed again.

Dennis McKenna: Okay. So, let me understand. So, what does GA stand for? Gibberellic acid?

Matt Metcalf: That’s right.

Dennis McKenna: Okay. And Shive is the growth solution.

Matt Metcalf: Okay. So, that’s just the growth.

Dennis McKenna: So, but indole and keto… those are the responses?

Matt Metcalf: One is a plant hormone and the other is one of the drugs we are testing.

Dennis McKenna: I see.

Matt Metcalf: And it mimics… one’s a plant hormone, which can probably be guessed, but the drugs we are testing mimic the response seen in the plant hormone, which agrees with the literature.

For the next step, we use calibrated monofilaments. These are typically used to test for diabetic neuropathy in patients’ feet by measuring the specific force in Newtons required to bend the filament. We are going to use a calibrated set of them to detect the exact force required to cause leaf closure. The growth solution should require the least amount of force, whereas the active drugs should require more force. This will allow us to start doing dose-response curves.

Dennis McKenna: So, you’ve surveyed a variety of compounds. How can you apply this to a generalized drug evaluation protocol? In mammalian or cellular systems, you have functional and receptor binding assays. When I was a postdoc, I did a lot of receptor binding assays where you could look at hundreds of different neurotransmitter systems. Are your assays translatable to a generalized screening system for drug discovery?

Matt Metcalf: Right now, I don’t think it’s adaptable for high-throughput screening. My goal is to target that third “R” of animal testing: replacement.

Reduction means using as few animals as possible (such as using the same animal for multiple pain tests). Refinement means making the animals more comfortable. Replacement completely swaps the animal assay for another.

I’m looking at established animal drug assays that don’t yield much new information but are still performed to show drug activity. Similar to David Macht correlating digitalis extract effects on seedlings to animal data, we want to show bioequivalence and dose-response curves through a selective mechanism. Showing that this assay is about 200 times cheaper and offers better statistics provides a strong incentive for replacement. It’s a proof of concept.

Dennis McKenna: Yeah, these are all at high concentrations.

Matt Metcalf: Yes, we haven’t done a dose-response curve yet, but that’s next.

Dennis McKenna: This is definitely a viable alternative to animal testing. You also mentioned a “pea assay.” Let’s talk about that one.

Matt Metcalf: When Leo and Megan graduated, nobody was available to pick it up, but I have a new student starting who will. I also want to look at the transmission of aromatic oils through the air, and change the incubation bath to specific compounds that plants produce.

Let me bring up this slide. I have a drug assay using pea seedlings that we are very close to publishing. I’ve spent a decade working on this. We run the assay by measuring the roots and shoots of the seedling initially, and then we measure them again after a few days to generate these dose-response curves.

We compared our data to a historical animal assay: the acetic acid anti-writhing assay in mice. This is a very non-specific pain assay—everything from opioids to Tylenol, ibuprofen, and even amphetamines shows activity in it. Because it’s a non-specific assay, it’s low-hanging fruit for us to replace with a cheaper, statistically superior plant model.

Another student, Ezra, did time-lapse photography of this to get a qualitative response, which worked well. Then we were asked if we could make it quantitative. Last year, some students used commercially available software to measure the plants digitally, but it required intensive manual effort. Now, we have developed a custom AI model that automatically measures all plant characteristics from every photograph over a seven-day time-lapse.

Dennis McKenna: Once again, AI comes to the rescue. This sounds like a highly useful and positive application of AI, so I’m all in favor of it. AI is a double-edged sword, but having it as a tool for this is amazing. Can you show us an example of this time-lapse?

Matt Metcalf: Yes. We sprout the peas in sphagnum moss. If you use a denser medium like potting soil or coconut fiber, the roots break off when you harvest them. We incubate them in test tubes.

Here is the time-lapse. The drugs are arranged by concentrations; the leftmost tubes have the highest drug concentration, decreasing as you move right, with the controls on the far right.

Dennis McKenna: mhm. And so this is what we take a look at.

Matt Metcalf: You can clearly see that the roots on the left are heavily affected by the drug. The tubes on the right labeled “L” are the controls.

Just like in mouse assays—where some mice don’t respond to morphine during a tail-flick test while others are highly sensitive—plants show individual variations. This variation is actually a strength because it represents a true living response.

Our AI model can separate the main root, lateral roots, pea seed, shoot, leaves, tendrils, and internode distance.

Dennis McKenna: And so basically, the variable you are measuring primarily in this assay is inhibition of root elongation? Am I being too simplistic?

Matt Metcalf: Nope. That’s exactly right. We are focused on the inhibition of primary root growth. When exposed to drugs, the roots make a distinct little hook that doesn’t occur in the controls.

There are also many secondary qualitative changes we’ve noticed that we hope the AI model can help us quantify. I hope to publish an initial draft on bioRxiv by June.

Dennis McKenna: This is marvelous work, Matt. We need better non-animal models, and if you can marry this with chemical libraries, you could develop incredibly powerful methods. Sooner or later, Stockholm is going to be calling you.

Matt Metcalf: I hope so.

Dennis McKenna: Because you’re doing very creative work. We are near the top of the hour, and you mentioned you had an aurora video and a crystallization video. Shall we close with those, or is there anything else we should cover first?

Matt Metcalf: Let me show you those videos. I think this research was fostered because I’m a bit of a heretic. I am at a primary teaching institution, so I’m not highly competitive for massive federal funding right now. That has allowed me to work on a shoestring budget and slow down. Whereas, as your brother used to say, you find the best stuff when you “take your eye off the ball.”

Dennis McKenna: Well, necessity is the mother of adventure. You are finding cheap, highly informative assays. If you had a massive budget, you wouldn’t be forced to be this creative. I imagine you work mostly with undergraduate students?

Matt Metcalf: Well, they are graduate students in our accelerated PharmD program.

One correction I’ll make: these plant assays are not fast. While an animal tail-flick assay takes a couple of hours, these plant assays take about two weeks from start to finish.

Regarding my passion for auroras, I shoot these from my porch. This one is from November 11th.

Dennis McKenna: And oh, wow.

Matt Metcalf: Those green lights are proton auroras, which are quite rare but were very widespread that night. You can even see some deer walking through my neighbor’s yard in the background.

This next video is a standard coffee cup. I put some saltwater in it, and because the glaze was cracked, the salt started crystallizing through the cup. I thought it was a cool time-lapse to capture.

Dennis McKenna: Well, that’s interesting. Yeah.

Matt Metcalf: It is obviously because the glaze is bad. And I just went to check it—I actually have this cup right here. And I knew it, but I ignored the voice in my head that told me to soak it in distilled water to prevent the salt from cracking the ceramic further, and unfortunately, it did ruin the cup.

Dennis McKenna: Right.

Matt Metcalf: But I just thought that was pretty interesting to take a look at. Some people are just like, “Oh, that’s nice,” and then they just walk on by. But I love looking at those little details that other people walk past. There’s one more I could show you.

Dennis McKenna: Sure. That is somewhat interesting.

Matt Metcalf: What you can do with time-lapse. Good stuff, you know.

Dennis McKenna: Okay.

Matt Metcalf: So, this is a sped-up video of a rainbow which is exhibiting what’s called “wagon wheel spokes” that I was able to capture back in June. This is sped up 16x. You can see the lines that go through it. They’re just the sunlight getting blocked out by clouds, and that creates that visual effect of like a ray that goes through it.

Dennis McKenna: Okay.

Matt Metcalf: So, just an atmospheric phenomenon that isn’t seen too often, but that’s just kind of the things that I look for these days. Did it play?

Dennis McKenna: We’re not seeing… Oh, it didn’t play. Oh, I’m so sorry. All right. Fascinating. I want to see.

Matt Metcalf: Okay. Yeah. Let me… Okay, there’s a rainbow, and it gets split up. It’s related to the phenomenon of crepuscular and anticrepuscular rays which are… if you look up in the sky, you see like sunbeams cascading down one side and then across to the other side of the horizon.

Dennis McKenna: Right. Right.

Matt Metcalf: And here these are called wagon wheel spokes. And that’s just clouds that are blocking the light, and that goes through the rainbow.

Dennis McKenna: Oh, what you can’t do with time-lapse photography. This is great. Yeah. Well, you’re doing very interesting work, Matt.

Matt Metcalf: Thank you.

Dennis McKenna: Um, you should look at the fungi.

Matt Metcalf: There might be other promising organisms you could adapt to this kind of work. You know, as soon as you said that, I wrote it down. David Macht looked at… he has one paper on slime molds. He didn’t explore that work too far. And I always thought it was odd that he didn’t explore opioids either, because he looked at cocaine and some other what are now controlled substances. But he didn’t publish anything on opioids.

Dennis McKenna: My guess is, since he was an opioid researcher, he looked and looked and he couldn’t find anything either, is my guess.

Matt Metcalf: Awesome. So, it’s got to be a more subtle system in plants. But you’re right, fungi would be the next step to look at, too. And that’s just putting the imagination on it. And slime molds would be great—their response times are quick, like plants.

Dennis McKenna: And, you know, could be good. Well, this is fascinating work. I guess we’ve covered most of what you wanted to talk about.

Matt Metcalf: So, I think so. I’d like to leave it with a quote from David Macht. It struck me when I was reading his papers, and I felt like maybe it’s why… one of the reasons why I felt so compelled to do this and I’m so obsessed with it now. He would always write this similar quote at the end of his talks. And back then, self-plagiarism was not as controlled as it is today—you can find a couple of papers that are word-for-word copies of each other, but he had said: “The work is not upon thee to finish, nor art thou free to desist from it.” And he’s citing a book called Ethics of the Fathers Part Two that was written in 16 CE. So, I kind of feel like I got to keep going on this and see if we can get it at least prominent enough that other people say, “Oh, I could be doing that, too,” and pick up the mantle as well.

Dennis McKenna: Yes. Well, it seems like the method you develop could be easily adapted, and you don’t have to be… it’s not rocket science, and that’s sort of the point. Anyone can do it. It needs patience and time and a whole team of enthusiastic graduate students and AI, and you can get stuff done here. So, thank you for sharing all that with us, Matt. I really appreciate it. I know our listeners are going to be fascinated by this, and I’ll get these up and have you come back sometime when you make your next breakthrough.

Matt Metcalf: Yeah, let me… I’ll come tell you what, if you’ll have me, I’ll come back and I’ll lay the whole thing out for you once we get the draft of the paper up, and hopefully, knock on wood, that’s June or July.

Dennis McKenna: Absolutely. We’re happy to catch up. Keep us posted, and keep doing what you’re doing. You’re doing very interesting work. I’m a little bit jealous that I don’t have the academic resources to do it, but I was never a very good scientist anyway. I was better talking about it than doing it. So, you’re doing it.

Matt Metcalf: I think you did great work. I mean, I wouldn’t be where I am without you. And I’m so grateful for knowing you and you letting me teach a couple of lectures in your classes. I’m sure that helped me get my current job. And I appreciate your offer to do that.

Dennis McKenna: Oh, yeah. I gratefully accept. Our education people will be in touch with you about this. We definitely want a course or two, and an introduction at least to medicinal chemistry.

Matt Metcalf: So, I’m glad. I thank you for your offer, and we will definitely follow up because we’re trying to expand our educational offerings, and this is stuff that people are interested in, you know.

Dennis McKenna: So, yeah, I just want to know your format, and then I can turn those out pretty quickly.

Matt Metcalf: Yeah, we’ll talk. I’ll put you in touch with our course designer, and it’s real easy, you know, and he helps people develop the courses. And he uses AI, I have to admit, to take material. But so far, I’ll send you a link to our ethnobotany courses, and you can see what we are doing. But thank you so much. Have a wonderful day and weekend, and we’ll be in touch.

Dennis McKenna: Links, you know, when this comes on, which will be probably a couple of months anyway, unless you want it to drop sooner. We have a lot of things in the queue, you know, but this has been wonderful. I’ve learned a lot. So, thank you.

Matt Metcalf: Yeah, thank you, too, Dennis. Can I do one more thing? I’m sorry you wrapped everything up. I just want to say thank you to my current students.

Dennis McKenna: Sure. Of course.

Matt Metcalf: Loey, Nate, Emily, Jackson, Sophia, Joe, Afnon, and Sarilli. I hope I didn’t forget anybody—I don’t think I did. I think that’s the current group. But thank you very much, guys. Wouldn’t be here without you.

Dennis McKenna: And, absolutely. Every professor needs good graduate students, and it’s a mutual symbiosis. So that’s great. Wish them all my best, and they can watch the podcast. So we’ll be in touch, Matt. Thanks again.

Matt Metcalf: Definitely. Yeah. Thanks again, Dennis. My pleasure and honor to be here.