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Your weekly dose of drug facts while dispelling fiction
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You're listening to locally produced programming created in KUNV Studios on public radio. KUNV 91.5. Welcome to another episode of The Chemical Collective.
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The Chemical Collective offers a weekly dose of drug facts while dispelling fiction. Today we'll be diving into the mysterious world of Mandrake and discussing its active compound effect on the brain and its role throughout history.
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I don't know very much about Mandrake until this episode.
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So where did it come from and when did humans start consuming it? Yeah, it's actually a really interesting background. Mandrake is a plant with a rich history of use in various cultures around the world, from its medicinal and mystical properties. The plant is known by a variety of names such as mandrake root, mandragora, alron, love apple, or cape mandrake. I'm going to be referring to it as mandrake to indicate the entirety of the plant and not just the root. But the plant belongs to the nightshade family and it's commonly thought to be native to the Mediterranean region. However, its use can be traced back to ancient times with references to its use in various cultures, including the Greeks, Romans, Egyptians, as well as African tribes. In ancient Greece, Mandrake was believed to have the power to cure diseases and was associated with the goddess Aphrodite in South Africa. Mandrake was used in various rituals and it was believed to have magical powers that could aid in things like fertility. And mandrake has also been used in traditional medicine in the Middle East where it was believed to have analgesic properties and was used to treat things like pain and inflammation. The use of mandrake for its psychoactive effects, however, is thought to have emerged much later, more so in the Middle Ages. But mandrake overall was believed to have powers to induce like visions and altered states of consciousness.
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Very cool. And to those nightshades, they're kind of a really interesting group of plants too. For a long time, they were all thought about as like drugs and poisons. But do you guys know what a common nightshade that we all take part in now? Tomatoes, peppers, eggplants. These are all part of that nightshade family. So for a while people believed if you ate tomatoes you would turn into a wolf and possibly because they were part of this family.
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And so related to this, if there's different beliefs about what different strains can produce, could you tell me more about different variations of mandrake? Yeah, like anything in a big family,
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there's many different subsets, and we call these different subsets species or varietals. And so they vary not only in their Latin or Greek name, but also kind of how they look. The most common is the Mandagorio fissionarum, which is a nice way of saying mandrake. And within this, there's several subspecies that differ in their morphology, the chemical composition, the number of, you know, alkaloids that are kind of important for what we're talking about in the show today, and then obviously also the geographic distribution, so where they grow naturally. In addition to this, most of these different subspecies that exist have other attributes such as the plant, the leaf, et cetera. Some that vary widely from this are the Mandagoria, Terracura, I can't say that word, Terracorum anaca and Mandagoria colinescens, which are found in different parts of the world, more so Asia, Iran, and Turkey.
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And so we've talked about nightshade and tomato too. Are there other plants that have been used for similar purposes as mandrake? Just to wrap my mind around what mandrake is.
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No, it's a great question. There are actually several plants that have been used for either the similar purpose of mandrake or are similar in the overall appearance. There's something called Mayapple, also referred to as Potophyllium peltatum. There's Velodona, as well as Datura. But specifically, the Mayapple is more so known as the American mandrake due to it being native to North America. It was traditionally used by indigenous peoples for a variety of medicinal purposes. Specifically, the root and fruit of the May apple contain a toxic compound called photophthalatoxin, which is used to make drugs for like cancer, as well as other conditions. And then the belladonna, this plant is commonly known for being a part of that nightshade that Dr. Hines was just talking about, but being more so native to Europe, North Africa, as well as Western Asia. And then, Datura, it's largely known for its psychoactive properties. And like Mandrake, as well as Beladonin, Datura contains the alkaloids that can cause hallucinogens and delirium. But it's been traditionally used as medicine and throughout spiritual practices in many
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parts of the world.
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And spoiler alert, I can easily see whole episodes on both Belladonna and Datorra. They're fascinating, fascinating plants.
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If mandrake is being used in different contexts, how is it prepared? Do they prepare the whole plant, parts of the plant?
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Well, the first thing to know is don't prepare it, don't use it. This is an extremely dangerous plant if prepared incorrectly, and there's a high chance that you will prepare it incorrectly. So it's a terrible idea. So there has been deaths because of just improper handling from this plant. The preparation is typical of the nightshades. The plant is typically either harvested initially, clean, dried and then if it does have fruit, it's dried out further, boiled, and then made into a powder or a tincture. So in essence, you're concentrating that alkaloid. In some cultures, mandrake root is believed to also have mystical properties. I don't know how much we're going to get into Harry Potter and all the ideas related to mandrake. But these rituals typically include singing and dancing and all kinds of incantations. Overall, though, because it's so toxic, the preparation of this should only be done by trained professionals, which is my way of saying no one. And it's something that should be attempted, should not be attempted at home by people without proper intent or
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guidance.
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It seems like the culture surrounding mandrake use is really important for the properties that are being received from it. So how has the culture surrounding Mandrake changed over time?
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Yeah, Mandrake over time has been reflected throughout changes in cultural beliefs surrounding it, medicinal knowledge, as well as societal attitudes towards it. In ancient times, Mandrake was often associated with things like pagan rituals and believed to have the power to cure a wide range of ailments from infertility, as we mentioned, as well as all the way to things like demonic possession. During the Middle Evil period, mandrake was considered a potent remedy and its roots specifically were often used in medical treatments. However, it was also associated with things like dark magic and was often used to curse or do spells if you will. And then by the modern era, the use of mandrake shifted more towards medicinal application with some traditional medical systems continuing to use the plant for its supposed therapeutic properties. However, as our understanding of medicine and toxicology has advanced, we know that the mandrake is highly toxic as a plant and may cause the mandrake to be more so controversial because of this. And some medical professionals are warning against it due to it being very high in toxicity. But today the use of Mandrake is mostly limited to traditional or alternative medicines as well as some magical practices that take place in the
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wizarding world. Which is not real. So don't do it. But yes. I actually wonder that. I wonder if because of the popularity of those books in Mandrake, if there's some people that unfortunately stumbled onto it. I actually don't know the answer to that. I hope not.
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And because a big part of this show is kind of teasing apart fact from fiction, is there any evidence of actual traditional customs or ceremonies associated with Mandrake?
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Yeah, and Mandrake has absolutely been associated with many different customs and ceremonies. And like most deliriums, which this fits into the category of, it's kind of a purgative. So these are things that you're going to cleanse yourself or prepare yourself for some big journey. So as mentioned, in pagan ritual, it's believed to be these properties that the person that takes it gets instilled upon them. And so in ancient times, it believed if you took the root while it was screaming, it would give you all these different powers that the plant had. And mandrake is often used then in fertility rituals. It's believed that carrying a piece of the root could help a woman conceive because the root had this magic to grow anywhere and it would give the woman that ability to somehow magically grow a baby. love potion or cause someone to harm one's enemies, which is kind of amazing, right? You could poison somebody and then they would love you. In some traditional medical systems such as, you know, the Indian Ayurveda and traditional Chinese medicine, it's still used and supposedly has therapeutic uses. In these cases, the preparation is very, very careful and involves rituals and customs such as incantation, reciting repairs. However, it's not really used that much anymore again because it's really hard to get that dose just correctly.
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Because of the difficulty of figuring out the correct dose of Mandrake, can you tell me more about how Mandrake works in the brain and what receptors are involved in its effects?
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Sure thing. Mandrake contains various biological active compounds including alkaloids, such as hyacinamine, scopamine, as well as atropine. These compounds have psychoactive effects on the central nervous system and can cause a range of psychological as well as physiological effects. When ingested or inhaled, the alkaloids and mandrake can bind to specific receptors in the brain, known as muscarinic acetylcholine receptors. These receptors are part of the cholinergic system, which play an important role in regulating various bodily functions like muscle movement, heart rate, and cognitive processes. But the alkaloids in mandrake can also bind to other receptors that I hope we get to get into a little bit more later if you're interested. But the exact mechanism of action of mandrake in the brain is complex and not fully understood. However, it is known that alkaloids and mandrake can interfere with the normal functioning of the cholinergic
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system.
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All right. So, alkaloids have been brought up in multiple episodes, and I think they're fascinating. So, how do the alkaloids and mandrake bind to these muscarinic acetylcholine
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receptors?
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Yeah. So, let's back up. So, when we say alkaloids, I don't know, we have the benefit of living in a desert. Have you ever been out in the desert and you see one of those dry lake beds and there's that white crusty stuff all over the place? Those are basically alkaloids. Okay, so they're just salts and minerals that plants take up and then kind of make into little packages, kind of like we do proteins. And so most of what is happening in the mandrake is that you're making these alkaloids that then bind or interact with the muscarinic acetylcholine receptors. These receptors kind of have five different flavors. We call the flavors the subtypes. And in neuroscience, sometimes these are really ugly, but here it's nice. They're M1 through 5. And they're all, what we keep talking about, the two flavors of receptors, inotropic and metabotropic. These are all G-protein coupled metabotropic receptors. So that means as soon as the alkaloid binds to the M1 through 5 receptors, some little cascade inside the cell starts happening and releases all kinds of other molecules of which, you know, acetylcholine or acetate and choline can come together to make things happen. Scopolamine is one of the major ways in which this plant exhibits its effects in the brain and this is largely by blocking the M1 and M2 muscarinic acetic choline receptors which are primarily found pretty much everywhere in the brain, truthfully, but in the cortex, the outer part of your brain, that's really for thought processing, attention, planning, and sequencing, and then also very exclusively in the part of your brain that's highly involved in memory called the hippocampus. So, and we've talked about this in the past. There's kind of two ways to affect a receptor. You can make a receptor go up, you can make a receptor go down. If we're making a receptor kind of work the way it should, we call that an agonist. And if we block a receptor, we call it an antagonist. And there's another kind of weird group that's a competitive antagonist. of these, they're going to work as antagonists at the M1 and M2. That's mostly for scopolamine, which is the major constituent of these plants. And then atropine is really an antagonist at the M3.
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The alkaloids in Mandrake are antagonizing acetylcholine receptors to make those deliriant properties. So I know about hallucinations and hallucinogenic drugs. How, what is a deliriant and how is that different?
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Deliriants are fascinating. Deliriants and hallucinogens are two categories of psychoactive substances that can cause altered states in consciousness, but they have some important differences in terms of their effects and mechanisms of action. Delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, delirium, or frightening and unpleasant, and they can be difficult to control or distinguish from reality. In contrast, hallucinogens, such as LSD, psilocybin, or mescaline, can produce vivid alterations in sensory perception, mood, and thought. They typically cause visual as well as auditory hallucinations, changes in time perception, and altered states of consciousness. Hallucinogens typically act on serotonin receptors in the brain and can have long-lasting effects on mood and perception even after the drug has worn off.
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Yeah, and you know, I think about dreams for everything because really hallucination is just a waking dream. Have you ever had like the flu or a fever and then you have all these random feverish dreams that don't make sense and they upset you all night long? That's a deliriant. And then if you have this, you know, possibly dream where you're Superman or woman and you're flying and all things are amazing, that's kind of more like a hallucination. Now that doesn't mean you can't have bad hallucinations, but that's kind of the big difference. I can't think of anyone knowingly, soundly taking a deliriant. It's not headed for a good place ever. You might want a curative aspect of that, but that's not guaranteed.
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And so do each of these alkaloids in Mandrake have different or unique effects on the brain?
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Yeah, absolutely. The alkaloids that are found in Mandrake have very different effects on the brain because they're different chemicals, frankly. So the main alkaloid in Mandrake is hyoskemene, scopolamine, and atramine. That hyoskemene is really the anticholinergic, and it's what blocks that neurotransmitter in the brain. It can cause all kinds of effects, mostly sedation, amnesia, dizziness, blurred vision, and hallucinations. Also, scopolamine, the other one, is an anticholinergic also, and the effects of scopolamine in medicine are used really as a preparative medication to reduce anxiety and to prevent nausea and vomiting. So, I'm not sure of any medical use of hyoskemine, but scopolamine is used a lot in the lab, actually quite a bit. Atropine is another one that we use a lot, especially the salt of it, atropine sulfate, and it's competitive antagonist of the muscarinic receptors, and it's used for a whole bunch of things. One of the big things it's used for, that I've even used it for, is seasickness or travel motion sickness. It's also used for cardiovascular and respiratory systems, so if somebody has a lot of asthma, we can give them atropine, and it can kind of dry out their lungs. And similarly, when you're going to undergo surgery or have anesthesia, you don't want, when you're on the respirator, to have all that fluid building up, so we'll typically give somebody a lot of atropine.
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Okay, so mandrake is definitely not the type of plant to just uproot and use, that much is clear. Is there any evidence of an approved dose of mandrake or anything coming from mandrake?
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Yeah, no, there's not much evidence on the dosage of mandrake. Doses can vary depending on the number of factors including like potency of the plant, method of consumption, and individual factors that we always talk about. But it's important to note that mandrake is again potent and potentially dangerous substance, so even ingesting a small amount of mandrake can lead to
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serious side effects. And this question is really good here with the delirium, it's kind of like lighting a fire. How much match do you need to light the fire? You're just really waiting for it to take, which to me seems like a terrible idea. Okay, yeah, now I'm delirious. That was probably enough.
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Because of these effects, I'm going to guess that Mandrake affects other neurotransmitter systems in the brain. Do we know about any of these?
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Yeah, Mandrake has a lot of polypharma, like many of these things that hit multiple systems. So, we've mostly been talking about a neurotransmitter system called acetylcholine. So, we talk about the muscarinic acetylcholine receptors, that's what we're talking about. But there's also going to be a lot of dopamine and serotonin release. So, scopolapine is one of those main alkaloids that we talked about. And it's been shown to increase dopamine in very certain areas such as the nucleus accumbens and the prefrontal cortex. These are kind of all your planning and thinking areas. So you can imagine now you have these areas that are supposed to have some sort of linear plan or pathway, we release all of the dopamine, you can jump all over the place. That's kind of part of the effects of the delirium. Atropine, the other main alkaloid found is shown to interact with serotonin receptors, which may contribute to these psychoactive effects. And years ago, I had a big interest in how atropine and serotonin interact. And I can tell you, there's not a lot of information. We really don't understand serotonin that well.
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And so we've been talking about the effect of delirium. And it seems like a characteristic of that is possibly losing time. And you mentioned that these cholinergic receptors are expressed in the hippocampus, which is responsible for learning and memory. Does Mandrake have an effect on memory consolidation then?
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Yeah, there's actually some evidence to suggest that Mandrake may have an effect on how memories are stabilized and stored in the brain. Specifically scopolamine has been shown to impair things like memory consolidation and specifically disrupt the consolidation of new memories into long-term memory storage while leaving cognitive functions relatively intact.
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Well, outside of the brain, what are the effects of Mandrake in the body?
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This is gonna be a place where you can see this is not something you'd probably take. So if we look at the anticholinergics, these are things that are used to dry out your mouth. They also cause this blurred vision and they also cause massive constipation. So dry mouth, you know, it's gonna be obviously your mouth and all your mucosal membranes, then blurred vision, your visual system, and then constipation, your gut. Cardiovascular, massive increases in heart rate and blood pressure. Back to the lungs, again, we're going to dry out those lungs mostly because we're going to depress respiration. And then we already kind of mentioned the GI system, but you know, in light of constipation, you can also have nausea, vomiting, all kinds of abdominal pain. That does not seem like something that you should do. Yeah. Okay. And so if Mandrake also affects
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dopaminergic signaling in the brain, is Mandrake considered addictive? Mandrake has the potential to be addictive, particularly due to the psychoactive effects of its alkaloids, as they can produce feelings of euphoria and altered perception, which can lead to repeated use and potential addiction. However, Mandrake is not considered to be a commonly abused substance due to its potency and potential for serious effects.
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And does mandrake cause any symptoms of withdrawal then?
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Well, back to kind of exactly what Kendra was saying, April, is it's not likely you're going to take mandrake and get that dried mouth, terrible experience, heart rate, constipation, and say, I'm going to do that again tomorrow. So there's really limited research on the withdrawal effects of mandrake, but again, it's likely due to that potency and limited use in modern medicine. It's possible, though, if you look at those receptors, again, they're G-protein couple receptors, so if you use mandrake often, it could lead to dependence where you're not making enough of the acetylcholine because the receptor starts to internalize, I would suspect, but it doesn't seem to be something that is a worry because nobody's going to
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be taking mandrake every day. Definitely not. And so we talked about delirium, hallucinations, and dreaming. Is there any evidence that Mandrake interferes with
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your sleep? Yeah, it's kind of hairy. I think that they're the effects of it that are on the side, the things that Dr. Hines mentioned, the dry mouth, that things like that might lead you to wake up more frequently throughout the night maybe or mandrake causing you to sweat, making you discomfortable.
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Those kind of things can interfere with staying asleep. And it doesn't seem like mandrake has very many therapeutic effects, at least from what we've talked about. Is there any evidence that it can play a role though in an anxiety and depression?
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Yeah, I think if you could get some of the compounds in the right level, in the right plant, then you might have a potential treatment for anxiety. However, I doubt it. There's no research on that and again, anxiety and depression are very different disorders and I can't see any way of taking Mandrake for mental health without way kind of the physical detriments that you get to your body. This is, I'm not against plants, I'm very pro plants, but this is one plant that you again would want to synthesize what you needed out of it and kind of leave the bad things behind.
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Hmm, and so is it possible to overdose on mandrake?
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Yeah, it's possible to overdose. It can lead you to those potentially life-threatening side effects upon use and produce a range of effects that go from anywhere from confusion to seizures and respiratory dysfunction and depression, but it's definitely possible, specifically the alkaloids that we talked about can lead to anticholinergic syndrome.
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All right, and we've definitely touched on the health risk in using a mandrake, but what are probably major long-term problems?
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Well, long-term problems are that you would die, which is a pretty serious problem. You know, you're going to, all those organs that we talked about, your vision, your mouth, your heart, your gut, you know, multiple use of these are going to definitely start to become toxic on each of those systems. So you're going to have system shutdown and all kinds of other things. Again, I don't think it's going to be a problem because nobody's going to take this drug long term. But, you know, I think the big risk is that acute high bolus that can do anything from long-term damage to death.
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And so I imagine now that Mandrake is scheduled, in the US at least, what's the status on that?
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Mandrake is actually not listed as a scheduled substance under the United Nations Convention of Psychotropic Substances, or the Single Convention on Narcotic Drugs. However, the legality of Mandrake in the US can vary depending on the state and the intended use of the plant specifically. So mandrake isn't a controlled substance under federal law in the U.S. However, it's considered a poisonous plant and is regulated under state drug laws in some areas. So, for example, in California, Louisiana, and Tennessee, it is illegal to sell, possess, or cultivate mandrake without a permit.
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So there's no regulation at all in the U.S.?
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Yeah, so that's the interesting thing. I mean, when we look at the drugs in the U.S., I think we're trying to do our best, but sometimes I think we fall short. So, you know, scheduling of pretty serious things like alcohol and tobacco, none. Something that is absolutely deadly, do what you want, right? So, as Kendra said, there is no scheduling, but at the federal level. But, you know, places like Tennessee, California, Louisiana, and I don't know this, but I would suspect those are places that geographically it seems to
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more. Okay. Is there any regulation in other countries? Yeah, it varies by country. For example, in Europe, it's classified as a medicinal plant. Australia, as a schedule for substance under the poisonous standard. And then in places like Canada and Japan, it's not regulated as a controlled substance. Okay, I think we have time for one student Q&A question. We received two of them and I think this second one is the best. Is mandrake root similar to absinthe? No. So mandrake root and absinthe have been associated with psychoactive effects. Do you know what absinthe is?
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It's in distilled alcohol, no? But it comes from... It is a distilled alcohol, yeah. And who was famous for absinthe? Vincent van Gogh. So a lot of people say that he cut off his ear because he was tripping on absinthe and Absinthe is a distilled alcohol But what they do is they take wormwood and wormwood is this toxic thing? It's a delirium much like we have here and so the alcohol pulls the delirium out of the wormwood and makes all kinds Of crazy visions and can you imagine if your visions were all scattered and a delirium it might look like stormy night. So it kind of gives you insight into, but anyways, that's what absinthe is.
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Thank you. So it looks like we've reached time for today. Thank you all for the great discussion. And those listening for coming to the Chemical Collective
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to get your weekly dose of drug facts while dispelling fiction. to get your weekly dose of drug facts while dispelling fiction.
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I'm out.