Natural Benzodiazepines?

I've noted below, some articles which indicate some benzodiazepines (diazepam and desmethyldiazepam, and others) occur in nature .. in plants like the potato and mammalian brains.

Has this topic been discussed before on bb? & Has anyone ever suffered from Naturally Occurring Benzo (NOB) Dependence &/or Withdrawal/Cessation from Naturally Occurring Benzos, like from potatoes?

https://www.biopsychiatry.com/natural-benzos.htm

"Detection of desmethyldiazepam and diazepam in brain of different species and plants"

by

Unseld E, Krishna DR, Fischer C, Klotz U.

Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie,

Stuttgart, Federal Republic of Germany.

Biochem Pharmacol. 1989 Aug 1;38(15):2473-8.

ABSTRACT

Recent data suggest that desmethyldiazepam (DD), a major metabolite of several benzodiazepines (BZD), might be of natural origin. Therefore we tried to quantify DD and diazepam (D) in animals during maturation (e.g. hen, chicken, eggs), in brain of species at different evolutionary stages e.g. salmon, frog, monitor/reptile, rat, cat, dog, deer, bovine) including newborn and adult humans. Since low concentrations of DD (range 0.01-0.04 ng/g wet wt) and D (range 0.005-0.02 ng/g) could be measured in different species by sensitive and specific mass spectrometry (GC-MS), we analysed also several plants (e.g. maize corn, lentils, potatoes, soybeans, rice, mushrooms). Again, DD and D could be detected in low amounts (0.005-0.05 ng/g) in some plant products. This would suggest that DD and D might be of natural origin and incorporated via the foodchain into the animal and human body. The biological role or clinical relevance of these intriguing findings need still to be elucidated."

https://www.ncbi.nlm.nih.gov/pubmed/2849941

"Increase of natural benzodiazepines in wheat and potato during germination."

"Abstract

Aqueous acid extracts of wheat grains and potato exhibit after HPLC separation a series of compounds that are able to inhibit the binding of benzodiazepines to benzodiazepine receptors of rat brain membranes. In wheat one of the inhibiting compounds was shown to be identical to diazepam by means of HPLC characterization and gas chromatography combined with mass spectrometry. In potato one of the most prominent components in terms of binding inhibiting activity was identified as lormetazepam. In wheat and potato germination increases total inhibiting activity of the whole plant extracts as well as the content of the benzodiazepines approximately by factor five. Because uptake of benzodiazepines from the surrounding was excluded these findings indicate the biosynthesis of the benzodiazepines diazepam and lormetazepam by the plants investigated."

https://med.stanford.edu/news/all-news/2013/05/brain-makes-its-own-version-of-valium-scientists-discover.html

"Brain makes its own version of Valium, scientists discover"

Researchers at the Stanford University School of Medicine have found that a naturally occurring protein secreted only in discrete areas of the mammalian brain may act as a Valium-like brake on certain types of epileptic seizures.

The protein is known as diazepam binding inhibitor, or DBI. It calms the rhythms of a key brain circuit and so could prove valuable in developing novel, less side-effect-prone therapies not only for epilepsy but possibly for anxiety and sleep disorders, too. The researchers’ discoveries were published May 30 in Neuron.

“This is one of the most exciting findings we have had in many years,” said John Huguenard, PhD, professor of neurology and neurological sciences and the study’s senior author. “Our results show for the first time that a nucleus deep in the middle of the brain generates a small protein product, or peptide, that acts just like benzodiazepines.” This drug class includes not only the anti-anxiety compound Valium (generic name diazepam), first marketed in 1965, but its predecessor Librium, discovered in 1955, and the more recently developed sleep aid Halcyon.

Valium, which is notoriously addictive, prone to abuse and dangerous at high doses, was an early drug treatment for epilepsy, but it has fallen out of use for this purpose because its efficacy quickly wears off and because newer, better anti-epileptic drugs have come along.

For decades, DBI has also been known to researchers under a different name: ACBP. In fact, it is found in every cell of the body, where it is an intracellular transporter of a metabolite called acyl-CoA. “But in a very specific and very important brain circuit that we’ve been studying for many years, DBI not only leaves the cells that made it but is — or undergoes further processing to become — a natural anti-epileptic compound,” Huguenard said. “In this circuit, DBI or one of its peptide fragments acts just like Valium biochemically and produces the same neurological effect.”

Other endogenous (internally produced) substances have been shown to cause effects similar to psychoactive drugs. In 1974, endogenous proteins called endorphins, with biochemical activity and painkilling properties similar to that of opiates, were isolated. A more recently identified set of substances, the endocannabinoids, mimic the memory-, appetite- and analgesia-regulating actions of the psychoactive components of cannabis, or marijuana.

DBI binds to receptors that sit on nerve-cell surfaces and are responsive to a tiny but important chemical messenger, or neurotransmitter, called GABA. The roughly one-fifth of all nerve cells in the brain that are inhibitory mainly do their job by secreting GABA, which binds to receptors on nearby nerve cells, rendering those cells temporarily unable to fire any electrical signals of their own.

Benzodiazepine drugs enhance GABA-induced inhibition by binding to a different site on GABA receptors from the one GABA binds to. That changes the receptor’s shape, making it hyper-responsive to GABA. These receptors come in many different types and subtypes, not all of which are responsive to benzodiazepines. DBI binds to the same spot to which benzodiazepines bind on benzodiazepine-responsive GABA receptors. But until now, exactly what this means has remained unclear.

Huguenard, along with postdoctoral scholar and lead author Catherine Christian, PhD, and several Stanford colleagues zeroed in on DBI’s function in the thalamus, a deep-brain structure that serves as a relay station for sensory information, and which previous studies in the Huguenard lab have implicated on the initiation of seizures. The researchers used single-nerve-cell-recording techniques to show that within a GABA-secreting nerve-cell cluster called the thalamic reticular nucleus, DBI has the same inhibition-boosting effect on benzodiazepine-responsive GABA receptors as do benzodiazepines. Using bioengineered mice in which those receptors’ benzodiazepine-binding site was defective, they showed that DBI lost its effect, which Huguenard and Christian suggested makes these mice seizure-prone.

In another seizure-prone mouse strain in which that site is intact but the gene for DBI is missing, the scientists saw diminished inhibitory activity on the part of benzodiazepine-responsive GABA receptors. Re-introducing the DBI gene to the brains of these mice via a sophisticated laboratory technique restored the strength of the GABA-induced inhibition. In normal mice, a compound known to block the benzodiazepine-binding site weakened these same receptors’ inhibitory activity in the thalamic reticular nucleus, even in the absence of any administered benzodiazepines. This suggested that some naturally occurring benzodiazepine-like substance was being displaced from the benzodiazepine-binding site by the drug. In DBI-gene-lacking mice, the blocking agent had no effect at all.

Huguenard, Christian and their colleagues also showed that DBI has the same inhibition-enhancing effect on nerve cells in an adjacent thalamic region — but also that, importantly, no DBI is naturally generated in or near this region; in the corticothalamic circuit, at least, DBI appears to be released only in the thalamic reticular nucleus. So, the actions of DBI on GABA receptors appear to be tightly controlled to occur only in specific brain areas.

Huguenard doesn’t know yet whether it is DBI per se, or one of its peptide fragments (and if so which one), that is exerting the active inhibitory role. But, he said, by finding out exactly which cells are releasing DBI under what biochemical circumstances, it may someday be possible to develop agents that could jump-start and boost its activity in epileptic patients at the very onset of seizures, effectively nipping them in the bud.

The study received funding from the National Institute of Neurological Disorders and Stroke (grants NS034774, NS006477 and T32NS007280), the Epilepsy Foundation and a Katharine McCormick Advanced Postdoctoral Fellowship at the School of Medicine. Other Stanford co-authors were postdoctoral scholar Susanne Pangratz-Fuehrer, DVM; neurology resident Rebecca Holt; and research assistants Anne Herbert, MD, Kathy Peng and Kyla Sherwood.

Information about Stanford’s Department of Neurology and Neurological Sciences, which also supported the work, is available at http://neurology.stanford.edu."

https://www.semanticscholar.org/paper/Occurrence-of-pharmacologically-active-in-trace-in-Wildmann-Vetter/1bd489b880f47d5b09888bcda14f59a8d5be64dc

"Occurrence of pharmacologically active benzodiazepines in trace amounts in wheat and potato."

Published in Biochemical pharmacology 1988

DOI:10.1016/0006-2952(88)90384-X

Aqueous acid extracts of wheat grains and of potato tuber were found to contain a series of compounds displaying a high affinity to the central type benzodiazepine receptor (BZR) in mammalian brain. Further analysis using different HPLC systems, as well as mass spectrometry and gas chromatography combined with mass spectrometry lead to the identification of compounds belonging to the classical 5-phenyl-1,4-benzodiazepinones. In wheat grains diazepam, N-desmethyldiazepam, delorazepam, deschloro-diazepam, delormetazepam, lormetazepam and isodiazepam were identified, while potato tuber contained diazepam, N-desmethyldiazepam, delorazepam, lorazepam and delormetazepam. The concentration of the benzodiazepines (BZ) was in the low ppb range. Their biosynthesis most probably takes place in the plant tissue. The availability of BZs in plant nutritives points to a possible source for the previously reported presence of BZ in brain and peripheral tissues of several animal species and man.

I read the historical account on how benzodiazepines were invented (source: https://www.amazon.com/dp/B001P2NI38/ref=dp-kindle-redirect?_encoding=UTF8&btkr=1), and it appears that benzodiazepines are a class of chemicals that is chemically unrelated to anything previously out there, whether in nature, or in existence as a medication/drug.

From the book:

Deferring to his father’s wishes, Sternbach studied pharmacology at the University of Krakow in Poland. His school grades had been mediocre, but because the program gave preferential status to the children of pharmacists, he landed one of the program’s thirty coveted spots. He earned his degree in 1929 and stayed on as a doctoral student in organic chemistry, studying dyes and synthesizing several substances known as benzheptoxdiazines, which would be critical to his later work on benzodiazepines. After receiving his Ph.D. in 1931, he continued to work as a research assistant and lecturer.

 

Tone, Andrea. The Age of Anxiety (p. 121). Basic Books. Kindle Edition.

Sternbach’s first breakthrough was the synthesis of B7 (biotin), a vitamin that breaks down fatty acids and carbohydrates. Even today, it is a staple ingredient of multivitamins. Along with benzodiazepines, it’s the achievement Sternbach valued most. In the mid-1950s, as profits for synthesized vitamins declined in the wake of patent expirations and increased competition, Roche gave its chemists a new imperative: develop a drug that will outsell Miltown and Thorazine, now the bestselling major tranquilizer. The new tranquilizers, particularly Miltown, were the envy of the ethical pharmaceutical trade: every company wanted in on that market. It was, in the words of one journalist, the time of the “Great Tranquilizer War.” Sternbach remembered the corporate ambience of those years as one of great uncertainty and high expectation. “We chemists were asked to submit proposals for the synthesis of tranquilizers which we then could follow up,” he recalled. “So I submitted something.” The proposal seemed sufficiently promising to the research director, who reassigned Sternbach to Roche’s tranquilizer team.14 Ensconced in his Nutley laboratory, Sternbach considered how best to formulate a compound that would satisfy Roche’s management. A medicinal chemist has several options for creating new compounds. One is to synthesize natural medicinal products. Roche had already done this with vitamins, and other companies were beginning to do this with hormones. Another approach is molecular modification, sometimes disparagingly called molecular manipulation. It is this chemical tinkering that underlies the phenomenon of “me-too” drugs with a similar therapeutic and chemical profile to those already available. Today they represent an astounding 77 percent of new prescription drugs on the American market. Zeroing in on a profitable therapeutic, chemists tweak its molecular structure to create a drug that is not particularly innovative but new enough to secure patent protection and thus higher prices. Pharmaceutical firms often time the launch of me-too drugs to coincide with the end of the patent life of a blockbuster medication. For example, when the patent protection on the popular allergy pill Claritin was scheduled to expire in 2002, Schering-Plough refigured Claritin’s active metabolite and patented the new compound as Clarinex. The new drug hit the pharmacy shelves just as Claritin was poised to go generic. In these cases and others, company chemists create me-too drugs hoping to extend a blockbuster’s profits.15 More often, as physician and writer Marcia Angell notes, chemists are asked to modify the structure of other companies’ drugs to capture a piece of a competitor’s market. Sternbach could have pursued this strategy, creating me-too drugs modeled after Smith Kline & French’s Thorazine or Carter’s Miltown. In fact, his superiors had asked him to pursue just this tack, which they saw as the quickest road to success. Beginning with Miltown’s chemical family, the meprobamates, he could “change the molecules a little. Make them different enough to avoid violating Wallace’s patent, but similar enough to produce a tranquilizer.” Sternbach balked. Molecular modification struck him as superlatively boring, and he assumed researchers in other companies would be doing the same. Sternbach wanted to be different. The management’s suggestion “did not appear to be very promising,” he remembered. “If you work with modifications of old drugs,” he once contended with gentle disdain, “you can only find drugs which are similar to those.”16

 

Tone, Andrea. The Age of Anxiety (pp. 123-125). Basic Books. Kindle Edition.

Sternbach revisited the benzheptoxdiazines, compounds he had worked with as a postdoctoral assistant at the University of Krakow in the early 1930s. At the time, he had hoped to identify new dyestuffs. That search had failed. But the benzheptoxdiazines had other advantages that made them well suited for Sternbach’s current mission. They were accessible, easily synthesized, and chemically malleable. Twenty years after Sternbach had worked with them, they remained relatively obscure. They crystallized well, which meant that it was possible to generate quickly a large batch of compounds. The benzheptoxdiazines had never been tested for biological activity, but in Sternbach’s mind, their molecular weight suggested that they might produce biologically active agents. Did he believe they would produce tranquilizers? Not initially. “I didn’t have any idea,” he admitted. But they seemed like a good place to begin. His section chief at Hoffman-La Roche, Wolf Goldberg, was less confident that Sternbach’s exploration would identify tranquilizing compounds. But he gave Sternbach his consent.19 Scrawling on his blackboard and poring through his notes, Sternbach began his benzheptoxdiazines experiment. The chemistry fascinated him. Ever the tinkerer, he tested multiple combinations, altering the temperatures at which they were mixed, changing the method by which they were dissolved. A scientist who rejected theory-based hypotheses in favor of intuition and gut feelings, he once likened his zeal for chemistry to an artist’s irresistible but inexplicable love of his craft. On a hunch, he synthesized some of the compounds with a chlorine in the side chain (a part of the molecule attached to the core structure) and reacted them with various secondary amines. (Amines are members of a family of nitrogen-containing organic compounds derived from ammonia. They are classified as primary, secondary, or tertiary depending on how many of the hydrogen atoms— one, two, or three—have been replaced by organic compounds.) Harking back to that moment, he remembers that inventing a blockbuster medication was not uppermost in his mind. “I wasn’t interested . . . in helping the whole world,” he said. “I was interested in working in the laboratory.”20 Leo in the Lab, 1941. A self-described “chemist’s chemist” who rejected theory-based hypotheses in favor of instinct, Sternbach was more interested in working in his laboratory than in creating a blockbuster medication. It was during a laboratory clean-up that Sternbach stumbled on Librium, a compound he and coworker Earl Reeder had forgotten to submit for pharmacological testing. Reproduced courtesy of the Sternbach Family. Sternbach synthesized some forty new benzheptoxdiazine derivatives. Each was submitted for testing to Dr. Lowell Randall, Roche’s new chief of pharmacology. To Sternbach’s chagrin, each proved pharmacologically inert, totally devoid of tranquilizing attributes. Roche executives were frustrated too, and in 1956 they reassigned Sternbach to antibiotic research, chiding the chemist for failing to produce something useful. Before Sternbach concluded his tranquilizer experiments, however, he and coworker Earl Reeder treated one of the derivatives with methylamine, a primary amine (given that secondary and tertiary amines had produced consistently negative results). He labeled the result Ro 5–0690 and shelved it for later evaluation.21 By 1957, the most remarkable feat Sternbach could claim in his antibiotic work was the clutter he and his coworkers had created in the laboratory. It was, he remembered, a chaotic and hopeless situation. Laboratory benches were “covered with dishes, flasks, and beakers—all containing various samples and mother liquors. The working area had shrunk almost to zero, and a major spring cleaning was in order.” It was during the April cleanup that Earl Reeder drew his attention to the untested sample, the white crystalline powder he and Sternbach had created the year before. The two debated whether they should throw it out. Reeder encouraged Sternbach to submit it, the last of the benzheptoxdiazine derivatives, for pharmacological evaluation. Sternbach sent the sample to Randall on May 7, 1957. It was Sternbach’s forty-ninth birthday.22 A month earlier, the New York Times had reported Roche’s entry into the mental health market. The drug of note was iproniazid, trade name Marsilid. It was one of two potent drugs Roche had developed in 1951 for the treatment of tuberculosis, still the world’s deadliest scourge. Doctors observed unexpected and remarkable psychological changes in TB patients on Marsilid: they gained weight and became energetic and cheerful. Psychiatrists took notice. Nathan Kline, director of research at Rockland State Hospital, proceeded to test the drug on hospitalized schizophrenics and private-practice neurotics. As Kline told colleagues at the annual meeting of the American Psychiatric Association, the drug produced remarkable mood improvement among both groups. The results suggested that the drug would be effective “with severely depressed patients who are sometimes made worse by the tranquilizers.” Roche wasn’t sure how to market Marsilid. In 1957 scientists were beginning to discuss chemical explanations for depression, but there was as yet no market for antidepressants. The company’s research had focused exclusively on the hunt for a tranquilizer. Marsilid was clearly no tranquilizer. “Marsilid increases what doctors call psychic energy whereas the tranquilizers reduce energy,” one report explained. Roche latched onto this descriptor, initially marketing Marsilid as a psychic energizer. Although Roche withdrew the drug in 1961 because of adverse effects on the liver, its success in launching what would later be considered the first MAO inhibitor helped advance the company’s legitimacy in the field.23 With Ro 5–0690, Randall applied the standard protocol to assess whether experimental compounds had tranquilizing attributes. In what is known as the inclined screen test, mice were fed the experimental compound and placed at the bottom of a tilted screen. Undrugged mice scramble to the top without difficulty. Tranquilized mice, on the other hand, eventually slide, as if commanded by gravity, in a relaxed stupor to the bottom. Remarkably, although the mice in Randall’s test slid to the bottom of the screen—proof of the agent’s muscle relaxant and anticonvulsant properties—they remained alert and active. Mice hung limply when held by one ear but were able to walk when prodded. The compound also passed the industry-wide “cat test.” Medicated cats held by the nape of the neck hung flaccidly and without struggle; those that had once been considered “mean” became both amenable to handling and “contented, sociable, and playful.” Randall tested the properties of Ro 5–0690 against meprobamate, chlorpromazine, and phenobarbital, drugs used widely in clinical practice. He released the results to his superiors on July 26, 1957. Randall’s words became part of the benzodiazepine legend. “The substance has hypnotic, sedative, and antistrychnine effects in mice similar to meprobamate,” he reported. But it was vastly more potent. It was also less toxic and sedating than any tranquilizer on the market. Indeed, it was the most interesting antianxiety compound Randall had seen. Through luck, intuition, and the long process of trial and error, Leo Sternbach had landed Roche a winner. The company christened Ro 5–0690 Librium, from the last syllables in “equilibrium.”24 Sternbach discovered something else. Mapping the molecular structure of Ro 5–0690, he learned that he had unwittingly created chemicals unrelated to the structure of his forty previous derivatives. A step in Sternbach’s synthesis—what he might later have dismissed as a chemical error had it not portended success—had unintentionally created a new class of chemicals, the benzodiazepines. Presently there are dozens of benzodiazepines on the global market, but Ro 5–0690, generic chlordiazepoxide, was the first. Benzodiazepines share a chemical structure that consists of a benzene ring of six carbon atoms attached to a seven-membered diazepine ring.25 Scholars debate who or what should get credit for the discovery of a new technology. Does innovation spring from the inventor, from the community and collective actions that lead to its discovery, or from the long pedigree of ideas that readied the way? What counts as a breakthrough? How do we distinguish genuine innovation from pedestrian improvement? The birth of the benzodiazepines highlights these complexities. Had Miltown not been a commercial success—had patients and physicians not come to understand anxiety as meriting pharmaceutical treatment—there surely would have been no tranquilizer war to inspire Sternbach’s hunt. Miltown’s triumph laid the commercial and cultural topsoil that created an enabling environment for the invention of benzodiazepines. But benzodiazepines also sprang from the acts and predispositions of a number of individuals: Leo Sternbach’s determination to create a new rather than a me-too compound and the chemical misstep that generated Ro 5–0690, Earl Reeder’s discovery of the shelved sample and his insistence on testing it, and Lowell Randall’s recognition and determination of the pharmacological properties of benzodiazepines. Librium’s genesis was nested in the confluence of diverse factors, personalities, and events. Over time, however, the birth of the benzodiazepines came to be known to the public as Leo Sternbach’s heroic achievement as well as his lucky break.26 Official clinical trials of Ro 5–0690 began in 1958, but Sternbach conducted the first unofficial trial on himself. This was not an uncommon practice among psychopharmacologists in the 1950s. At a time when results from randomized clinical trials were increasingly being counted as objective evidence of a drug’s effects, many succumbed to the desire to know what drugs felt like, firsthand. Roche did not condone self-testing in the 1950s, and now it strictly forbids researchers from serving as “two-legged rats.” Sternbach did it anyway, on the sly. He swallowed 50 mg of Librium in the fall of 1957. (Today, 10–40 mgs is considered an appropriate onetime dose for anxiety relief.) The time was 8:30 A.M. By 10:00, he wrote in his journal, he was starting to feel “slightly soft in the knees.” By the afternoon, he felt drowsy, and by 6:00 P.M. the effects had passed. In the spring of 1958 he applied for a patent on the compound. The application described the novelty of the benzodiazepine and the methods for producing it. But it made no mention of its therapeutic applications, which clinical trials were only beginning to demonstrate.27

 

Tone, Andrea. The Age of Anxiety (pp. 126-131). Basic Books. Kindle Edition.

LorazepamFree, I appreciate your annotations from the book and found them interesting.

Although Leo Sternbach did discover the very potent crystalline molecules, Librium and Valium, through his laboratory work, the links I provided above indicate that similar molecules do exist in nature albeit in much less potent proportions.

Regarding benzos, this phrase, "the dose makes the poison" appears to bear some truth and is an adage intended to indicate a basic principle of toxicology. It is credited to Paracelsus.(1)

(1) https://en.wikipedia.org/wiki/The_dose_makes_the_poison