Analysis of information sources in references of the Wikipedia article "LSD" in English language version.
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LSD has been reported to potentiate the neurotoxic action of MDMA in animal experiments.85 In these experiments, the MDMA-induced neurotoxicity was dose dependently increased by LSD and attenuated by 5-HT2A/2C receptor antagonist MDL 11,939.
Subsequent experiments on volunteers of the Sandoz research laboratories confirmed the extraordinary activity of lysergic acid diethylamide on the human psyche. These showed that the effective oral dose of LSD in human beings is 0.03—0.05 mg. [...] LSD is by far the most active and most specific psychotomimetic. It is about 5,000—10,000 times more active than mescaline or about 100–200 times more active than psilocybin.
Several other classes of drugs are categorized as drugs of abuse but rarely produce compulsive use. These include psychedelic agents, such as lysergic acid diethylamide (LSD)
Subsequent experiments on volunteers of the Sandoz research laboratories confirmed the extraordinary activity of lysergic acid diethylamide on the human psyche. These showed that the effective oral dose of LSD in human beings is 0.03—0.05 mg. [...] LSD is by far the most active and most specific psychotomimetic. It is about 5,000—10,000 times more active than mescaline or about 100–200 times more active than psilocybin.
Recent studies have suggested that psychedelics such as LSD directly interact with TrkB with high affinity, promoting BDNF-mediated neuroplasticity and antidepressant-like effects via allosteric potentiation of BDNF signaling in active synapses.8 To investigate this, we screened LSD across 450 human kinases, including TrkB, but found no significant interactions between LSD and any tested human kinases. Further experiments in transfected cells revealed no effect of LSD or psilocin on BDNF-mediated activation of a TrkB reporter. We note that similar negative preliminary results, which have not yet been published in a peer-reviewed journal, were recently reported by Boltaev et al.63
In contrast to the users of other substances of abuse, hallucinogen users do not experience withdrawal symptoms and, therefore, this trait is not a criterion for diagnosing hallucinogen dependence.
Although LSD is the most well-known psychedelic, only a very few structural modifications can be made to its structure, and nearly all of those attenuate its activity by about an order of magnitude. In addition, there is a paucity of structure–activity data for ergolines, principally due to the synthetic difficulty inherent in their chemistry. [...] Although LSD is the most potent psychedelic agent in humans, its affinity and potency at the human 5-HT2A receptor is rather unremarkable compared with much simpler molecules such as DOI. [...] Because of its structural complexity and tedious approaches to its total synthesis, only a few structural modifications of LSD have been reported. [...] Unfortunately, only a few of them have been assessed in human psychopharmacology, most being much less active than LSD itself.
{{cite journal}}: CS1 maint: DOI inactive as of March 2026 (link)The data to establish dose-response relationships for LSD is limited by the availability of studies that cohere to current research standards, as LSD has only recently returned to basic and clinical research. The range of LSD doses employed in current research is on average markedly below the doses administered in studies from the 1950 to 70 s. At that time, high doses mostly ranging between 400 and 600 μg were applied, especially in the treatment of alcohol use disorder, whereas in recent studies doses of 200 μg have not been exceeded, neither in healthy subjects [22], nor in clinical samples [15, 16, 23].
Provoking doses were unclear, but 150 participants received doses of LSD, up to 2000 μg (roughly 10-fold the current norms of a therapeutic dose), in up to 10 sessions. [...] In the aforementioned study involving repeated doses of LSD, up to 2000 μg, there was 1 suicide death and 1 unexplained death in the weeks following LSD treatment.22 Another study that administered LSD, up to 1000 μg, to 162 inpatient participants with neurotic and personality disorders between 1 and 50 times recorded 3 suicide attempts and 1 death from alcohol or barbiturate exposure in the 18 months following discharge.36
Patients in the drug groups were pretreated with an anticonvulsant, restrained in a bed, and then given 800 mcg of LSD or 60 mg of ephedrine. [...] Baker found that larger dosages of LSD were better able to break open "repressive barriers" and clearly reveal unconscious conflicts. He gave first-time patients between 100 and 600 mcg intramuscularly. [...] In some cases, he used upwards of the highest dosages reported in the therapeutic literature. [...] With this success, Baker increased the dosage for the next session to 1,600 mcg, which did not produce a change in the remaining paralyzed limb. Next time, Baker administered the whopping dose of 2,000 mcg (20 times the standard adult dose) and the man regained "use of this limb within 10 minutes of injection."33 [...] A few months later, [Pam Hyatt's] husband had his own, unsuccessful LSD sessions with Solursh. In one session, after taking 1,000 mcg, he "died 18 times," and subsequently became depressed.
When "snorted," a typical "line" of cocaine contains approximately 50-100 mg of parent compound, although it is often "cut" or adulterated with other substances.20
The largest number of structural analogs of LSD that have been prepared involve the opening of one or more of the rings of the parent lysergic acid system. [...] A recent review covers this chemistry (Campaigne and Knapp, 1971), but there is apparently no human psychopharmacology as yet known.
Importantly, the idea of increased risk for developing serotonin syndrome and/or serotonin toxicity, when [antidepressants (ADs)] are co-administered with high doses of psychedelics, has recently been challenged, in part because classic psychedelics are partial agonists of the 5-HT2A receptor and would also compete for serotonin binding (Malcolm and Thomas, 2022; Rickli et al., 2016; Sarparast et al., 2022). Based on this clinical rationale, the concomitant use of ADs and classic psychedelics may be preferred, or patients could temporarily reduce the dose of ADs around dosing days with psychedelics to have minimal interactions. Simultaneously, the competition for 5-HT2A receptors could impede the biological action of psychedelics during concomitant use of ADs and potentially limit efficacy (Halman et al., 2024), particularly as the 5-HT2A receptor induces neuroplasticity (Cameron et al., 2023; Ly et al., 2018; Vargas et al., 2023).
We now have molecular-level details regarding how psychedelic drugs interact with and activate 5-HT2A receptors (39) (Figure 2B). Studies on a related serotonin receptor (5-HT2B) have clarified how LSD can stabilize distinct signaling complexes (40, 41). A key finding of these studies was the discovery that once LSD binds to the 5-HT2A receptor, a lid is formed over the binding pocket, which "traps" LSD for several hours (39, 40) (Figure 2B). These findings imply that at least part of the reason for the long duration of action of drugs like LSD is the trapping of the receptor via conformational changes that occur after drug binding. These studies also showed that this prolonged action of LSD is due in part to a specific residue within the binding pocket, which is found in humans but not in mice or rats (39). This residue (Ser242) also is essential for the high-affinity interactions of LSD, psilocybin, and perhaps other such drugs at the human and nonhuman primate 5-HT2A receptors.
Based on the time-course data, LSD appeared to show the largest disconnect between plasma exposure and generalisation profile. By 8 h post-dosing, plasma LSD levels were undetectable, yet drug lever generalisation levels were at 54%; even at 24 h post-dose, there was some residual (10%) drug lever responding. LSD is recognised to have a long residence time when bound to the 5-HT2A receptor, which, in the human receptor form, is due to a conformational change on binding that traps an LSD molecule within the binding pocket (Gumpper et al., 2025; Kim et al., 2020). A further feature of LSD is a time-dependent change in the pharmacology of its discriminative cue (Marona-Lewica et al., 2005; Marona-Lewica and Nichols, 2007). Thus, a long residence time bound to the 5-HT2A receptor and/or time-dependent changes in its discriminative cue may explain the PK/PD disconnect in rats. Dolder et al. (2015, 2017) have described a similar disconnection in humans where 100 and 200 µg doses of LSD had a plasma half-life of 2.6 h, yet the subjective effects lasted 8–12 h.
Recent studies have suggested that psychedelics such as LSD directly interact with TrkB with high affinity, promoting BDNF-mediated neuroplasticity and antidepressant-like effects via allosteric potentiation of BDNF signaling in active synapses.8 To investigate this, we screened LSD across 450 human kinases, including TrkB, but found no significant interactions between LSD and any tested human kinases. Further experiments in transfected cells revealed no effect of LSD or psilocin on BDNF-mediated activation of a TrkB reporter. We note that similar negative preliminary results, which have not yet been published in a peer-reviewed journal, were recently reported by Boltaev et al.63
LSD has been reported to potentiate the neurotoxic action of MDMA in animal experiments.85 In these experiments, the MDMA-induced neurotoxicity was dose dependently increased by LSD and attenuated by 5-HT2A/2C receptor antagonist MDL 11,939.
Also, the concomitant use of other substance classes, either intentionally or unintentionally due to adulterations, could be a health risk since LSD has been shown to potentiate the neurotoxic effect of MDMA in animals [85].
It is rapidly metabolized to the following five metabolites which have been identified in urine or blood from human users: N-demethyl-LSD (nor-LSD), 2-oxoLSD, 2-oxo-3-hydroxy-LSD, 13-hydroxyLSD and 14-hydroxy-LSD [187–189]. The 13- and 14-hydroxy metabolites are additionally excreted as glucuronides [188]. [...] 2-oxo-3-hydroxy-LSD was shown to be the main human urinary metabolite with concentrations four- to 40-times higher than that of LSD [187,188,191]. As concluded by Yu in his review on indolalkylamines, almost nothing is known regarding the contribution of specific drug-metabolizing enzymes to the production of individual LSD metabolites in humans.
[LSD] is metabolized to the following five metabolites: N-demethyl-LSD (nor-LSD), 2-oxo-LSD, 2-oxo-3-hydroxy-LSD, 13-hydroxy-LSD, and 14-hydroxy-LSD [72–74]. The 13- and 14-hydroxy metabolites are additionally excreted as glucuronides [74]. 2-Oxo-3-hydroxy-LSD was shown to be the main human urinary metabolite with concentrations 4–40 times higher than that of LSD [73–75]. In incubations of LSD with human liver microsomes and hepatocytes, 2,3-dihydroxy-LSD could be identified [71]. So far, the contribution and importance of specific enzymes in the formation of the LSD main metabolites, such as 2-oxo-3-hydroxy-LSD, remain unclear.
In 1938 the Swiss chemist Albert Hofmann produced lysergic acid diethylamide (LSD)—the first, and most prominent, of these chemically synthesized agents—in the course of a systematic investigation of partially synthetic amides of lysergic acid in the Sandoz Pharmaceutical Laboratories in Basel (Hofmann 1970). [Taking] LSD by accident in 1943, Hofmann discovered its psychoactivity. He then experimented with it on himself and found that it produced a peculiar restlessness, extreme activity of the imagination, and an uninterrupted stream of images. Hofmann did not publish the results of his experiment, though he became quite famous later. Hofmann and Arthur Stoll, the head of the Sandoz pharmaceutical laboratory in Basle, published the first paper on the synthesis of LSD in 1943, while Stoll went on to publish the first paper on the effects of lysergic diethylamide acid in 1947. [...] Stoll, Arthur and Hofmann, Albert. 1943. Partialsynthese von Alkaloiden vom Typus des Ergobasins. Helv. Chim. Acta 26:944. Stoll, Arthur. 1947. Lysergsäure-diäthylamid, ein Phantastikum aus der Mutterkorngruppe. Schweiz. Arch. Neurol. Psychiat. 60:279. [The first paper on the hallucinogenic effect of LSD.]
Lysergic Acid N, N-diethylamide (LSD) is the most "famous" (notorious?) of the psychedelics. That dubious distinction came about not only because of its effects, but also because of its extremely high potency. The type of effect it produced was not completely unknown, however, because mescaline had been relatively available to interested persons since the late 1920s, and produced a similar mental state. Aldous Huxley's book The Doors of Perception also generated a great deal of interest in mescaline in the 1950s, at least in certain circles, but its low potency (one gram is only 3-4 doses) made it somewhat uneconomical for manufacture. This cost factor may be one of the reasons that it never achieved the popularity gained by LSD in the 1960s and 1970s. By contrast, LSD was easily made from relatively available starting materials such as ergotamine, and its high potency made it economical to manufacture in relatively large quantities. One gram of LSD probably costs no more than a few hundred dollars in raw materials to manufacture, whereas it represents approximately 10,000 clinical doses that could "retail" on the street for upwards of $50,000. Combine this strong economic incentive with the high potency of the drug, which makes distribution easy because doses are very small and easily hidden, and one readily sees some of the factors that led to the high popularity of LSD. [...]Indeed, the potency of LSD at the 5-HT2A receptor is not as great as that of some of the amphetamine hallucinogens such as DOB or DOI, yet its human potency is about ten times greater. [...] Furthermore, there is a cavity within these receptors that accommodates and is complementary to the activating drug, in this case LSD. What we are forced to conclude is that the area within the receptor that binds to the diethylamide function of LSD is a specific region that must be just large enough to contain the diethyl groups. [...]
Although LSD is the most well-known psychedelic, only a very few structural modifications can be made to its structure, and nearly all of those attenuate its activity by about an order of magnitude. In addition, there is a paucity of structure–activity data for ergolines, principally due to the synthetic difficulty inherent in their chemistry. [...] Although LSD is the most potent psychedelic agent in humans, its affinity and potency at the human 5-HT2A receptor is rather unremarkable compared with much simpler molecules such as DOI. [...] Because of its structural complexity and tedious approaches to its total synthesis, only a few structural modifications of LSD have been reported. [...] Unfortunately, only a few of them have been assessed in human psychopharmacology, most being much less active than LSD itself.
High Times: Why was it four years from your discovery of the psychic effects of LSD [in 1943] until your report was published? [...] Hofmann: [...] After confirmation of the action of this extraordinary compound by volunteers of the Sandoz staff, Professor Arthur Stoll, who was then head of the Sandoz pharmaceutical department, asked me if I would permit his son, Werner A. Stoll—who was starting his career at the psychiatric hospital of the University of Zurich—to submit this new agent to a fundamental psychiatric study on normal volunteers and on psychiatric patients. This investigation took a rather long time, [...] This excellent and comprehensive study was not published until 1947.
The largest number of structural analogs of LSD that have been prepared involve the opening of one or more of the rings of the parent lysergic acid system. [...] A recent review covers this chemistry (Campaigne and Knapp, 1971), but there is apparently no human psychopharmacology as yet known.
Table 5.2 Binding affinities using 3 H-LSD at 5-HT2A EL2 mutants [...] Table B.1 Binding affinities for 5-HT2A, 5-HT2C, 5-HT1A receptors using 3 H-LSD [...]Alt URL
Although LSD is the most well-known psychedelic, only a very few structural modifications can be made to its structure, and nearly all of those attenuate its activity by about an order of magnitude. In addition, there is a paucity of structure–activity data for ergolines, principally due to the synthetic difficulty inherent in their chemistry. [...] Although LSD is the most potent psychedelic agent in humans, its affinity and potency at the human 5-HT2A receptor is rather unremarkable compared with much simpler molecules such as DOI. [...] Because of its structural complexity and tedious approaches to its total synthesis, only a few structural modifications of LSD have been reported. [...] Unfortunately, only a few of them have been assessed in human psychopharmacology, most being much less active than LSD itself.
{{cite journal}}: CS1 maint: DOI inactive as of March 2026 (link)The data to establish dose-response relationships for LSD is limited by the availability of studies that cohere to current research standards, as LSD has only recently returned to basic and clinical research. The range of LSD doses employed in current research is on average markedly below the doses administered in studies from the 1950 to 70 s. At that time, high doses mostly ranging between 400 and 600 μg were applied, especially in the treatment of alcohol use disorder, whereas in recent studies doses of 200 μg have not been exceeded, neither in healthy subjects [22], nor in clinical samples [15, 16, 23].
Provoking doses were unclear, but 150 participants received doses of LSD, up to 2000 μg (roughly 10-fold the current norms of a therapeutic dose), in up to 10 sessions. [...] In the aforementioned study involving repeated doses of LSD, up to 2000 μg, there was 1 suicide death and 1 unexplained death in the weeks following LSD treatment.22 Another study that administered LSD, up to 1000 μg, to 162 inpatient participants with neurotic and personality disorders between 1 and 50 times recorded 3 suicide attempts and 1 death from alcohol or barbiturate exposure in the 18 months following discharge.36
Patients in the drug groups were pretreated with an anticonvulsant, restrained in a bed, and then given 800 mcg of LSD or 60 mg of ephedrine. [...] Baker found that larger dosages of LSD were better able to break open "repressive barriers" and clearly reveal unconscious conflicts. He gave first-time patients between 100 and 600 mcg intramuscularly. [...] In some cases, he used upwards of the highest dosages reported in the therapeutic literature. [...] With this success, Baker increased the dosage for the next session to 1,600 mcg, which did not produce a change in the remaining paralyzed limb. Next time, Baker administered the whopping dose of 2,000 mcg (20 times the standard adult dose) and the man regained "use of this limb within 10 minutes of injection."33 [...] A few months later, [Pam Hyatt's] husband had his own, unsuccessful LSD sessions with Solursh. In one session, after taking 1,000 mcg, he "died 18 times," and subsequently became depressed.
One hundred of 150 patients with non-psychotic functional psychiatric disorders were benefited by the use of LSD psychotherapy. The dosage of LSD employed was 25 to 2000 micrograms intramuscularly per session for from one to 10 sessions. [...] LSD is administered intramuscularly in doses ranging from 100 to 2000 micrograms (μg.). Alcoholics, drug addicts and highly obsessional or near-psychotic personalities require higher doses. [...] we have not used a total dose of more than 2000 μg. LSD in any individual session.
When "snorted," a typical "line" of cocaine contains approximately 50-100 mg of parent compound, although it is often "cut" or adulterated with other substances.20
Importantly, the idea of increased risk for developing serotonin syndrome and/or serotonin toxicity, when [antidepressants (ADs)] are co-administered with high doses of psychedelics, has recently been challenged, in part because classic psychedelics are partial agonists of the 5-HT2A receptor and would also compete for serotonin binding (Malcolm and Thomas, 2022; Rickli et al., 2016; Sarparast et al., 2022). Based on this clinical rationale, the concomitant use of ADs and classic psychedelics may be preferred, or patients could temporarily reduce the dose of ADs around dosing days with psychedelics to have minimal interactions. Simultaneously, the competition for 5-HT2A receptors could impede the biological action of psychedelics during concomitant use of ADs and potentially limit efficacy (Halman et al., 2024), particularly as the 5-HT2A receptor induces neuroplasticity (Cameron et al., 2023; Ly et al., 2018; Vargas et al., 2023).
We now have molecular-level details regarding how psychedelic drugs interact with and activate 5-HT2A receptors (39) (Figure 2B). Studies on a related serotonin receptor (5-HT2B) have clarified how LSD can stabilize distinct signaling complexes (40, 41). A key finding of these studies was the discovery that once LSD binds to the 5-HT2A receptor, a lid is formed over the binding pocket, which "traps" LSD for several hours (39, 40) (Figure 2B). These findings imply that at least part of the reason for the long duration of action of drugs like LSD is the trapping of the receptor via conformational changes that occur after drug binding. These studies also showed that this prolonged action of LSD is due in part to a specific residue within the binding pocket, which is found in humans but not in mice or rats (39). This residue (Ser242) also is essential for the high-affinity interactions of LSD, psilocybin, and perhaps other such drugs at the human and nonhuman primate 5-HT2A receptors.
Based on the time-course data, LSD appeared to show the largest disconnect between plasma exposure and generalisation profile. By 8 h post-dosing, plasma LSD levels were undetectable, yet drug lever generalisation levels were at 54%; even at 24 h post-dose, there was some residual (10%) drug lever responding. LSD is recognised to have a long residence time when bound to the 5-HT2A receptor, which, in the human receptor form, is due to a conformational change on binding that traps an LSD molecule within the binding pocket (Gumpper et al., 2025; Kim et al., 2020). A further feature of LSD is a time-dependent change in the pharmacology of its discriminative cue (Marona-Lewica et al., 2005; Marona-Lewica and Nichols, 2007). Thus, a long residence time bound to the 5-HT2A receptor and/or time-dependent changes in its discriminative cue may explain the PK/PD disconnect in rats. Dolder et al. (2015, 2017) have described a similar disconnection in humans where 100 and 200 µg doses of LSD had a plasma half-life of 2.6 h, yet the subjective effects lasted 8–12 h.
Recent studies have suggested that psychedelics such as LSD directly interact with TrkB with high affinity, promoting BDNF-mediated neuroplasticity and antidepressant-like effects via allosteric potentiation of BDNF signaling in active synapses.8 To investigate this, we screened LSD across 450 human kinases, including TrkB, but found no significant interactions between LSD and any tested human kinases. Further experiments in transfected cells revealed no effect of LSD or psilocin on BDNF-mediated activation of a TrkB reporter. We note that similar negative preliminary results, which have not yet been published in a peer-reviewed journal, were recently reported by Boltaev et al.63
LSD has been reported to potentiate the neurotoxic action of MDMA in animal experiments.85 In these experiments, the MDMA-induced neurotoxicity was dose dependently increased by LSD and attenuated by 5-HT2A/2C receptor antagonist MDL 11,939.
It is rapidly metabolized to the following five metabolites which have been identified in urine or blood from human users: N-demethyl-LSD (nor-LSD), 2-oxoLSD, 2-oxo-3-hydroxy-LSD, 13-hydroxyLSD and 14-hydroxy-LSD [187–189]. The 13- and 14-hydroxy metabolites are additionally excreted as glucuronides [188]. [...] 2-oxo-3-hydroxy-LSD was shown to be the main human urinary metabolite with concentrations four- to 40-times higher than that of LSD [187,188,191]. As concluded by Yu in his review on indolalkylamines, almost nothing is known regarding the contribution of specific drug-metabolizing enzymes to the production of individual LSD metabolites in humans.
{{cite journal}}: CS1 maint: DOI inactive as of March 2026 (link)The data to establish dose-response relationships for LSD is limited by the availability of studies that cohere to current research standards, as LSD has only recently returned to basic and clinical research. The range of LSD doses employed in current research is on average markedly below the doses administered in studies from the 1950 to 70 s. At that time, high doses mostly ranging between 400 and 600 μg were applied, especially in the treatment of alcohol use disorder, whereas in recent studies doses of 200 μg have not been exceeded, neither in healthy subjects [22], nor in clinical samples [15, 16, 23].
Provoking doses were unclear, but 150 participants received doses of LSD, up to 2000 μg (roughly 10-fold the current norms of a therapeutic dose), in up to 10 sessions. [...] In the aforementioned study involving repeated doses of LSD, up to 2000 μg, there was 1 suicide death and 1 unexplained death in the weeks following LSD treatment.22 Another study that administered LSD, up to 1000 μg, to 162 inpatient participants with neurotic and personality disorders between 1 and 50 times recorded 3 suicide attempts and 1 death from alcohol or barbiturate exposure in the 18 months following discharge.36
One hundred of 150 patients with non-psychotic functional psychiatric disorders were benefited by the use of LSD psychotherapy. The dosage of LSD employed was 25 to 2000 micrograms intramuscularly per session for from one to 10 sessions. [...] LSD is administered intramuscularly in doses ranging from 100 to 2000 micrograms (μg.). Alcoholics, drug addicts and highly obsessional or near-psychotic personalities require higher doses. [...] we have not used a total dose of more than 2000 μg. LSD in any individual session.
Importantly, the idea of increased risk for developing serotonin syndrome and/or serotonin toxicity, when [antidepressants (ADs)] are co-administered with high doses of psychedelics, has recently been challenged, in part because classic psychedelics are partial agonists of the 5-HT2A receptor and would also compete for serotonin binding (Malcolm and Thomas, 2022; Rickli et al., 2016; Sarparast et al., 2022). Based on this clinical rationale, the concomitant use of ADs and classic psychedelics may be preferred, or patients could temporarily reduce the dose of ADs around dosing days with psychedelics to have minimal interactions. Simultaneously, the competition for 5-HT2A receptors could impede the biological action of psychedelics during concomitant use of ADs and potentially limit efficacy (Halman et al., 2024), particularly as the 5-HT2A receptor induces neuroplasticity (Cameron et al., 2023; Ly et al., 2018; Vargas et al., 2023).
On the West Coast in the early 1960s LSD and morning glory seeds were readily available, so I sampled those, too.
Subsequent experiments on volunteers of the Sandoz research laboratories confirmed the extraordinary activity of lysergic acid diethylamide on the human psyche. These showed that the effective oral dose of LSD in human beings is 0.03—0.05 mg. [...] LSD is by far the most active and most specific psychotomimetic. It is about 5,000—10,000 times more active than mescaline or about 100–200 times more active than psilocybin.
Table 5.2 Binding affinities using 3 H-LSD at 5-HT2A EL2 mutants [...] Table B.1 Binding affinities for 5-HT2A, 5-HT2C, 5-HT1A receptors using 3 H-LSD [...]Alt URL
Also, the concomitant use of other substance classes, either intentionally or unintentionally due to adulterations, could be a health risk since LSD has been shown to potentiate the neurotoxic effect of MDMA in animals [85].
In 1938 the Swiss chemist Albert Hofmann produced lysergic acid diethylamide (LSD)—the first, and most prominent, of these chemically synthesized agents—in the course of a systematic investigation of partially synthetic amides of lysergic acid in the Sandoz Pharmaceutical Laboratories in Basel (Hofmann 1970). [Taking] LSD by accident in 1943, Hofmann discovered its psychoactivity. He then experimented with it on himself and found that it produced a peculiar restlessness, extreme activity of the imagination, and an uninterrupted stream of images. Hofmann did not publish the results of his experiment, though he became quite famous later. Hofmann and Arthur Stoll, the head of the Sandoz pharmaceutical laboratory in Basle, published the first paper on the synthesis of LSD in 1943, while Stoll went on to publish the first paper on the effects of lysergic diethylamide acid in 1947. [...] Stoll, Arthur and Hofmann, Albert. 1943. Partialsynthese von Alkaloiden vom Typus des Ergobasins. Helv. Chim. Acta 26:944. Stoll, Arthur. 1947. Lysergsäure-diäthylamid, ein Phantastikum aus der Mutterkorngruppe. Schweiz. Arch. Neurol. Psychiat. 60:279. [The first paper on the hallucinogenic effect of LSD.]
We now have molecular-level details regarding how psychedelic drugs interact with and activate 5-HT2A receptors (39) (Figure 2B). Studies on a related serotonin receptor (5-HT2B) have clarified how LSD can stabilize distinct signaling complexes (40, 41). A key finding of these studies was the discovery that once LSD binds to the 5-HT2A receptor, a lid is formed over the binding pocket, which "traps" LSD for several hours (39, 40) (Figure 2B). These findings imply that at least part of the reason for the long duration of action of drugs like LSD is the trapping of the receptor via conformational changes that occur after drug binding. These studies also showed that this prolonged action of LSD is due in part to a specific residue within the binding pocket, which is found in humans but not in mice or rats (39). This residue (Ser242) also is essential for the high-affinity interactions of LSD, psilocybin, and perhaps other such drugs at the human and nonhuman primate 5-HT2A receptors.
LSD produced subjective drug effects that lasted up to 12 h (Fig. 3a) and correlated well with the concentrations of LSD in the blood plasma over time (Fig. 3b and c). The half-life of LSD in plasma was 3.5 h. In contrast to LSD, the half-life of MDMA is longer (8 h), but the effects of MDMA last only up to 6 h despite the continued presence of the substance in the body (Fig. 3d). Thus, there is marked acute tolerance to the effects of MDMA. [...] Fig. 3: Pharmacokinetics-Pharmacodynamics of LSD. LSD effects last up to 12 h (a), corresponding to its plasma-concentration time curve (b) and exhibiting no hysteresis in the LSD concentration-effect plot (c). In contrast, the MDMA concentration-effect plot shows pronounced hysteresis consistent with acute tolerance (d).
Several other classes of drugs are categorized as drugs of abuse but rarely produce compulsive use. These include psychedelic agents, such as lysergic acid diethylamide (LSD)
Although LSD is the most well-known psychedelic, only a very few structural modifications can be made to its structure, and nearly all of those attenuate its activity by about an order of magnitude. In addition, there is a paucity of structure–activity data for ergolines, principally due to the synthetic difficulty inherent in their chemistry. [...] Although LSD is the most potent psychedelic agent in humans, its affinity and potency at the human 5-HT2A receptor is rather unremarkable compared with much simpler molecules such as DOI. [...] Because of its structural complexity and tedious approaches to its total synthesis, only a few structural modifications of LSD have been reported. [...] Unfortunately, only a few of them have been assessed in human psychopharmacology, most being much less active than LSD itself.
Table 5.2 Binding affinities using 3 H-LSD at 5-HT2A EL2 mutants [...] Table B.1 Binding affinities for 5-HT2A, 5-HT2C, 5-HT1A receptors using 3 H-LSD [...]Alt URL
In 1938 the Swiss chemist Albert Hofmann produced lysergic acid diethylamide (LSD)—the first, and most prominent, of these chemically synthesized agents—in the course of a systematic investigation of partially synthetic amides of lysergic acid in the Sandoz Pharmaceutical Laboratories in Basel (Hofmann 1970). [Taking] LSD by accident in 1943, Hofmann discovered its psychoactivity. He then experimented with it on himself and found that it produced a peculiar restlessness, extreme activity of the imagination, and an uninterrupted stream of images. Hofmann did not publish the results of his experiment, though he became quite famous later. Hofmann and Arthur Stoll, the head of the Sandoz pharmaceutical laboratory in Basle, published the first paper on the synthesis of LSD in 1943, while Stoll went on to publish the first paper on the effects of lysergic diethylamide acid in 1947. [...] Stoll, Arthur and Hofmann, Albert. 1943. Partialsynthese von Alkaloiden vom Typus des Ergobasins. Helv. Chim. Acta 26:944. Stoll, Arthur. 1947. Lysergsäure-diäthylamid, ein Phantastikum aus der Mutterkorngruppe. Schweiz. Arch. Neurol. Psychiat. 60:279. [The first paper on the hallucinogenic effect of LSD.]
High Times: Why was it four years from your discovery of the psychic effects of LSD [in 1943] until your report was published? [...] Hofmann: [...] After confirmation of the action of this extraordinary compound by volunteers of the Sandoz staff, Professor Arthur Stoll, who was then head of the Sandoz pharmaceutical department, asked me if I would permit his son, Werner A. Stoll—who was starting his career at the psychiatric hospital of the University of Zurich—to submit this new agent to a fundamental psychiatric study on normal volunteers and on psychiatric patients. This investigation took a rather long time, [...] This excellent and comprehensive study was not published until 1947.
Like Herbert, many scientists and engineers also report heightened states of creativity while using LSD. During a press conference on Friday, Hofmann revealed that he was told by Nobel-prize-winning chemist Kary Mullis that LSD had helped him develop the polymerase chain reaction that helps amplify specific DNA sequences.
On the West Coast in the early 1960s LSD and morning glory seeds were readily available, so I sampled those, too.
[LSD] is metabolized to the following five metabolites: N-demethyl-LSD (nor-LSD), 2-oxo-LSD, 2-oxo-3-hydroxy-LSD, 13-hydroxy-LSD, and 14-hydroxy-LSD [72–74]. The 13- and 14-hydroxy metabolites are additionally excreted as glucuronides [74]. 2-Oxo-3-hydroxy-LSD was shown to be the main human urinary metabolite with concentrations 4–40 times higher than that of LSD [73–75]. In incubations of LSD with human liver microsomes and hepatocytes, 2,3-dihydroxy-LSD could be identified [71]. So far, the contribution and importance of specific enzymes in the formation of the LSD main metabolites, such as 2-oxo-3-hydroxy-LSD, remain unclear.
Like Herbert, many scientists and engineers also report heightened states of creativity while using LSD. During a press conference on Friday, Hofmann revealed that he was told by Nobel-prize-winning chemist Kary Mullis that LSD had helped him develop the polymerase chain reaction that helps amplify specific DNA sequences.
Lysergic Acid N, N-diethylamide (LSD) is the most "famous" (notorious?) of the psychedelics. That dubious distinction came about not only because of its effects, but also because of its extremely high potency. The type of effect it produced was not completely unknown, however, because mescaline had been relatively available to interested persons since the late 1920s, and produced a similar mental state. Aldous Huxley's book The Doors of Perception also generated a great deal of interest in mescaline in the 1950s, at least in certain circles, but its low potency (one gram is only 3-4 doses) made it somewhat uneconomical for manufacture. This cost factor may be one of the reasons that it never achieved the popularity gained by LSD in the 1960s and 1970s. By contrast, LSD was easily made from relatively available starting materials such as ergotamine, and its high potency made it economical to manufacture in relatively large quantities. One gram of LSD probably costs no more than a few hundred dollars in raw materials to manufacture, whereas it represents approximately 10,000 clinical doses that could "retail" on the street for upwards of $50,000. Combine this strong economic incentive with the high potency of the drug, which makes distribution easy because doses are very small and easily hidden, and one readily sees some of the factors that led to the high popularity of LSD. [...]Indeed, the potency of LSD at the 5-HT2A receptor is not as great as that of some of the amphetamine hallucinogens such as DOB or DOI, yet its human potency is about ten times greater. [...] Furthermore, there is a cavity within these receptors that accommodates and is complementary to the activating drug, in this case LSD. What we are forced to conclude is that the area within the receptor that binds to the diethylamide function of LSD is a specific region that must be just large enough to contain the diethyl groups. [...]
Subsequent experiments on volunteers of the Sandoz research laboratories confirmed the extraordinary activity of lysergic acid diethylamide on the human psyche. These showed that the effective oral dose of LSD in human beings is 0.03—0.05 mg. [...] LSD is by far the most active and most specific psychotomimetic. It is about 5,000—10,000 times more active than mescaline or about 100–200 times more active than psilocybin.
Also, the concomitant use of other substance classes, either intentionally or unintentionally due to adulterations, could be a health risk since LSD has been shown to potentiate the neurotoxic effect of MDMA in animals [85].
