Introduction
Lysergic acid diethylamide (LSD) was first synthesized in 1938 by Albert Hofmann (Passie, Halpern, Stichtenoth, Emrich, & Hintzen, 2008). It is a prototypical hallucinogen and has one of the most potent hallucinogenic effects (Wacker et al., 2017). LSD is derived from lysergic acid and there are four optically-active isomers known (Passie et al., 2008). Out of four isomers, d- and l-LSD and d-l and l-isolysergic acid diethylamide, only d-LSD isomer has psychoactive properties (Passie et al., 2008). There are many homologs and analogs, but only one’s with comparable potency to LSD are derivates substituted at the N-6 (Passie et al., 2008).
LSD was initially used to study psychotic-like states but it later showed promising results for the treatment of various psychological disorders, including depression, substance abuse, and anxiety (De Gregorio, Enns, Nunez, Posa, & Gobbi, 2018; Passie et al., 2008; Strajhar et al., 2016; Wacker et al., 2017). LSD can produce long-lasting positive psychological effects if taken under controlled conditions, however, if taken under uncontrolled conditions, it can lead to traumatic experiences and flashback phenomena (Passie et al., 2008). Moreover, it can impair psychomotor functions and cognition, lead to mild autonomic, biochemical and endocrinological changes and also induce changes in sleep cycle (Passie et al., 2008).
Since LSD gained popularity between recreational drug users in 1950s and 1960s, it was made illegal, which consequently paused the research on humans (Carhart-Harris et al., 2016). In 2008 Passie et al. reported that since 1966 no study has been conducted regarding the effects of LSD on the human brain. However, in the last decade there has been renewed interest in research with psychedelics, including LSD (De Gregorio et al., 2018; Dolder, Schmid, Haschke, Rentsch, & Liechti, 2015; Dolder et al., 2017; Strajhar et al., 2016; Wacker et al., 2017). The current paper will, therefore, focus on the pharmacokinetics (PK) and pharmacodynamics (PD) of LSD and the neurological changes induced by it.
Absorption / Resorption
If LSD is administrated preoral (p.o.), it is completely absorbed in the digestive tract (Passie et al., 2008). A dose of 200 μg in humans produces maximal concentration after 1.5 hours (Dolder et al., 2015) Absorption, however, is dependent on the pH of the stomach and can be influenced by the fullness or emptiness of the stomach (Passie et al., 2008).
Distribution
Axelrod, Brady, Witkop, and Evarts (1957) have researched the distribution of LSD in a cat. The animal received 1 mg/kg of LSD intravenously (i.v.) (Axelrod et al., 1957). After 90 minutes they found that LSD was mostly localized in the bile and plasma but only a small amount of it was present in the fat and feces. Authors suggested that, although LSD was secreted into the intestines, it was then reabsorbed. They also examined the presence of the drug in the brain and cerebrospinal fluid (CSF) and concluded that it can pass the blood-brain barrier (BBB) but found no differences in the distribution between different brain regions (Axelrod et al., 1957).
This finding differs from Snyder and Reivich (1966) who found that LSD is differently distributed between the brain regions. They conducted an experiment on squirrel monkeys to investigate the distribution of LSD in the brain tissue (Snyder & Reivich, 1966). Four monkeys received 2, 2, 1 and 0.5 mg/kg of LSD and were killed 20 minutes after the i.v. administration. They found the highest concentrations of LSD in pituitary and pineal glands, which were 7-8 times higher than in the cortex (Snyder & Reivich, 1966). Higher concentrations than in cortex were also found in the limbic system structures, visual and auditory areas of the deep cerebral structures and hypothalamus. However, LSD was not notably concentrated in the visual cortex, although its concentration in iris was 18 times higher than in cortex. Snyder and Reivich (1966) also reported that the concentration of LSD in the blood matched the cortical concentration. They concluded that uneven distribution between brain regions is not due to the regional blood flow, lipid solubility and consequent predilection for white matter.
Metabolism and Excretion
The metabolism rate of LSD varies between species. The half-life in mice is 7 minutes, compared to cats where half-life is 130 minutes and in humans 175 minutes if LSD is administrated p.o. (Axelrod et al., 1957; Passie et al., 2008). Administration of 2 μg/kg LSD i.v. to humans persists in plasma for about 8 hours, with half-life of 3 hours (Snyder & Reivich, 1966). Siddik et al. (1979) further investigated metabolism of LSD in rats (1 mg/kg i.p.), guinea pigs (1 mg/kg i.p.) and rhesus monkeys (0.15 mg/kg i.m.). They found out that most of the drug is metabolized before excretion and also identified metabolites – glucuronides of 13- and 14-hydroxy-LSD (Siddik, Barnes, Dring, Smith, & Williams, 1979). However, metabolites varied between species, for example, urine of rhesus monkeys contained at least nine metabolites, where 13- and 14-hydroxyl-LSD were represented only in small amounts (Siddik et al., 1979).
In humans, LSD is metabolized by NADH-dependent microsomal liver enzymes to the inactive 2-oxy-3-hydroxy LSD (O-H-LSD) and other metabolites, namely lysergic acid ethylamide (LAE), nor-LSD, di-hydroxy-LSD, 2-oxo-LSD, 13- and 14-hydroxy-LSD, lysergic acid ethyl-2-hydroxyethylamide (LEO) and trioxylated LSD (Passie et al., 2008). However, the major metabolite in urine is O-H-LSD, which is also detectable for a longer period than LSD (Dolder et al., 2015).
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Siddik et al. (1979) also investigated elimination of LSD in rats, guinea pigs and rhesus monkeys. Rats excreted 73% in feces and 16% in urine, guinea pigs 40% in feces and 28% in urine and rhesus monkeys 23% in feces and 39% in urine (Siddik et al., 1979). In humans LSD excretion is maximum after 4-6 hours after administration of 200 μg p.o. (Passie et al., 2008). Within the first 8 hours of orally administrated 200 μg, approximately 56% of nonmetabolized LSD was excreted through urine and renal clearance was approximately 1.6% of total clearance, which predicted oral bioavailability of 71% (Dolder et al., 2015).
A recent study combined date of two similar studies where 24 and 16 healthy subjects were administrated 100 and 200 μg of LSD, respectively (Dolder et al., 2017). In both studies, LSD was detected in subjects up to 24 hours after administration. Mean maximum plasma concentration (Cmax), area under the concentration-time curve, plasma half-lives and Tmax (estimated time to reach Cmax) were not significantly different between the doses (Dolder et al., 2017). Concentration-time curves revealed first-order kinetics for both doses, with avarage half-life of 2.6 hours (Dolder et al., 2017). However, in study with the administration of 200 μg of LSD, the authors noticed an inconsistent slower decrease in concentration after 12 hours, suggesting a redistribution of LSD from tissue or less precise quantification of low plasma levels (Dolder et al., 2015).
Toxicology and tolerance
LSD shows no acute tolerance after administration of 200 μg in humans (Dolder et al., 2015). The study also reported no severe adverse effects, however acute adverse effects include impaired concentration, headaches, exhaustion and dizziness, all which can last up to 24 hours (Dolder et al., 2015). There have been no known deaths from LSD overdose in human, however LD50 for rabbits, rats, and mice is 0.3, 16.5, and 46-60 mg/kg i.v., respectively (Passie et al., 2008). Klock, Boerner, and Becker (1974) reported a case of accidental intranasal consumption of LSD, which resulted in plasma levels of 1000-7000 μg per 100 ml blood plasma. Subjects experienced comatose states, hyperthermia, vomiting, light gastric bleeding, and respiratory problems but left the hospital without residual effects (Klock et al., 1974). Passie et al. (2008) also reported no known teratogenic, mutagenic or carcinogenic effects after LSD use in humans and teratogenic effects in rodents only after extremely high dose of 500 μg/kg.
PK-PD relationship
Dolder et al. (2017) reported increased blood pressure (BP), heart rate (HR), and body temperature (BT) in humans administrated 100 or 200 μg LSD p.o., compared to placebo (Dolder et al., 2017). Moreover, Dolder et al. (2015) observed a linear relationship between the LSD concentration and its dynamic effects (BP, HR, BT). The EC50 mean value was 1.3 +/- 0.7 ng/ml after 200 μg of LSD (Dolder et al., 2015). Authors also noticed higher dynamic values later in time, compared to plasma concentration.
Neurophysiological actions
Early studies of neurophysiological changes induced by LSD were mostly conducted with electroencephalography (EEG) (Passie et al., 2008). Their conclusions were brief; they reported reductions in oscillatory power, increase in the frequency of alpha rhythms, and activation of medial temporal lobe regions (Carhart-Harris et al., 2016; Passie et al., 2008). Modern neuroimaging techniques allowed more deeper understanding of brain connectivity patterns (De Gregorio et al., 2018).
More recently, Carhart-Harris et al. (2016) conducted a study with multimodal neuroimaging. Twenty healthy participants were i.v. administrated 75 μg of LSD or 10 ml of placebo. They conducted an fMRI scan, followed by the magnetoencephalography (MEG) and arterial spin labeling (ASL) scan, and blood oxygen level-dependent (BOLD) measures. Findings of the study revealed that LSD increases visual cortex cerebral blood flow (CBF) and resting state functional connectivity (RSFC), and decreases alpha and delta power, default-mode network (DMN) integrity, and decreases RSFC between parahippocampal-retrosplenial cortex (PH-RSC) (Carhart-Harris et al., 2016). Those changes predicted the magnitude of visual hallucinations and also correlated with changes in consciousness. Moreover, the changes in consciousness correlated more positively with DMN disintegration than with visual system, revealing the mechanism by which LSD alters one’s consciousness (Carhart-Harris et al., 2016).
Interaction with receptors
LSD mostly interacts with serotonin (5-HT) receptors where it inhibits serotonergic cell firing but leaves postsynaptic receptor intact (Passie et al., 2008). It mostly binds to 5-HT1A and 5-HT2A receptors where it produces an effect in agonistic manner (De Gregorio et al., 2018). However, when bind to 5-HT1 receptor LSD produces an inhibitory effect, whereas bind to 5-HT2 the effect is stimulatory (Passie et al., 2008).
Considering psychotic-like properties of LSD, it is not surprising that it also produces an effect on dopaminergic system (De Gregorio et al., 2018). LSD interacts with D1 and D2 receptors especially in the ventral tegmental area (VTA) (De Gregorio et al., 2018; Passie et al., 2008). Interestingly, after administration LSD first activates 5-HT2A and later D2, suggesting an interaction between both systems (Passie et al., 2008).
Although LSD does not bind to glutamate receptors directly, it has become clear that they play an important part in the overall effect (De Gregorio et al., 2018; Moreno, Holloway, Albizu, Sealfon, & Gonzalez-Maeso, 2011). Moreno et al. (2011) conducted an experiment with LSD on metabotropic glutamate receptor 2 (mGluR2) knock out (KO) mice. They have discovered that LSD did not produce an effect in mGluR2-KO mice, suggesting the necessary involvement of mGluR2 in producing a hallucinogenic effect (Moreno et al., 2011).
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