Sources:

There are two main sources of LSD; ergot, known as a poison or toxin for many centuries, and the morning glory plant.²

Ergot:

Ergot is the rhizomorph of Claviceps purpurea, the parasite fungus which grows in the heads of members of the grass (Gramineae) family. Rye is the principal plant, but enough is found in wheat to worry agriculturists. The fungus destroys the ovaries of the grain and instead of a normal kernel of grain one finds a brownish violet, horn-shaped mass protruding from the head of the grain.²

Morning glory:

Ololiuqui is Rivea corymbosa (Ipomoea sidaefolia [HBK]), Choisy, Turbina corymbosa (L.) Raf. The plant is a large woody vine with broadly cordate leaves 5 to 9 cm. long with many long white or whitish flowers. The seeds are roundish and rather woody. Rivea is found in the East Indies, Africa, South and Middle America, and in the West Indies. Only Rivea corymbosa is native to the New World, R. Corymbosa contains two active fractions: (a) a glucoside, its structure is unknown; and (b) ergot alkaloids, identified as ergine (iso-lysergic acid amide), isoergine (lysergic acid amide), chanoclavine, clymoclavin, and lysergol. Of these, the D-Lysergic acid amide is the most powerful hallucinogen, having 10 percent the activity of D-LSD. The amide is also present in ergot growing on some grasses. ²

Synthesis:

Lysergic acid derivatives are synthesized from ergot alkaloids. Take 1.2 g of ergotamine hydrochloride and add to 4 ml of anhydrous hydrazine, heat 1 hour at 90°. Add 20 ml of water and evaporate, to get d-iso-lysergic acid hydrazine. 1 g of the lysergic hydrazine is powdered and added to 40 ml of 0.1 N (ice cold) HCl acid. To this, cooled to 0°, is added 4 ml of 1 N Na nitrite, with good stirring. Over 2-3 min, add 40 ml of 0.1 N HCl acid to get pH to 5. Let stand for 5 min, basify with 1 N NaHCO3, extract with 100 ml of ether, and then with 50 ml of ether. Wash the ether layer with water and dry, then evaporate at 10°. Dissolve the resulting yellow azide in about 5 ml of diethylamine at 0° and then heat in a metal bomb at 60° for 1 hour. Remove heat after time elapses and let stand (after bleeding off pressure for bomb method of heating) for 2 hours and evaporate to get 0.7 g of LSD and 0.15 g of iso-LSD. ³

Chemistry:

Figure 2.: Lysergic acid diethylamide

LSD is a semisynthetic derivative of lysergic acid as found in the rye fungus Claviceps purpurea. The molecule consists of an indole system with a tetracyclic ring (C₂₀H₂₅ON₃). In the structure of LSD 5 and 8 carbons are asymmetric: therefore, four isomeric, optically-active LSD isomers are possible. These isomers are d- and l-LSD and d- and l-isolysergic acid diethylamide. Only the isomer d-LSD has psychoactive properties. D-LSD crystallizes from benzene in the pointed prisms. It is water-soluble having melting point 83ºC. LSD is stabilized in solution as its tartrate salt. The molar mass of LSD is 323.42 g/mol. A number of homologs and analogs of LSD molecules has been studied. These derivatives consist of variations of substituents on the amide group, sometimes by substituents on the indolic pyrrole ring. Except for derivatives substituted at the N-6, no other derivate has shown potency comparable to that of LSD.⁴

Ergolines are tetracyclic molecules, ultimately derived from alkaloids produced by the ergot fungus. The most important one, from the perspective of 5-HT_2A agonists, is LSD. LSD is the most potent of the psychedelic agents in the humans, although its affinity and functional potency at the human 5-HT_2A receptor are fairly unremarkable compared with simpler compounds such as DOI. Numerous clinical studies of LSD and certain of its congeners were performed in the 1950s and 1960s.^{4, 5,}

· Both carbons 5 and 8 are chiral, and it is only ergolines with the 5R, 8R-configuration, which have biological activity.⁷

· That isomer is dextrorotatory, so LSD is referred to as (+)-LSD or d-LSD 5S, 8S-(−)-LSD, had 2500-fold lower affinity. The 8-position readily epimerizes to provide (+)-isolysergic acid diethylamide, which has about 30-fold lower affinity and is inactive as a hallucinogen. This transformation is facile and occurs under slightly acidic pH.⁷

· Because of its complex structure, only a few modifications of LSD have been carried out, and those involved alterations of the amide function, reduction of the position 2, 3- or 9, 10-double bonds, any substitutions on the indole nitrogen or at the 2-position, and changes in the alkyl group on the basic nitrogen atom of the structure. Halogenation at the 2-position of LSD as in 2-bromo-LSD (BOL-148) or 2-iodo-LSD produces molecules that has 5-HT_2Aantagonist activity.⁸

· Reduction of the 9, 10-double bond of LSD reduces hallucinogenic property.⁹

· Reduction of the 2, 3-bond of the indole nucleus leads to a compound having about one-eighth the psychoactivity of LSD.¹⁰

· Extension of the N (6)-methyl group of LSD to longer alkyl groups gives compounds that are more potent than LSD in vivo in rodent behavior and which in some cases have potency comparable to, or slightly greater than LSD in humans.¹¹

· The in vivo potency of LSD is exquisitely sensitive to the presence and nature of the N, N-diethylamide moiety. any change, however slight, results in about one order of magnitude loss in potency.¹²

Pharmacodynamics of LSD:

LSD affects the G protein-coupled receptors, including most serotonin receptor and its subtypes, all dopamine receptor and its subtypes, and all adrenoreceptor subtypes, as well as other receptor sites. Most serotonergic receptors psychedelics are not significantly dopaminergic, and LSD is, therefore, atypical in this regard. The agonism activity of the D₂ receptor by LSD may contribute to its psychoactive effects in humans. LSD binds to most serotonin receptor subtypes except for the two that is 5-HT₃ and 5-HT₄ receptors.¹³

Mechanism of action of LSD:

The effects of LSD on brain functioning are complex and not fully understood. LSD affects diverse neurotransmitter systems,^{13, 14}but its psycho sensory effects are mediated by the activation of the 5-HT_2A receptors, with modulation by 5HT_2C and 5HT_1A receptors as well.^{13, 15}No neuroimaging studies have been conducted with LSD, whereas neuroimaging studies with the LSD-related molecules psilocybin and dimethyltryptamine have yielded inconclusive results, presumably it is because of the methodological challenges. The few definite results that came out through different studies are activation of the right hemisphere, altered thalamic functioning, and increased activity in paralimbic structures and frontal cortex.

5-HT_2A receptor activation is coupled with several intracellular signaling pathways. Gq-mediated signaling activates the inositol triphosphate–diacylglycerol pathway, leading to activation of protein kinase C. Signaling through G protein Gi/o, leading to activation of Src and expression of the immediate early genes egr-1 and egr-2, may be necessary to produce the hallucinogenic effects of LSD. The metabotropic glutamate receptor 2 which forms complexes with 5-HT_2A receptors is required for the pharmacological and behavioral effects. 5-HT_2A agonists activate pyramidal cells in the cerebral cortex by increasing glutamatergic neurotransmission within the intracortical networks, particularly those involving cortical layer. The human serotonin receptor binding affinities (Ki) of LSD for different serotonergic receptors 5HT_1A, 5HT_1D, 5-HT_2A, 5HT_2B, 5HT_2C, and 5H_T6 are respectively 0.64–4.92 nM, 14 nM, 0.76–21.4 nM, 0.977–8.91 nM, 1.1–45.7 nM, and 2.29 nM.^{14, 20}

Pharmacokinetics of LSD:

The effects of LSD normally last for 6 and 12 hours depending on dosage, tolerance, body weight, and age of patient.¹⁶

Pharmacology of LSD:

Psychological Effects:

State of consciousness is significantly altered by a moderate dose (75-150 μg p.o.). This alteration is characterized by stimulation (euphoria), increased capability for self-contemplation, and alteration in the psychological functioning within the direction of Freudian primary processes, referred to generally as hypnagogic experience and dreams. Particularly significant are perceptual changes like pseudo-hallucinations, illusions, synesthesias, and alterations of thinking and perception of time. Changes of self-perception and sense of self capacity also usually occur. The acute psychological effects of LSD last in the vicinity of 6 to 10 hours, depending on the dosage. The minimally recognizable dose of LSD in humans is about 25 μg p.o. The ideal dosage for a standard LSD reaction is estimated to be about 100–200 μg. Traumatic encounters (called “bad trips”) can have durable consequences for LSD abusers, including emotional episodes and infrequently ﬂashback phenomena. It should be noted, however, that these generally take place in uncontrolled conditions. Conversely, it has been shown that under controlled and supportive conditions, the LSD experience may have lasting positive effects on attitude and personality.³

Acute Neurocognitive Effects:

One downside with acute cognitive testing is that once a clinical dose of LSD (100 μg or more) is given, subjects turn out to be too impaired to collaborate because of the intensity of sensory activity and physical changes. Lower doses may not capture the genuine cognitive impacts of LSD. Nonetheless, several tests are given and the most representative studies are cited. Psychomotor functions like coordination and reaction time are promptly impaired when LSD is administered. LSD additional decreases performance on tests of concentration and attention. About 100 μg of LSD is required to impair recognition and recall of various stimuli.

The process of learning was additionally found to be unaffected by 75–150 μg LSD. 100 μg LSD signiﬁcantly hindered performance on arithmetic while 50 μg had no such effect. Memory was likewise influenced by LSD. Impairment of visual memory was additionally observed. Thinking processes are more resistant yet can be additionally influenced when higher doses of LSD are administered. Subjects can overestimate time intervals, under the inﬂuence of LSD. Intellectual functions were also found to be impaired under LSD. The outcomes were interpreted as a regression of intellectual functions to an ontogenetically younger state of development.

There were no evident chronic neurocognitive after-effects from LSD exposure.¹⁷

Toxicological Data:

The LD₅₀ of LSD fluctuates from species to species. The most sensitive species is the rabbit, with an LD₅₀of 0.3 mg/kg i.v. The LD₅₀ for rats (16.5 mg/kg i.v.) is considerably higher; however mice tolerate doses of 46– 60 mg/kg i.v. These animals may die by respiratory failure and paralysis. Monkeys (Macaca mulatta) can been injected with doses as high as 1 mg/kg i.v. with no lasting somatic effects. There are no reported human deaths from an LSD overdose. Eight individuals who accidentally administered a very high dose of LSD intranasally (mistaking it for cocaine) had plasma levels of 1000–7000 μg per 100 ml blood plasma and suffered from comatose states, hyperthermia, light gastric bleeding, regurgitating, and respiratory problems. However, all survived with hospital treatment and without residual effects. In 1967, a report gave evidence for LSD-induced chromosomal damage. This report could not rise up to scrupulous scientiﬁc examination and was disproved by later studies. Observational examinations demonstrated no evidence of teratogenic or mutagenic impacts from use of LSD in humans. Teratogenic effects in animals (mice, rats, and hamsters) were discovered only with phenomenally high doses (up to 500 μg/kg s.c.). The most vulnerable period in mice was the ﬁrst 7 days of pregnancy. LSD has no carcinogenic potential.

Somatic Effects:

The threshold dose for quantifiable adrenergic effects in humans is 0.5–1.0 μg/kg LSD p.o. A moderate dose of LSD for humans is measured to be 75–150 μg LSD p.o. Administering animals (rats and cats) with very high doses of LSD (up to 100 μg/kg i.v.) leads to mild autonomic changes of mydriasis, hyperthermia, tachycardia, hypertonia, tachypnea, and hyperglycemia. These changes may be the result of an excitatory syndrome caused by central stimulation of the sympathetic system. Bradycardia and lowering of blood pressure was observed in the affected animals, and it was concluded that the sympathomimetic effects of LSD require the activation of higher cortical centers. Autonomic changes shows stimulation of both branches of the autonomic nervous system.

In most subjects, sympathetic stimulation is observed, by a pupillary dilation and light to moderate tachycardia and mild increase in blood pressure; other more inconsistent signs are slight hyperglycemia and, rarely, hyperthermia. For the most part respiration remains unaltered. Other symptoms propose parasympathetic stimulation such as frequent diaphoresis and salivation. Nausea may also occur, emesis is exceptional, and ﬂushing of the face is more frequent than paleness. Sympathicotonia typically predominates, however there are extraordinary individual variations and a marked parasympathicotonia with bradycardia and hypotension seen in some subjects. A temporary headache and near-syncope have occasionally been reported.

There is no evidence that LSD affects liver functioning. Reports of changes in adrenaline levels because of LSD are opposing, which may reﬂect individual variations of sympathicotonia induced by individually different experiences on a psychological level. The most consistent neurological effect is an exaggeration of the patellar (and other deep tendons) reﬂexes. More unusual signs include slight unsteadiness of gait to full ataxia, positive Romberg's sign, and mild tremor.

Other physiological measures are unaffected. There are other somatic symptoms experienced by some subjects, beyond objectively measurable somatic changes. ¹⁴

Table 1: Typical sensory and psychological effects under the inﬂuence of a medium dose of LSD (100–200 μg p.o.)

Sensory alterations (visual, auditory, taste, olfactory, kinesthetic)	· Illusion Pseudo-hallucination. · Intensiﬁcation of colour perception. · Metamorphosis – like the change in objects and faces. · Intense (kaleidoscopic or scenic) visual imagery with transforming content.
Alterations of affectivity	· Intensiﬁcation of emotional experience: euphoria, dysphoria, anxiety, mood swing.
Alterations of thinking	· Less abstract and more imaginative thought. · Broader and unusual association. · Attention span shortened.
Alterations of body perceptions	· Change in body image. · Unusual inner perception of bodily processes. · Metamorphic alteration of body contours.
Memory changes	· Re-experiencing signiﬁcant biographical memories. · Hypermnesia. · Age-regression.

Psychological Effects (Acid Trips):

The most widely recognized psychological effects of LSD are illusions and visual hallucinations (colloquially referred to as “trips"), which can differ enormously relying upon how much is administered and how the brain responds. Trips usually start by 20–30 minutes of administering LSD orally (less if snorted or taken intravenously), peak three to four hours after ingestion, and lasts for 12 hours. Negative encounters, known as "bad trips", produce intense negative emotions, like irrational fears and anxiety, paranoia, rapid mood swings, panic attacks, wanting to harm others, intrusive thoughts of hopelessness, and suicidal ideation. It is difficult to anticipate when a bad trip will occur. Good trips are stimulating and pleasurable, and usually involve feeling as if one is disconnected from reality, floating, euphoria (known as "rush"), feelings of joy or decreased inhibitions, and the belief that one has extreme mental clarity or superpowers. ²¹

Uses of LSD:

LSD in drug dependencies:

Historically, lysergic acid diethylamide was reported to be beneficial in the management of drug addiction. However, widespread indiscriminate abuse and reports of adverse effects resulted in the declaration of the drug as an ‘illicit agent’. But in the last decade or so, a new generation of researchers were interested in harnessing the therapeutic benefits of some ‘illicit drugs’ for post-traumatic stress disorder (PTSD), drug and alcohol dependency, and smoking cessation.

One study reviewed the administration of LSD, ibogaine, peyote, and ayahuasca in the treatment of drug dependencies. Evidence suggests that these drugs help in recovery from drug dependency through many therapeutic mechanisms, mostly involving serotonin. These serotonin based dynamics are directly relevant to treat addiction because, in addicted individuals, serotonin levels are usually low, and serotonin also modulates other neurotransmitter systems. A meta-analysis of controlled trials has shown a consistent and clinically significant beneficial effect of high-dose LSD in recovery from drug dependency.¹⁸

Effects on prepulse inhibition (PPI):

In a fascinating investigation, LSD (200 μg) and placebo were given to 16 healthy subjects in a double-blind, randomized, placebo-controlled, crossover study. The measures for outcome included psychometric scales, investigator ratings, prepulse inhibition (PPI) of the acoustic startle response, autonomic, endocrine, and adverse effects. LSD created noteworthy changes in waking consciousness and predominantly induced visual hallucinations, audio-visual synesthesia, and positively experienced derealization and depersonalization phenomena. LSD also showed increase in subjective happiness, closeness to others, wellbeing, openness, and trust. LSD decreased PPI compared with placebo and showed significant hypertension, tachycardia, hyperthermia, mydriasis, plasma cortisol, oxytocin, prolactin, and epinephrine. LSD disturbed PPI and created sensorimotor defects similar to those observed in schizophrenia which may be because of its action at 5-HT_2A receptor. It is to be noted that PPI is additionally influenced by genetic variations in the 5-HT_2Areceptor gene.¹⁸

For anxiety associated with life-threatening diseases:

Recently conducted trials studying the utility of psychedelics in psychotherapy have exhibited safety and impressive efficacy in treating anxiety related to terminal diseases. In one study assessing the part of LSD in combating severe anxiety disorder, 100 out of 150 patients with nonpsychotic functional psychiatric disorders benefited from the use of LSD (25–2500 µg). LSD has been considered to allow ‘perceptualization of the transference’ and expands the scope and value of the psychotherapeutic approach in such cases.

Another double-blind, randomized, active placebo-controlled, crossover pilot study was directed to analyze the safety and efficacy of LSD-assisted psychotherapy (20 and 200 µg) in 12 patients with anxiety associated with terminal diseases. At the 2-month follow-up, positive effects were discovered by means of the State–Trait Anxiety Inventory (STAI) scale in reductions in trait anxiety with no acute or chronic adverse effects enduring beyond 1 day after treatment or treatment-related serious adverse events. STAI reductions were sustained for 12 months. These outcomes indicate that when taken safely in a rigorous and supervised setting, LSD can reduce anxiety.

Recently LSD has been assessed more in pilot therapeutic trials as a treatment for anxiety in patients with terminal diseases. Additionally, LSD can increase plasma oxytocin levels and oxytocin is thought to contribute to the empathogenic prosocial effects. LSD likewise increased circulating levels of prolactin and cortisol [Watts et al. 1995]. In view of these studies and a recent study using psilocybin, LSD can be explored further for use in such conditions.¹⁸

To boost human creativity:

Using psychedelic (hallucinogenic) drugs to boost creative minds in art and literature started in the 1960s. The psychological experience produced in people under the influence of such agents is purely multifarious and idiosyncratic, however, a broad range of common characteristics have been observed. These include alterations in the person’s perceptions (in all the sensory modalities), alterations in the emotions and expansion in an individual’s sense of identity, thought, and creativity.¹⁸

For treatment of alcohol addiction:

LSD is considered as an important tool in hastening effective results of psychotherapy in alcoholics who are generally hard to treat. In the 1950s through to the early 1970s, over 30 publications reported on these effects. Early reports of clinical outcomes and uncontrolled trials had variable but promising results, especially when the psychedelic model was used. At least a dozen trials with some form of the control group were ultimately used, but these studies were mostly underpowered and the results were not confirmatory. Krebs and Johansen were the first to conduct quantitative meta-analysis of LSD alcoholism clinical trials. From the 536 participants in six trials, 59% of subjects receiving LSD (210–800 µg) reported lower levels of alcohol abuse compared with 38% of subjects receiving placebo.¹⁸

LSD for the treatment of Alzheimer’s disease:

LSD can be used for the treatment of Alzheimer's disease using lysergic acid diethylamide and pharmaceutically acceptable salts thereof. It has shown promising results in improving memory and learning capacity, delaying the loss of memory and loss of learning capacity, reducing the severity of dementia, delaying the onset of dementia, reducing the severity of depression, delaying the onset of depression, reducing the severity of anxiety, and/or delaying the onset of anxiety in the subjects.¹⁹

Adverse reactions:

1. Chronic drug dependence with followed by personality changes and depression; and

2. Acute loss of subjective self-identity.

These adverse reactions usually occur in already emotionally sensitive people. Most of these users can be divided into two groups, those who have unresolved identity problems and those with severe ego abnormality.

Most of the adverse reactions are of the chronic drug dependence type and are usually seen in adolescents and young adults who have not negotiated the age-appropriate tasks of forming and integrating the various identities that are the composite of their life experiences.¹

Abuse:

Abuse of LSD is not preferable; the drug produces such an absurd euphoria that daily administration is almost impossible. Therefore LSD use does not lead to physical dependence. However, the tolerance disappears after a few days of abstinence without producing craving for the drug. So, LSD dependence is mostly psychological and not physical.¹⁴

Tolerance:

Drug tolerance is deﬁned as a decrease in responsiveness to a drug after repeated administration. LSD shows tolerance in humans and animals. After a few moderate daily doses of LSD, tolerance of LSD to autonomic and psychological effects occurs in humans. A recent animal experiment with rats (130 μg/kg LSD i.v. for 5 consecutive days), who were previously trained to discriminate LSD from saline, indicated a reduction in 5-HT_2A receptor signaling caused by a reduction of 5-HT_2A receptor density. This decrease in receptor density may apprehend possible mechanism for the development of acute tolerance to LSD. Pre-treatment with BOL-148, a non-hallucinogenic congener of LSD with serotonin antagonist properties like LSD, will not block the effects of LSD. Besides other derivatives of LSD, such as UML-491 and MLD41, are able to induce cross-tolerance if applied in the days prior to LSD. There is partial cross-tolerance (depending on whether LSD is given prior or later) among LSD, mescaline, and psilocybin. A complete cross tolerance is to mescaline in LSD-tolerant subjects. One study showed that one-way cross-tolerance from LSD to DMT does not occur. Studies with 9 tetrahydrocannabiol (THC) in subjects tolerant to LSD did not show a cross-tolerance between these drugs. There is no cross-tolerance between LSD and amphetamine.³

CONCLUSION:

Lysergic acid diethylamide (LSD) is described as a classical hallucinogen which began its journey from the middle of the last century after its accidental discovery. Since then, it was used as a common and notorious substance of abuse all over the globe. Its beneficial role as a supplement to psychotherapy came to be known after some ‘benevolent' experiments were carried out over time to investigate some of its potential uses. However, many of its effects were uncertain and seemed to be a psychedelic enigma. Pharmacological treatments for psychiatric disorders and for drug abuse show limited efficacy, leaving severe and persistent symptoms in treated patients. Preliminary studies in animals and humans showed that lysergic acid diethylamide (LSD) may have anxiolytic, anti-depressive, and anti-addictive properties.

ACKNOWLEDGEMENT:

The authors are grateful to the authorities of Bharati Vidyapeeth college of Pharmacy, Kolhapur for the facilities.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

REFERENCES:

1. Eveloff H. H., the LSD syndrome. A review, California Med, 109 (5); 1968:368–373

2. Hoffer A., D-Lysergic acid diethylamide (LSD): A review of its present status. Clinical Pharmacology and Therapeutics, 6 (2); 1965: 183-255.

3. Professor Buzz, Recreational Drugs, Rhodium Archive, 2004.

4. Brimblecombe RW, Pinder RM. Hallucinogenic Agents. Bristol: Wright-Scientechnica, 1975.

5. Nichols DE. Hallucinogens. In: Verderame M, ed. Handbook of CNS Agents and Local Anesthetics. Boca Raton: CRC Press Inc.; 1986: 303–325.

6. Shulgin AT. Chemistry of psychotomimetics. In: Hoffmeister F, Stille G, eds. Handbook of Experimental Pharmacology. New York: Springer-Verlag; 1982; pp.29.

7. Bennett JP Jr, Snyder, SH. Serotonin and lysergic acid diethylamide binding in rat brain membranes: relationship to postsynaptic serotonin receptors. Mol Pharmacol, 12; 1976: 373–389.

8. Ginzel KH, Mayer-Gross W. Prevention of psychological effects of d-lysergic acid diethylamide (LSD 25) by its 2-brom derivative (BOL 148). Nature 1956; 178-210.

9. Hartig PR, Kadan MJ, Evans MJ, Krohn AM. 125ILSD: a high sensitivity ligand for serotonin receptors. Eur J Pharmacol, 89; 1983: 321–322.

10. Gorodetzky CW, Isbell H. A comparison of 2,3- dihydro-lysergic acid diethylamide with LSD-25. Psychopharmacologia, 6; 1964: 229–233.

11. Hoffman AJ, Nichols DE. Synthesis and LSD-like discriminative stimulus properties in a series of N(6)-alkyl norlysergic acid N, N-diethylamide derivatives. J Med Chem, 28; 1985: 1252–1255.

12. David E. Nichols, Structure–activity relationships of serotonin 5-HT2A agonists, WIREs Membr Transp Signal, 1(1); 2012: 559–579.

13. Nichols DE., Hallucinogens. Pharmacology and Therapeutics. 101(2); 2004: 131-811

14. Passie, T. et al. The pharmacology of lysergic acid diethylamide: a review. CNS Neurosci Ther, 14; 2008: 295–314.

15. Vollenweider F. et al. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport, 9; 1998: 3897–3902

16. Alexander, Shulgin A. TIHKAL: The Continuation, Berkeley: Transform Press, California, 1997.

17. Halpern JH, Pope HG Jr., Do hallucinogens cause residual neuropsychological toxicity?, Drug Alcohol Depend, 53; 1999: 247–256.

18. Das, Saibal et al. "Lysergic Acid Diethylamide: A Drug of ‘use’?" Therapeutic Advances in Psychopharmacology, 6(3); 2016: 214-228.

19. RAZ, S. U.S. Patent No. WO 2016145193 A1. Washington, DC: U.S. Patent and Trademark Office. (2016)

20. Kowalchuk A, Reed BC. Substance use disorders. Textbook of Family Medicine. Rakel RE, Rakel DP, eds. Elsevier. Philadelphia, PA; 2016; 9th ed: chap 50.

Received on 25.07.2017 Modified on 11.08.2017

Research J. Pharm. and Tech 2017; 10(12): 4415-4422.

DOI: 10.5958/0974-360X.2017.00814.9