properties of serotonergic hallucinogens and therapeutic opportunities 1st draft.docx

8/10/2019 Properties of Serotonergic Hallucinogens and Therapeutic Opportunities 1st draft.docx

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Serotonergic Hallucinogens and Therapeutic Opportunities

Introduction

The word hallucinogen has a broad and unclear definition in the eyes of both thegeneral public and scientific persons alike.

The term classic hallucinogen is also used to refer to

Three of the most well known of the psychedelic drugs whose effects arepredominately attributed to the activation of the serotonergic system will be examined

here. These are lysergic acid diethylamine (LSD), psilocybin and N,N-

dimethyltryptamine (DMT). These drugs have been chosen due to the

Though the mechanism through which hallucinogens produce their psychedelic

properties is not completely understood, it is generally believed that the binding of

these compounds to 5-HT2Ais responsible. LSD, psilocybin and DMT all bind to 5-

HT2Aaswell as the other serotonin receptor subtypes shown in Table 1. The

serotonergic hallucinogens display a high affinity to certain 5-HT sites due to their

structural similarities to serotonin (shown in Figure 1).

5-HT2Ais an excitatory G-protein coupled receptor that is coupled to a Gq alpha

subunit

References

[1]


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History of Clinical Research

Despite the wealth of research into hallucinogens that had taken place during the 50s

and 60s, all research into the psychotherapeutic potential of hallucinogens ceased by

the 1970s [1]. This is attributed to the scheduling of these drugs worldwide [2],

limiting their availability for research.

References:

[1] Safety and Efficacy of Lysergic Acid Diethylamide-Assisted Psychotherapyfor Anxiety Associated With Life-threatening Diseases

[2] History, Rationale and Potential of Human Experimental Hallucinogenic Drug

Research in Psychiatry


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LSD

Lysergic acid diethylamide (LSD) is a semisynthetic

derivative of lysergic acid [1]and is one of the most

well known of the hallucinogenic drugs. In the UK,

LSD is classed as a schedule 1 controlled drug underthe misuse of drugs act 1971 [2], meaning it has no

recognized medicinal use and is subject to the strictest

of controls (possession and supply are both illegal

without a license supplied by the Home Office).

The drug was first synthesized by Albert Hofmann in

the November of 1938 [3] and has been the subject of

clinical research since 1949 [4]. The drug was researched heavily during the 1950s

and the 1960s due to its perceived use in psycholytic therapy [?], however, during

the 1970s research into potential medical applications of LSD tapered to an almost

halt. Since the start of the 21stcentury there has been resurgence in studies searchingfor potential therapeutic uses of LSD.

In terms of chemistry, this drug is an example of an ergoline. Ergolines are

derivatives of the chemical ergoline - a tryptamine analogue with a much more rigid

structure [5].

References:

[1] Passie, T. (2008). The Pharmacology of Lysergic Acid Diethylamide: A

Review. CNS Neurosci Ther. 14(4), 295-314

[2] Great Britain. Misuse of Drugs Act 1971. Chapter 38. London: Stationery

Office; 2000.

[3] WEB LINKhttp://www.maps.org/news-letters/v06n3/06346hof.html

[4] Grinspoon, L. and Bakalar, J.B. Psychedelic Drugs in the Twentieth Century.

In: Psychedelic Drugs Reconsidered. New York: Basic Books, Inc. p. 62

[5] Nichols, D.E. (2004). Hallucinogens.Pharmacol Ther.101(2), 131-181

[Image] Nichols, D.E. (2004). Hallucinogens. Pharmacol Ther. 101(2), 131-181
http://www.maps.org/news-letters/v06n3/06346hof.htmlhttp://www.maps.org/news-letters/v06n3/06346hof.htmlhttp://www.maps.org/news-letters/v06n3/06346hof.htmlhttp://www.maps.org/news-letters/v06n3/06346hof.html


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Psilocybin

Psilocybin is an alkaloid found in the

psychedelically active species of mushroom

belonging to the genusPsilocybe. The compound

is found in numerous species such asP.semilanceata, P. cubensis andP. mexicanaand is

responsible for their psychoactive properties when

ingested [1].

The compound belongs to the indolealkylamine

(simple tryptamine) family of serotonergic

hallucinogens and is the most clinically

researched of all the classic hallucinogens [2].

Psilocybin is not itself pharmacologically active,

it is infact a prodrug for the active compound psilocin. The dephosphorylation ofpsilocybin to form psilocin takes place in the intestinal mucosa and is carried out by

alkaline phosphatase and nonspecific esterase [3].

References:

[1]

[2]

[3] Tyl, F., lene, T. and ore, J. (2014). PsilocybinSummary of

knowledge and new perspectives. Eur. Neuropsychopharmacol. 24(3), 342-356

[Image] Nichols, D.E. (2004). Hallucinogens. Pharmacol Ther. 101(2), 131-

181


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DMT

References:

[1]

[Image] Nichols, D.E. (2004). Hallucinogens. Pharmacol Ther. 101(2), 131-

181


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Current Clinical Research

Many of the perceived potential uses of hallucinogens in modern medicine are in the

treatment of mental disorders such as anxiety and obsessive-compulsive disorder, and

many of the most up-to-date trials of these compounds have been investigating their

uses in such conditions.

Another significant, and unorthodox, use for the serotonergic hallucinogens is in the

treatment of cluster headaches. Cluster headache is a form of trigeminal autonomic

cephalalgiaa headache characterised by unilateral, orbital pain along with cranial

autonomic symptoms such as nasal congestion, rhinorrhea and tearing in the eye on

the affected side of the face [1]. These headaches are notorious for the extraordinary

pain and suffering they inflict on patients during episodes, with a study by Rozen and

Fishman [2] finding that 55% of responders to a survey on cluster headaches had

undergone suicidal ideation during attacks. The condition is linked to other distressing

statistics such as

Pharmacological treatments do exist for cluster headache, with varying degrees of

efficacy. NICE guidelines recommend sumatriptan as a first line in terminatingheadaches [3]. When the triptans were developed during the 1990s, they were

celebrated as wonder drugsin treating both migraine and cluster headache. But,

despite the high success rate of sumatriptan in reducing the severity of cluster

headaches (reported as 74% in a study by The Sumatriptan Cluster Headache Study

Group [4]), some patients remain unresponsive to conventional drug therapy.

This, paired with the debilitating nature of cluster headaches, has led to a significant

number of patients resorting to the use of psychedelic drugs, as both an acute

treatment to terminate episodes and as a prophylactic to prevent recurrence of

episodes. As stated earlier, the serotonergic hallucinogens have a high affinity to

various subtypes of serotonin receptors, including 1B and 1D (see Table 1).Sumatriptan belongs to the triptan class of drugs, whose mode of action is attributed


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to agonist activity at the serotonin receptors 1B and 1D [5]. It shouldnt be too

difficult then, to imagine that hallucinogens may share the headache relieving

capabilities of the triptans.

The increase in patients self-prescribing hallucinogens seems to have been fuelled by

internet-based forum discussions as well as recent spates of online newspaper articlespurporting these drugs to be the long sought after miracle curefor cluster headaches.

Some websites seem to openly encourage sufferers of cluster headache to treat

themselves with LSD and magic mushrooms and provide advice on dosing and

administration. Though the recommendations made by these websites could quite

quickly be dismissed as irresponsible, it is worth remembering that for a significant

portion of patients the marketed drugs licensed for cluster headache provide no help

whatsoever.

The evidence base for the use of such drugs appears to be largely anecdotal however.

As well as the action of hallucinogens at serotonin receptors, it is worth noting that

psilocybin has been found to reduce cerebral blood flow in the hypothalamus [7],

which could also be a contributing factor to its supposed efficacy in treating cluster

headache.

Regardless of their supposed efficacy though, treating cluster headaches with

powerful hallucinogens is far from ideal for patients. Due to the psychedelic nature of

these drugs, patients could be rendered non-functional in carrying out every day tasks

by the trip they would be forced to endure every time a headache occured. The

efficacy of LSD in the treatment of cluster headache has, however, recently prompted

a small study into the use of a supposedly non-hallucinogenic derivative of LSD, 2-

bromo-lysergic acid diethylamide (BOL-148), as a potential therapy [6]. BOL-148 is

produced by the bromination of LSD at carbon 2, a process that supposedly removes

the hallucinogenic properties of LSD, making it far more suitable for use in patients.

Although the trial was small (being made up of only 5 patients), the compound seems

to show promise, with one patient experiencing a two-month remission of attacks.

Due to the low specificity of the hallucinogens to 1B/1D receptors, a greaterfrequency of ADRs can be expected (Triptans and ergot alkaloids in the

acute treatment of migraine: similarities and differences)


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These guidelines also suggest the use of verapamil as a prophylactic measure,

however it should be noted that this is an off-label use of verapamil and the evidence

used to form the basis of this recommendation has been described as being of low

quality [3].

References

[1] Matharu, M.S.; Goadsby, P.J. Trigeminal Autonomic Cephalalgias.J Neurol

Neurosurg Psychiatry.2002, 72(S2), 19-26

[2] Rozen, T.D.; Fishman, R.S. Cluster Headache in the United States of America:

Demographics, Clinical Characteristics, Triggers, Suicidality, and Personal Burden*.

Headache. 2012, 52(1), 99-113

[3] http://cks.nice.org.uk/headache-cluster#!topicsummary

[4] The Sumatriptan Cluster Headache Study Group. Treatment of acute cluster

headache with sumatriptan.N Engl J Med. 1991, 325 (5), 322-326

[5] Tepper, S.J.; Rapoport, M.D.; Sheftell, F.D. Mechanisms of Action of the 5-

HT1B/1D Receptor Agonists.Arch Neurol. 2002, 59 (7), 1084-1088

[6] Karst, M.; Halpern, J.H.; Bernateck, M.; Passie, T. The non-hallucinogen 2-

bromo-lysergic acid diethylamide as preventative treatment for cluster headache: An

open, non-randomized case series. Cephalalgia. 2010, 30 (9), 1140-1144

[7] Carrhart-Harris, R.L. et al. Neural correlates of the psychedelic state as

determined by fMRI studies with psilocybin.Proc. Natl. Acad. Sci. U.S.A.2012, 109

(6), 2138-2143


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Critique

Discussion on the reliability of studies and the practicality of using hallucinogens.


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References


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Table 1

Relative Affinities

Receptor Subtype npKi (nM)LSD Psilocybin DMT

5-HT1A 3.73 2.88 0

5-HT1B 4.00 2.19 0

5-HT1D 3.70 3.40 3.97

5-HT1E 2.55 3.03 3.28

5-HT2A 3.54 2.14 2.58

5-HT2B 3.11 4.00 3.91

5-HT2C 3.11 2.52 3.42

The data in this table is adapted from a study conducted by Ray, T.S. (2010) and displays theaffinities of LSD, Psilocybin and DMT to different serotonin receptor subtypes. Affinity ismeasured by a normalized pKi, where the highest pKi is set to 4 and any Ki values greater

than 10,000 are set to 0.

These values are given by the formula:

npKi = 4 + pKi - pKiMax

This allows the potency of different drugs to be ignored and the affinities of a drug todifferent 5-HT receptors to be compared easily.

Reference:

Ray, T.S. Psychedelics and the human recepterome.PLoS ONE. 2010, 5 (2), DOI:10.1371/journal.pone.0009019


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Figure 1

The structure of serotonin alongside the structure of three of the most widely used

hallucinogens. Also included is the structure of sumatriptan, the recommended first

line treatment for cluster headache.

4cm x 5.5cm

The similarity in structure between the triptans and the indolealkylamine

hallucinogens is certainly worth noting. These drugs can both be described as


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substituted tryptamines, and share the structural backbone of serotonin in their

structures, accounting for their activity at 5-HT receptors.

properties of serotonergic hallucinogens and therapeutic opportunities 1st draft.docx

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