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The non-hallucinogen 2-bromo-lysergic acid diethylamide as preventative treatment for cluster headache: An open, non-randomized case series

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DOI: 10.1177/0333102410363490
2010 30: 1140 originally published online 26 March 2010Cephalalgia
Matthias Karst, John H Halpern, Michael Bernateck and Torsten Passie
headache: An open, non-randomized case series
The non-hallucinogen 2-bromo-lysergic acid diethylamide as preventative treatment for cluster
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International Headache Society
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Clinical Correspondence
The non-hallucinogen 2-bromo-lysergic
acid diethylamide as preventative
treatment for cluster headache: An open,
non-randomized case series
30(9) 1140–1144
!International Headache Society 2010
Reprints and permissions:
DOI: 10.1177/0333102410363490
Matthias Karst
, John H Halpern
, Michael Bernateck
Torsten Passie
Date received: 10 September 2009; accepted: 24 January 2010
Cluster headache (CH) is a stereotyped primary head-
ache characterized by strictly unilateral severe orbital
or periorbital pain and categorized as either episodic or
chronic (1,2). Its prevalence is 0.1% (3). Oxygen and
sumatriptan are the treatments of choice for individual
attacks, whereas verapamil, lithium, corticosteroids
and other neuromodulators can suppress attacks
during cluster periods (1). All standard medication
treatments may be ineective. Surgical treatment may
be an option for medication non-responders, including
deep brain (4) or occipital nerve stimulation (5).
However, serious complications from brain surgery,
including death, can occur (6).
An Internet survey of 53 CH patients reported on
claims that psilocybin is better at aborting acute attacks
than either oxygen or sumatriptan and that LSD and
psilocybin are both better at triggering and extending
remission than standard drugs (7). However, due to
hallucinogenicity and the absence of established medi-
cal indication, these drugs are criminalized and placed
within the most restrictive Schedule I of the Controlled
Substances Act, which sanctions only limited research
use. Although the hallucinogenic properties of LSD
and psilocybin are undesirable from both regulatory
and patient safety perspectives, it was unclear to us at
the outset whether a non-hallucinogenic analog could
also provide meaningful relief to CH patients. To
address the question of whether the CH relief asso-
ciated with these two structurally diverse compounds
is related to the mechanisms triggering intoxication,
we decided to investigate the ecacy of a non-
hallucinogenic analog of LSD. LSD’s hallucinogenic
eects are completely lost when the double bond in
the D ring is saturated and with substitution at R2
(e.g. by bromination in 2-bromo-LSD) (BOL-148) (8).
BOL-148 has been studied in volunteers (up to 20 mg
per os) (9) and in patients suering from vascular head-
aches but not, apparently, in patients with CH (9,10).
These past studies concluded that BOL-148 is non-toxic
and non-hallucinogenic. Only very mild side eects, if
any, have been observed, when given in the dose range
used in our project (30 mg/kg/body weight) (9). No
long-term behavioral or psychological eects from
BOL-148 have been reported from past studies with
more than 300 healthy, normal subjects (11), and
30 mg BOL-148 administered daily over four to five
weeks failed to alter active psychosis in chronically ill
schizophrenic women (12).
Case series
Patients referred to Hannover Medical School’s Pain
Clinic were identified with CH if they met the respective
diagnostic criteria of the International Classification of
Headache Disorders (2). All patients, who were ser-
iously aected by the disease, were non-responders to
verapamil (or could not tolerate its side eects at higher
doses) and to some extent to other prophylactic medi-
cations as well, although not all medication alternatives
(e.g. topiramate or prednisone), or more invasive pro-
cedures (e.g. intravenous dihydroergotamine or occipi-
tal nerve stimulator implantation), had been attempted.
Hannover Medical School, Germany.
McLean Hospital and Harvard Medical School, USA.
Corresponding author:
Matthias Karst, Department of Anesthesiology, Pain Clinic,
Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
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All patients signed an informed consent that declared
their agreement to participate in this project on the com-
passionate use of BOL-148 for CH. It was approved by
the local ethics committee in accordance with German
law. Patients kept a standardized daily diary of CH
symptoms (see for a copy)
starting at least two weeks prior to BOL-148 adminis-
tration. BOL-148 was manufactured by THC pharm
GmbH (Frankfurt am Main, Germany). A purity of
>99.2% was identified by high-performance liquid chro-
matography (HPLC) and other analytical tests. BOL-
148 30 mg/kg/body weight was dissolved in distilled
water and then given once every five days for a total of
three doses per os. BOL-148 was administered in the
presence of two of the authors (MK, TP). Alterations
in consciousness, thought disturbances, and vital signs
(blood pressure, heart rate) were measured during a
three-to-four-hour observational period, as BOL-148 is
typically active for two to three hours. Patients were
asked to continue completing daily headache diaries
for at least one month or until they experienced three
days of attacks, starting a new cluster series.
Results are summarized in Table 1 and Figure 1. One
patient (S2) with episodic CH, who was in an active
attack period, and four patients with the chronic form
participated. All but one patient (S1) had experienced
symptoms for more than 10 years. Patient S2’s cluster
period terminated after BOL-148 with a long-lasting
remission period of six months (at last follow-up) and
continuing. Patients S3 and S5 reported pronounced
reduction of attack frequency, including full remission
for more than one month, indicating transition from a
chronic to an episodic form. Cluster attacks resumed
after a two-month remission for patient S5. In nine
months since BOL-148 treatment, patient S3 describes
ongoing remission of cluster period, reporting only a few
solitary sporadic attacks. Patient S4 reported a pro-
found reduction in attack frequency, although without
one full month of remission and attack frequency
increasing approximately six months after BOL-148
treatment. In addition, patients S3 and S4 found the
pain intensity of remaining occasional attacks so
improved that they no longer administered an acute
intervention, as they had prior to BOL-148. Although
patient S1 did not experience pronounced attack reduc-
tion similar to the other four patients, he indicated a
decrease of attack intensity of about 30% within the
first four months. It is likely relevant that patient S1
continued to drink alcohol (contrary to advice), a
known and common trigger for attacks.
No changes to heart rate and blood pressure were
observed during BOL-148 treatment. Most of the
patients recorded some kind of ‘‘flabby’’ or ‘‘light
drunk’’ feelings. Patient S2 noted a ‘‘funny’’ feeling,
tense muscles, and sweaty palms. These mild subjective
eects lasted from one to two hours. No visual hallu-
cinations or distortions occurred, nor was there any
evidence of delusional thinking or overt psychosis.
The results show that three single doses of BOL-148
within 10 days can either break a CH cycle or consider-
ably improve the frequency and intensity of attacks, even
resulting in changing from a chronic to an episodic form,
with remission extending for many months or longer.
While for patients S3, S4, and S5 the remission is very
likely due to BOL-148 treatment, for S1, who charted in
his diary continued attacks with reduced pain, and S2,
who suered from episodic CH, the observed eects may
also be due to the natural course of the disease, despite
S1 and S2’s impression that their cluster attack cycle
improved in ways they had not experienced before
BOL-148. Except for very mild alterations of subjective
state and mild to no sympathetic reactions for about two
hours, no other side eects were observed.
Sicuteri et al. used LSD and some of its derivatives
(with BOL-148 among them) in the treatment of
migraine and other vascular headaches (10). Because
those studies were entwined with the task of identifying
the pathophysiological mechanism of vascular head-
aches (13), they lack exact documentation and
follow-up results of the exposed subjects. Especially
considering the results we report, no evidence has
been found that BOL-148 was administered specifically
for active CH in these earlier trials. A suerers-driven
interest in the clinical eects of LSD and psilocybin for
CH did not develop until recently, from anecdotal
observations to Internet-based discussions to the pub-
lished Internet survey (7) and subsequent science-media
interest. Interestingly, those reports describe a single
dose or a few doses resulting in long-lasting eects,
which we now also demonstrate from BOL-148.
Taken together and in regard to failure of other more
direct explanations, especially for the long-range remis-
sion extension, these results indicate that BOL-148, psi-
locybin, and LSD may influence the expression of genes
(epigenetics), which are responsible for the biological
clock of the organism (14). However, prolonged admin-
istration of BOL-148 does not result in cross-tolerance
to LSD (15). This, in turn, suggests that BOL-148’s
mechanism of action for CH is unrelated to those
receptor systems thought to be involved with hallucino-
genicity: 5-HT-1A and 5-HT-2A (16). Similarly, psilo-
cybin and LSD’s treatment eects for CH also, then,
may have little to do with their capacity to induce hal-
lucinogenic eects. The ergotamines (including BOL-
148, LSD, dihyroergotamine, and methysergide) likely
have positive treatment eects for CH through seroto-
nin-receptor-mediated vasoconstriction. BOL-148 was
Karst et al. 1141
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Table 1. Demographic data and clinical aspects
Subject S1 S2 S3 S4 S5
Sex (M/F) M M M M M
Age (years) 46 28 47 41 41
Body weight (kg) 83 68 106 105 74
Body height (cm) 180 168 188 195 174
Years of illness 3 10 10 33 32
Cranial side of attacks Left Right Left (1999–2005)
Right (since 2005)
Right Right
Cluster headache form Chronic Episodic Chronic since 2005 Chronic since 2001 Chronic since 2007
Attacks per week in
the pre-assessment
6 7 10 15 19
Mean intensity of
attacks (VAS) in the
8.4 8.3 5.5 6.4 7.0
Treatments (acute) Sumatriptan
20 mg IN
100% oxygen 15 l/min 100% oxygen 15 l/min 100% oxygen 15 l/min
Sumatriptan 6 mg SC
100% oxygen 15 l/min
240 mg/day*
Verapamil 240 mg/day* Verapamil 240 mg/day*
Frovatriptan PO (up to
2.5 mg TID)
Methysergide unknown dose
(for 1 year)
Prednisolone 80 mg
(for 5 days)
Verapamil 320 mg/day*
(for 3 months)
Lithium unknown dose
(for 3 months)
Verapamil 960 mg/day
(for several months)
4 cycles with prednisolone
starting with a daily dose
of 100 mg
lithium 450 mg/d (for 14 days)
Doxepine 10 mg/day
(for several months)
BOL-148 (30 mg/kg)
three times within
10 days (days 1, 5,
and 10)
2.5 mg 2.0 mg 3.1 mg 3.1 mg 2.2 mg
Side effects ‘‘Flabby feeling’’ for
about 2 h
‘‘Funny feeling’’ for
about 2 h
‘‘Slightly tipsy’’ for about
‘‘Slightly tipsy’’
for about 2 h
‘‘Slightly tipsy’’
for about 2 h
Vital signs Unchanged Unchanged Unchanged Unchanged Unchanged
M, male; F, female; VAS, visual analog scale; BOL-148, 2-bromo-LSD; IN, intranasal; PO, per os; SC, subcutaneous; h, hours; min, minutes; *Higher doses not tolerated.
1142 Cephalalgia 30(9)
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specifically created as a completely non-hallucinogenic
form of LSD, but methysergide was developed to have
even more potency at serotonin receptors (and less hal-
lucinogenic eects than LSD) (17). While methysergide,
an often eective preventative compound if taken on a
daily basis for up to six months (18), does not generally
induce remissions, the repetitive intravenous and sub-
cutaneous application of 1 mg dihydroergotamine for
up to three weeks has been shown in an open retrospec-
tive trial to sometimes break a cluster period (19).
However, dihydroergotamine is not approved for intra-
venous or subcutaneous injection in Germany. In addi-
tion, BOL-148 seems to exert its eects in a totally
dierent way, as outlined above. Although, after
extended and chronic use, both methysergide and dihy-
droergotamine may be associated with an increased risk
for fibrotic complications (such as retroperitoneal fibro-
sis), this risk is unknown for BOL-148 and seems to be
more unlikely from the limited, non-chronic dosing reg-
imen of BOL-148 we employed. Pointedly, there are no
pre-clinical studies linking LSD to fibrosis, and, despite
an extensive history of illicit use, only one case report is
identified in the PubMed database describing prior use
of LSD in two individuals with ‘‘idiopathic’’ retroper-
itoneal fibrosis (20). None of the approved ergot-based
medications for CH realize the type of profound and
lasting treatment response we report from just three
oral doses of BOL-148 or in the prior case series of
LSD and psilocybin use (7). BOL-148 apparently also
diers from methysergide in that prior research indi-
cates methysergide is a less eective preventative for
chronic CH than for episodic forms (21).
The results of this case series must be regarded as
preliminary, in that they are unblinded and
uncontrolled. In acute attack treatment trials, the fre-
quencies of placebo responders were up to 42% while
in chronic CH a placebo response as low as 14% was
reported in one trial (which employed a very strict end-
point of cessation of attacks), but no placebo response
(for ecacy) was noted in five of seven controlled trials
(22). Especially since chronic CH patients appear ‘‘to
have a relatively modest placebo response’’ (22), the
extended durability of response to three doses of BOL-
148 administered over ten days is unlikely to be an arti-
fact. An additional limitation to this report is that not all
known prophylactic alternatives had been tried with our
patients to confirm their extent of treatment resistance,
but all five subjects did respond to BOL-148. In contrast
to the compassionate use setting in this case series,
follow-up research with more specific inclusion criteria
(e.g. prior verapamil trial of at least 500 mg/day, sepa-
ration of evaluation of BOL-148 for either episodic or
chronic forms) will allow more specific conclusions to be
drawn about BOL-148 as a potential treatment for CH.
Given that the current standard of care involves inter-
ventions that break single headache attacks and reduce
pain duration, frequency and intensity of attack cycles,
and that identified treatments that extend remission are
lacking, the potential breakthrough treatment of BOL-
148 warrants wide dissemination of these early findings
to encourage aggressive development to randomized
controlled trials.
We are grateful for the kind support of Clusterbusters,
Lombard, IL, USA. Clusterbusters were neither involved in
the conduct of the compassionate use treatment in CH nor
collection, management, analysis, or interpretation of the data
Number of
4561 2 3 7 8 9 10 11 12
30 mg BOL-148/kg BW
every 5 days for 3
doses total
1614 1513
Figure 1. Course of cluster attacks during primary observational period. BOL-148 ¼2-bromo-LSD. BW ¼body weight.
Karst et al. 1143
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or preparation, review, or approval of the manuscript.
Dr Halpern co-holds a patent on BOL-148 for CH with
Dr Passie, which has not been licensed and has not gener-
ated any royalties or other payments. Drs Bernateck and
Karst report no conflicts of interest.
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... En un estudio posterior (Karst et al., 2010), el interés se volvió a centrar en el 2-Bromo-LSD y, partiendo del estudio preliminar de Sicuteri (1963), usaron el mismo rango de dosis. La sustancia se les administró a cinco pacientes con cefaleas en racimos (uno de ellos episódica y el resto crónica), una vez cada cinco días hasta un total de tres dosis. ...
... Algunos autores han incluido en sus estudios a derivados del LSD. Es el caso del 2-Bromo-LSD, que ha demostrado su eficacia en varios trabajos aun siendo un análogo no alucinógeno (Sicuteri, 1963;Karst et al., 2010;Schindler et al., 2015). En todas las investigaciones el 2-Bromo-LSD se ha usado con fines preventivos y en aquellos que permitieron comparar su eficacia con el LSD, se obtuvieron resultados contradictorios, con una menor utilidad que el LSD (Sicuteri, 1963), o resultando igual de efectivos (Schindler et al., 2015). ...
... Las alteraciones en el sueño se encuentran bajo investigación, pero puede formar parte de la fisiopatología de las cefaleas, donde los receptores 5-HT 2A también muestran su implicación, por lo que podría estar relacionado con el potencial terapéutico de estas sustancias (Schindler et al., 2018). No obstante, debemos tener en cuenta que el 2-Bromo-LSD (análogo no alucinógeno del LSD) ha mostrado cierta eficacia en algunos estudios, lo que sugiere que el mecanismo de acción implicado en las alucinaciones no está asociado (o solo parcialmente) con el potencial terapéutico para las cefaleas (Karst et al., 2010). Algunos estudios documentaron cefalea leve o moderada como efecto secundario de la psilocibina, lo que puede deberse a diferentes mecanismos, como por ejemplo la liberación retardada de óxido nítrico (NO), el agonismo de los receptores 5-HT 2B o la vasodilatación meníngea de rebote, entre otras hipótesis (Johnson et al., 2012). ...
Full-text available
Los alucinógenos incluyen a un grupo heterogéneo de sustancias que provocan cambios en la percepción sensorial, el pensamiento y la consciencia. El potencial terapéutico de diversas drogas alucinógenas está recibiendo un interés creciente en los últimos años. En este trabajo presentamos una revisión bibliográfica centrada en el posible uso de los alucinógenos (LSD, psilocibina y ketamina) en el tratamiento y prevención de las cefaleas. Para ello, se ha realizado unabúsqueda (sin límite temporal) en las bases de datos de Web of Sciences, Scopus y Pubmed, además de una búsqueda manual en las referencias de los artículos. Los resultados constatan la eficacia del LSD, especialmente a nivel profiláctico, mientras que la ketamina podría ser de utilidad para abortar los ataques agudos y la psilocibina ha demostrado ser efectiva en ambos aspectos. Los estudios existentes se han llevado a cabo principalmente en pacientes con migraña y con cefalea en racimos, entre otros tipos de cefaleas. Asimismo, se señalan diversas limitaciones metodológicas que pueden dificultar la generalización de los resultados, y se sugiere la necesidad de realizar futuras investigaciones en este campo emergente.
... Although the results of these historical trials all show promising results, they lacked the methodological rigor of modern trials making it difficult to draw strong inferences on their findings. Contemporary studies suggest that psychedelics may be therapeutically useful in treating intractable headaches such as migraine and cluster headaches (62)(63)(64), and two recent reviews hypothesize potential mechanisms and applications for psychedelics in chronic pain (65,66). Pharmacologically, this concept is plausible. ...
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Background: Chronic Pain is among the leading causes of disability worldwide with up to 60% of patients suffering from comorbid depression. Psychedelic-assisted therapy has recently been found effective in treating a host of mental health issues including depression and has historically been found to be useful in treating pain. Reports of self-medication for chronic pain using psychedelic drugs have been widely documented, with anecdotal evidence indicating widespread success in a range of pathologies. Aims: In preparation for an upcoming trial, to better understand how those with lived experience of chronic pain self-medicate with psychedelic drugs, and to establish, in detail, their therapeutic protocols and practices for success. Methods: As part of patient-involvement (PI) for an upcoming trial in this population, 11 individuals who reported self-medicating with psychedelic drugs took part in a 1-h semi-structured discussion, which was then transcribed and thematically analyzed. Results: Across a range of psychedelic substances and doses, reported pain scores improved substantially during and after psychedelic experiences. Two processes, Positive Reframing and Somatic Presence, were reliably identified as playing a role in improvements in mental wellbeing, relationship with pain, and physical (dis)comfort. Inclusion of other strategies such as mindfulness, breathwork, and movement were also widely reported. Due to the data's subjective nature, this paper is vulnerable to bias and makes no claims on causality or generalisability. Together, these results have been used to inform study design for a forthcoming trial. Conclusion: This pre-trial PI work gives us confidence to test psychedelic therapy for chronic pain in a forthcoming controlled trial. The results presented here will be instrumental in improving our ability to meet the needs of future study participants.
... An interesting theme detected in our results is the consistently self-reported high efficacy of psilocybin mushrooms and LSD as preventive treatments [30,[32][33][34]. These results are also echoed in the excluded survey study by de Coo et al. [34] and other articles on the subject, such as a case report by Sempere et al. [41], a small case series by Karst et al. [9], and a thematic analysis of online discussions by Andersson et al. [42]. An exploratory controlled study by Schindler et al. [55•] found that the single administration of a low dose of psilocybin produced a significant and long-lasting reduction in migraine symptoms. ...
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Purpose of Review The use and efficacy of various substances in the treatment of CH have been studied in several retrospective surveys. The aim of the study is to systematically review published survey studies to evaluate the reported efficacies of both established and unconventional substances in abortive and prophylactic treatment of both episodic and chronic CH, specifically assessing the consistency of the results. Recent Findings No systematic review have been conducted of these studies previously. A systematic literature search with a set of search terms was conducted on PubMed. Retrospective surveys that quantified the self-reported efficacy of two or more CH treatments, published in English during 2000–2020, were included. Several key characteristics and results of the studies were extracted. A total of 994 articles were identified of which 9 were found to be eligible based on the selection criteria. In total, 5419 respondents were included. Oxygen and subcutaneous triptan injections were most reported as effective abortive treatments, while psilocybin and lysergic acid diethylamide were most commonly reported as effective prophylactic treatments. The reported efficacy of most substances was consistent across different studies, and there were marked differences in the reported efficacies of different substances. The reported order of efficacy is generally in agreement with clinical studies. The findings suggest that retrospective surveys can be used to obtain supporting information on the effects of various substances used in the treatment of CH and to form hypotheses about novel treatment methods. The consistently reported efficacy of psilocybin and LSD in prophylactic treatment indicates need for clinical studies.
The effects of psychedelic drugs in headache and chronic pain disorders have been reported for several decades, and now controlled studies are emerging. The existing evidence supports a lasting therapeutic benefit after limited dosing, a unique feature of the drug class that distinguishes it from conventional treatment. This commentary summarizes these reports of preventive effects of psychedelic drugs in headache and chronic pain disorders. The recently published controlled trial of psilocybin in migraine is reviewed, including its limitations. Several neurobiological targets of psychedelics that are related to headache and chronic pain are highlighted, though a clear separation of acute and lasting effects is key in uncovering the unique clinical effects of this drug class. Considerable investigation is required before the effects, safety, and mechanism of action of psychedelics in headache and chronic pain disorders can be known.
Psychedelic substances have played important roles in diverse cultures, and ingesting various plant preparations to evoke altered states of consciousness has been described throughout recorded history. Accounts of the subjective effects of psychedelics typically focus on spiritual and mystical-type experiences, including feelings of unity, sacredness, and transcendence. Over the past two decades, there has been increasing interest in psychedelics as treatments for various medical disorders, including chronic pain. Although concerns about adverse medical and psychological effects contributed to their controlled status, contemporary knowledge of psychedelics suggests that risks are relatively rare when patients are carefully screened, prepared, and supervised. Clinical trial results have provided support for the effectiveness of psychedelics in different psychiatric conditions. However, there are only a small number of generally uncontrolled studies of psychedelics in patients with chronic pain (e.g., cancer pain, phantom limb pain, migraine, and cluster headache). Challenges in evaluating psychedelics as treatments for chronic pain include identifying neurobiologic and psychosocial mechanisms of action and determining which pain conditions to investigate. Truly informative proof-of-concept and confirmatory randomized clinical trials will require careful selection of control groups, efforts to minimize bias from unblinding, and attention to the roles of patient mental set and treatment setting. Perspective: There is considerable promise for the use of psychedelic therapy for pain, but evidence-based recommendations for the design of future studies are needed to ensure that the results of this research are truly informative.
The therapeutic potential of psychedelics in headache and chronic pain disorders is documented over decades of anecdotal and early investigational reports, which have paved the way for the first controlled studies of psilocybin and lysergic acid diethylamide (LSD) in these disorders. The reported lasting clinical effects after limited dosing with psychedelics present a novel means for disease management, but considerable further study will be required to address disease-specific treatments, uncover mechanism(s) of action, and verify safety. In this chapter, these topics are reviewed with particular attention to the neurobiological systems that offer potential sources of psychedelics' unique clinical effects in headache and pain.
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The word “psychedelic” (psyche (i.e., the mind or soul) and delos (i.e., to show)) has Greek origin and was first coined by psychiatrist Humphry Osmond in 1956, who had been conducting research on lysergic acid diethylamide (LSD) at the time. Psychedelic drugs such as N,N-DMT/DMT (N,N-dimethyltryptamine), 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine), LSD (lysergic acid diethylamide), MDMA (3,4-methylenedioxymethamphetamine) and psilocybin have had significant value as an entheogen in spiritual, religious (shamanic) and sociocultural rituals in Central and South American cultures for thousands of years. In the 1960s, the globalization of these drugs and their subsequent spread outside of their indigenous, old-world cultures, led to the subsequent implementation of strict drug control laws in many Western countries. Even today, psychedelics are still classified as Schedule I drugs, resulting in a still lingering negative stigmatization/perception, vilification, and ultimate criminalization of psychedelics. This controversy still lingers and still limits scientific research and full medical acceptance. For many years up until recently, the spiritual, religious and medicinal value of these drugs could not be explored in a scientific context. More recently, a second wave of psychedelic research is now focusing on psychedelics as neuropharmaceuticals to treat alcohol and tobacco addiction, general mood and anxiety disorders and cancer-related depression. There is now a vast array of promising evidence-based data to confirm the years of anecdotal evidence of the medicinal values of psychedelics. Natural therapeutic alternatives such as psychedelic drugs may provide a safe and efficacious alternate to conventional drugs used to treat mood and anxiety disorders. In a Western context in particular, psychedelic drugs as therapeutic agents for mood and anxiety disorders are becoming increasingly of interest amidst increasing rates of such disorders globally, changing social constructions, the implementation of government regulations and increasing investment opportunities, that ultimately allow for the scientific study to generate evidenced-based data. Alternative psychotherapeutic interventions are gaining interest also, because of their low physiological toxicity, relatively low abuse potential, safe psychological effects, and no associated persisting adverse physiological or psychological effects during and after use. On the other hand, conventional psychotic drugs and anti-depressants are becoming less favorable because of their adverse side effects. Psychedelic neuropharmaceutical interventions may with medical oversight be the solution to conventional psychiatric disorders such as depression and anxiety, and an alternative to conventional psychiatric treatment options. This paper will review the therapeutic potential of psychedelic drugs as alternative therapeutic options for mood and anxiety disorders in a controlled, clinical setting, where the chances of adverse psychological episodes occurring are mitigated.
Cluster headache, a primary headache disorder, consists of short (15-180 minutes), frequent (up to eight a day), unilateral attacks of facial pain with associated ipsilateral autonomic features and restlessness. The attacks are suspected to be one of the most painful human experiences, and the disorder is associated with a high rate of suicidal ideation. Proper diagnosis is key, as some of the most effective treatments, such as high flow oxygen gas, are rarely used in other headache disorders. Yet diagnostic delay is typically years for this disorder, as it is often confused with migraine and trigeminal neuralgia, and secondary causes may be overlooked. This review covers the clinical, pathophysiologic, and therapeutic features of cluster headache. Recent updates in diagnosis include the redefinition of chronic cluster headache (remission periods lasting less than three months instead of the previous one month), and recent advances in management include new treatments for episodic cluster headache (galcanezumab and non-invasive vagus nerve stimulation).
Fibromyalgia (FM) is a difficult to treat chronic pain condition for which there is strong interest in alternative treatments. There is growing interest in the potential of psychedelic substances (e.g., psilocybin) in conjunction with psychotherapy to treat chronic pain. Via a cross-sectional, anonymous , online survey, we aimed to characterize knowledge, perceptions, and past use of serotonergic ("classic") and non-serotonergic psychedelics among a population of individuals with FM, and to investigate interest in psychedelic-based FM treatments. Among a North American population of 354 participants with FM, 29.9% reported past use of a psychedelic, with lysergic acid diethylamide (LSD) and psilocybin mushrooms being most commonly used. Perceptions of benefit from psychedelic use were generally neutral (59.4%) or positive (36.8%), with <3% reporting negative impacts on overall health or pain symptoms. Among 12 participants who used psychedelics with intentions of treating chronic pain, 11 reported improved symptoms. Regardless of past use, the majority of participants believed that psychedelics have potential for chronic pain treatments and would be willing to participate in a psychedelic-based clinical trial for their pain. These findings support the need for additional studies to understand the potential and effectiveness of psychedelic substances in managing FM symptoms.
The International Headache Society (IHS) considers classification and diagnostic criteria for headache disorders to be a very important issue. Therefore, its Headache Classification Committee prepared, in 1988, Classification and Diagnostic Criteria for Headache Disorders, Cranial Neuralgias and Facial Pain, which has been accepted throughout the world for scientific and clinical purposes. This classification has been translated into more than 20 different languages. Increasing knowledge of the pathogenesis of some types of headache and wide nosographic research led to a revision of the first edition of the IHS classification, called The International Classification of Headache Disorders, 2nd edition, which was presented during the XI Congress of the IHS in Rome in September 2003. Its full version was published in Cephalagia 2004, Volume 24, Supplementum 1. Members of the Committee of the Czech Headache Society translated this classification into the Czech language both for research and for clinical application, in accordance with the aims of the IHS, to improve the diagnostics, treatment and care of headache.
One consequence of the recent interest in psychotomimetic drugs has been a search for pharmacological agents that will "block" drug-induced psychological disturbances and hallucinations. Fabing1 reported that azacyclonol (Frenquel) in small doses prevented the occurrence of lysergic acid diethylamide (LSD-25) "psychoses" in man, although one of us (L. D. C.) was unable to verify this observation.2 Other investigators have reported that LSD-25 intoxication is ameliorated by premedication with chlorpromazine,3,4 serotonin,5 and reserpine.4 However, it has also been reported that serotonin6 and reserpine3 intensify LSD-25 effects. Hoch7 found that premedication with amobarbital (Amytal) sodium and chlorpromazine did not prevent LSD-25 or mescaline intoxication but pointed out that such drugs produced suppressive effects when given at the height of the intoxication. Several reasons exist for this confusing state of affairs. There has been a failure to distinguish between true pharmacological antagonism (blocking) and suppression.
Cephalalgia has been successful by a number of measures in the last 12 months: our circulation is up particularly through electronic penetration in libraries, our submission rate has risen substantially and our impact factor remains high amongst clinical neuroscience journals. We are entering our fifth and last year of the current publisher’s contract. In the life of the contract we have switched to a very successful on-line submission system, finalized details for a new CDROM containing all issues of Cephalalgia and Headache, and will publish this year the revised International Headache Society classification for headache (1). All of this is excellent progress The journal continues to attract a range of important, interesting and often very thought-provoking submissions. We have benefitted greatly from the broad range of interests of the Associate Editors we are able to recommend and solicit high-quality expert reviews that keep the scientific standards high. In keeping with our general philosophy there is a need for renewal amongst the Associate Editors, and Professor Peer Tfelt-Hansen will be standing down. Peer is widely regarded as one of the most authoritative figures on clinical trial methodology in headache, his wide contributions to the field have appropriately lead to his election as President of the International Headache Society. The journal thanks him for his contributions, and congratulates him on his election. After wide consultation I have invited Professor Nahib Ramadan, University of Chicago, to join the Associate Editors. Professor Ramadan was extensively involved in the journal under the previous Editor-in-Chief, Professor K. Michael Welch, and brings both excellence in academic life and a stint in industry with that important perspective to the Board. I welcome his acceptance of the invitation. From this issue Cephalalgia will become a monthly journal. We have a strong throughput of excellent work and rather than raise the rejection rate, and somewhat arbitrarily dismiss work that readers might be very interested in seeing, we felt it timely to increase to 12 issues a year. We hope this will allow more rapid publication of your accepted work and a greater range of interesting papers for readers in any one year. Let me close by thanking the Editorial Assistant Faye Cheeseman for her sterling efforts at the Blackwell’s Office in keeping the journal ticking over, our referees whose expertise is the key to our success, the Associate Editors who do so much for the journal, and you the reader for your continued support for Cephalalgia.
Es werden Herstellung und Eigenschaften von 2-Halogen-Derivaten der Lysergsure- und Dihydro-lysergsure-Reihe beschrieben.
Harold Wolff's theory of vasodilation in migraine is well-known. Less known is his search for a perivascular factor that would damage local tissues and increase pain sensitivity during migraine attacks. Serotonin was found to be among the candidate agents to be included. In the same period, serotonin was isolated (1948) and, because of its actions, an anti-serotonin drug was needed. Methysergide was synthesized from lysergic acid (LSD) by adding a methyl group and a butanolamid group. This resulted in a compound with selectivity and high potency as a serotonin (5-HT) inhibitor. Based on the possible involvement of serotonin in migraine attacks, it was introduced in 1959 by Sicuteri as a preventive drug for migraine. The clinical effect was often excellent, but 5 years later it was found to cause retroperitoneal fibrosis after chronic intake. Consequently, the use of the drug in migraine declined considerably, but it was still used as a 5-HT antagonist in experimental studies. In 1974 Saxena showed that methysergide had a selective vasoconstrictor effect in the carotid bed and in 1984 he found an atypical receptor. This finding provided an incentive for the development of sumatriptan. Bredberg et al. showed that methysergide is probably a prodrug for its active metabolite methylergometrine. Whereas methysergide is 'a clean drug', methylergometrine is 'a relatively dirty drug' with additional dopaminergic activity. The mechanism for the preventive effect of methysergide (methylergometrine) in migraine remains elusive. We describe the rise, fall and subsequent use as a third-choice drug of the first effective migraine prophylactic, methysergide.
Conventional management options in medically intractable chronic-headache syndromes, such as chronic migraine, chronic cluster headache and hemicrania continua, are often limited. This review summarizes the current concepts, approaches and outcome data of invasive device-based neurostimulation approaches using occipital-nerve stimulation and deep-brain stimulation. Recently, there has been considerable progress in neurostimulation approaches to medically intractable chronic-headache syndromes. Previous studies have analysed the safety and efficacy of suboccipital neurostimulation in drug-resistant chronic-headache syndromes such as in chronic migraine, chronic cluster headache and hemicrania continua. The studies suggest suboccipital neurostimulation can have an effect even decades after onset of headaches, thus representing a possible therapeutic option inpatients that do not respond to any medication. Similarly, to date over 50 patients with cluster headaches underwent hypothalamic deep-brain stimulation. From these, an average of 50-70% did show a significant positive response. These findings will help to further elucidate the clinical potential of neurostimulation in chronic headache.
Lysergic acid diethylamide (LSD) was synthesized in 1938 and its psychoactive effects discovered in 1943. It was used during the 1950s and 1960s as an experimental drug in psychiatric research for producing so-called "experimental psychosis" by altering neurotransmitter system and in psychotherapeutic procedures ("psycholytic" and "psychedelic" therapy). From the mid 1960s, it became an illegal drug of abuse with widespread use that continues today. With the entry of new methods of research and better study oversight, scientific interest in LSD has resumed for brain research and experimental treatments. Due to the lack of any comprehensive review since the 1950s and the widely dispersed experimental literature, the present review focuses on all aspects of the pharmacology and psychopharmacology of LSD. A thorough search of the experimental literature regarding the pharmacology of LSD was performed and the extracted results are given in this review. (Psycho-) pharmacological research on LSD was extensive and produced nearly 10,000 scientific papers. The pharmacology of LSD is complex and its mechanisms of action are still not completely understood. LSD is physiologically well tolerated and psychological reactions can be controlled in a medically supervised setting, but complications may easily result from uncontrolled use by layman. Actually there is new interest in LSD as an experimental tool for elucidating neural mechanisms of (states of) consciousness and there are recently discovered treatment options with LSD in cluster headache and with the terminally ill.
The prevalence of cluster headache (CH) in the Republic of San Marino (21,792 inhabitants; 10,893 men and 10,899 women) was studied, reviewing the past 15 years' medical records of neurological, ophthalmological, and otorhinolaryngological services. Further cases were searched for by means of a letter sent to each inhabitant. Control of the case collection method was performed on a random sample of 1314 inhabitants over 7 years, interviewed for possible past or present cluster headache. We found 15 cases of CH (14 men, 1 woman), for an estimated prevalence ratio of 69 cases per 100,000 population. No previous reports have been published on the prevalence of CH in the general population.