HUMAN PSYCHOPHARMACOLOGY

Hum[ Psychopharmacol[ Clin[ Exp[ 04\ 448Ð454 "1999#

Hallucinogenic Drugs Attenuate the Subjective

Response to Alcohol in Humans
SEAN P[ BARRETT\ JENNIFER ARCHAMBAULT\ MARLA J[ ENGELBERG and
ROBERT O[ PIHL
Department of Psycholo`y\ McGill University\ Montreal\ Canada

This study investigated possible interactions between alcohol and hallucinogens in 11 lysergic acid diethylamide
"LSD# and:or psilocybin users through retrospective structured interviews[ Of those who had used LSD with alcohol\
75=6 per cent reported a complete blockade of subjective alcohol e}ects\ while the remaining cases reported a
diminished response[ In addition\ 59 per cent of respondents who had used alcohol and psilocybin together reported
a partial antagonism of subjective alcohol e}ects[ T!test analyses revealed that LSD|s antagonism of alcohol e}ects
were signi_cantly greater than those associated with psilocybin[ It is proposed that LSD|s e}ect on alcohol intoxication
may involve interactions with various serotonergic and:or dopaminergic receptor systems[ Copyright Þ 1999 John
Wiley + Sons\ Ltd[

KEY WORDS * lysergic acid diethylamide^ alcohol^ psilocybin^ hallucinogens^ serotonin^ dopamine

INTRODUCTION partial agonist at dopamine "DA# receptors "Watts

The therapeutic use of lysergic acid diethylamide
"LSD# has been studied extensively as a possible
adjunct to psychotherapy for the treatment of
alcoholism "e[g[ Abraham et al[\ 0885^ Mangini\
0887#[ Such studies have produced inconsistent
results and this area of research was abandoned in
the early 0869s due to concerns over LSD|s safety
"Mangini\ 0887#[ Despite the fact that several clini!
cal trials were conducted over a 14!year period\ the
e}ects of the combined use of alcohol and LSD
were never elucidated[ Nevertheless\ the phar!
macological pro_les of these two substances suggest
the possibility of a clinically signi_cant interaction[
For example\ LSD binds with high a.nity at both
4!HT0 and 4!HT1 receptors "e[g[ Peroutka\ 0883#\
and drugs that act on either of these receptor sub!
types have been shown to alter both ethanol intake
and discriminative stimulus e}ects in rats "Szeliga
and Grant\ 0887^ Kostowski and Bienkowski\
0888#[ Furthermore\ LSD is thought to act as a
 Correspondence to] S[ P[ Barrett\ Department of Psychology\
McGill University\ 0194 Dr[ Pen_eld Avenue\ Montreal\ QC\
Canada H2A 0B0[ Tel] 403!871!4902[ Fax] 403!287!3785[ E!
mail] barrettÝego[psych[mcgill[ca
et al[\ 0884^ Giacomelli et al[\ 0887#\ and mid!brain
DA transmission has been implicated in several of
alcohol|s reinforcing properties "e[g[ Koob et al[\
0887#[ Given the fact that LSD is known to a}ect
neural systems implicated in ethanol intake\
reinforcement\ and discriminative stimulus\ one
might expect the subjective human response to etha!
nol to be altered by LSD administration[ Inter!
estingly\ a recent study of the drug taking patterns
of adolescent drinkers suggests that the simul!
taneous use of alcohol and hallucinogens is quite
common\ with 05 per cent of the sample reporting
combining alcohol with hallucinogens on at least
one occasion "Martin et al[\ 0885#[ The current
investigation presents systematically collected
information from individuals who have reported
using ethanol with LSD and:or psychotic mush!
rooms\ a related hallucinogenic drug[
METHODS
Participants for this retrospective self!report study
were recruited through the {snowball| method of
sampling[ This sampling method has been widely
used to study hidden or clandestine populations

Copyright Þ 1999 John Wiley + Sons\ Ltd[

459 S[ P[ BARRETT ET AL[
"Jackson\ 0886#\ and requires the researcher to
make an initial set of contacts and to ask these
contacts to introduce him:her to potential par!
ticipants[ In the present study four contacts whose
past hallucinogenic use was known a priori were
used to recruit subjects[ Potential participants were
contacted either in person or by telephone and were
asked if they would answer some questions about
their alcohol and drug use for a scienti_c study[
Of the 14 individuals contacted\ three declined to
participate\ leaving a _nal sample of 11 subjects[
Structured interviews were conducted orally and
recorded via audio!tape[ Participants were assured
of their anonymity and informed that their audio!
taped responses would remain strictly con_dential[
The interview consisted of a series of standardized
open!ended questions designed to elicit information
about the participant|s previous experiences with
alcohol\ LSD\ and psilocybic mushrooms when
used alone or in combination[ In order to avoid any
possible investigator in~uence\ all questions about
possible alcohol:hallucinogenic interactions were
always phrased as follows] have you ever used alco!
hol while under the in~uence of LSD "magic mush!
rooms# or LSD "magic mushrooms# while under
the in~uence of alcohol< Did you notice any di}er!
ence in the e}ect of either the alcohol or the LSD
"magic mushrooms# when you used the two to!
gether< What was the nature of the di}erence< Can
you give me a speci_c example about a time when
this happened< In order for a report to be con!
sidered usable\ the subject had to have used at least
the minimum dose required to detect the subjective
e}ects of each drug when used alone[
Reported drug interaction e}ects were rated by
the principal investigator and by an independent
rater who was blind to the study|s hypotheses[ Dis!
crepancies in the coding were resolved by having a
second independent rater score any interviews in
question[ Using a _ve!point Likert scale "0com!
pletely blocked\ 1somewhat diminished\ 2neu!
tral\ 3somewhat enhanced\ 4strongly
enhanced#\ the raters _rst scored the reported e}ect
of alcohol when it was taken with LSD[ Using the
same Likert scale\ the raters then coded the reported
e}ect of LSD when it was taken in conjunction with
alcohol[ Ratings of reported e}ects of alcohol and
psilocybin when the two drugs were used in com!
bination were assessed in the same manner[ Raters
were instructed to eliminate cases in which inter!
viewer bias was present[ A complete transcript of
all interviews is available from the authors upon
request[
Copyright Þ 1999 John Wiley + Sons\ Ltd[
RESULTS
Nineteen males and three females were interviewed
for the present study[ The participants ranged in
age from 07 to 17 years "M  12=62\ SD  1=75#[
Most participants reported extensive past use of
hallucinogens\ with 62 per cent of subjects reporting
19 or more lifetime uses of LSD and 62 per cent
reporting 19 or more lifetime uses of psilocybin[
Drug interaction e}ects were not analysed for four
subjects who reported that they had never used
intoxicating levels of alcohol in combination with
either LSD or psilocybin and for one participant
who provided inconsistent\ and thus uncodable\
responses to interview questions[ Only partial
e}ects were analysed for two subjects who reported
never having used intoxicating levels of alcohol with
LSD\ and for two subjects who reported never hav!
ing used intoxicating levels of alcohol with psilo!
cybin[
Pearson correlation coe.cients were calculated
in order to determine the inter!rater reliabilities for
the coding of the interviews[ These analyses
revealed a very high concordance between raters
for both LSDÐalcohol interactions "r  9=874\
p ³ 9=990# and psilocybinÐalcohol interactions
"r  9=760\ p ³ 9=990#[ An analysis of the interview
ratings revealed a striking antagonism of subjective
alcohol e}ects when it was used in combination
with LSD "see Table 0#[ Speci_cally\ 75=6 per cent
of the sample reported experiencing a complete
blockade of subjective alcohol e}ects\ while the
remainder reported a diminished e}ect[ No di}er!
ences in subjective LSD e}ects were associated with
alcohol use in any of the subjects[ There was also a
weaker tendency for subjects to report a diminished
e}ect of alcohol when used in conjunction with
psilocybic mushrooms\ with 59 per cent of the sam!
ple noting a diminished e}ect\ 23 per cent reporting
no change and 5=6 per cent reporting an enhanced
e}ect[ The majority of the sample "79 per cent# also
reported no change in psilocybin|s e}ects when it
was used with alcohol[ However\ two subjects
reported a diminished e}ect\ and one subject
reported an enhanced e}ect of psilocybin when used
in combination with alcohol[ In addition\ one par!
ticipant voluntarily reported experiencing a ple!
asant synergistic e}ect when taking psilocybin with
alcohol\ while another participant reported having
a very unpleasant synergistic e}ect[
In order to compare the e}ects of LSD and psi!
locybin on the subjective response to alcohol\ a
paired samples t!test was performed[ This analysis
revealed that LSD|s antagonism of the alcohol
Hum[ Psychopharmacol[ Clin[ Exp[ 04\ 448Ð454 "1999#
 ALCOHOLÐHALLUCINOGEN INTERACTIONS 450

Table 0[ Subjective e}ects associated with concurrent use of alcohol and hallucinogens

Id Age Sex Estimated Estimated Concurrent use of Concurrent use of alcohol and
lifetime lifetime alcohol and LSD psilocybin
use of LSD use of psilocybin
Subjective Subjective Subjective Subjective
alcohol LSD alcohol psilocybin
e}ects e}ects e}ects e}ects

A 10 M 099Ð049 49Ð099 blocked no change no change no change

B 15 M 19 19 blocked no change no change no change
C 10 M 49 39Ð49 Ð Ð diminished diminished
G 14 M 59Ð89 59Ð89 blocked no change diminished no change
H 16 F 59Ð64 29Ð24 blocked no change Ð Ð
I 17 M 29Ð49 19Ð29 blocked no change diminished no change
J 13 M 14 49 blocked no change no change no change
K 17 M 09Ð14 09Ð14 blocked no change diminished no change
L 14 M 24 49 diminished no change diminished no change
M 13 M 39 49 blocked no change no change no change
P 13 M ×49 29Ð39 Ð Ð diminished no change
R 13 F 29 1 blocked no change Ð Ð
S 12 F 2 29 blocked no change no change diminished
T 13 M 14 29 blocked no change enhanced enhanced
U 15 M 199Ð299 49 blocked no change diminished no change
V 17 M 14 49 blocked no change diminished no change
W 11 M 04 29Ð24 diminished no change diminished no change

e}ect is signi_cantly greater than that associated
with psilocybin t"01#  4=630\ p ³ 9=990[
REPRESENTATIVE SUBJECTIVE REPORTS
LSDÐalcohol interactions
G\ a 14!year!old male\ reported extensive experi!
ence with LSD\ using it on 59Ð89 separate
occasions[ Typically\ G can begin to discern the
e}ects of alcohol after four drinks and it takes
approximately seven or eight drinks for G to
become signi_cantly intoxicated[ According to G\
{When I was on LSD I found that no matter what
quantity of alcohol I consumed on the high\ I did
not notice any of the e}ects of the alcohol|[ G
recalled one speci_c occasion when he drank
approximately 01 beers over the course of an eve!
ning after ingesting LSD] {[ [ [ at that point\ I didn|t
notice the e}ects of the alcohol at all[ I was not
drunk\ nothing[ I just felt a little bloated[|
H\ a 16!year!old female\ reported extensive
experience with LSD\ using it on between 59 and
64 separate occasions[ She reported using an intoxi!
cating dose of alcohol "more than seven drinks# in
combination with LSD {several| times[ According
to H\ LSDÐalcohol interactions work two ways[
{The _rst example would be if I were to use LSD
and then drink\ I wouldn|t feel any of the e}ects of
alcohol until after the e}ects of the LSD had worn
o} [ [ [ and if I were to take LSD once I was already
subjectively feeling drunk\ the alcohol e}ects would
go away after taking the LSD[|
T\ a 13!year!old male\ reported using LSD on
14 occasions[ T reported that there were several
occasions where he consumed an intoxicating dose
of alcohol "more than six drinks# while under the
in~uence of LSD[ According to T\ {You can|t get
drunk when you are on LSD [ [ [ One time I drank
about 07 beers\ a half bottle of Bailey|s and a
Mickey of vodka on two hits of acid and I didn|t
feel anything from the booze [ [ [ it was just a normal
LSD high[|
PsilocybinÐalcohol interactions
B\ a 15!year!old male\ has used psilocybic mush!
rooms on 19 separate occasions[ When using alco!
hol concurrently with psilocybic mushrooms\ B
claims that {I could feel a combination of both[ It is
not like LSD where the alcohol e}ects are blocked[
Sometimes one would be stronger than the other\

Copyright Þ 1999 John Wiley + Sons\ Ltd[ Hum[ Psychopharmacol[ Clin[ Exp[ 04\ 448Ð454 "1999#
451 S[ P[ BARRETT ET AL[
but that would just depend on how much I took of
each|[
L\ a 14!year!old male\ has used psilocybic mush!
rooms on 49 separate occasions[ According to L\
when using psilocybin with a normally intoxicating
dose of alcohol "more than four drinks#\ {[ [ [ it pro!
duces a more mellow buzz[ The alcohol e}ect was
deadened|[ When asked to compare this experience
with that of LSD\ {I could feel the alcohol more for
sure on mushrooms|[
V\ a 17!year!old male\ reported 49 previous uses
of psilocybic mushrooms\ including several
occasions where he consumed a normally intoxi!
cating dose of alcohol "more than six drinks#[
According to V\ when using alcohol and psilocybic
mushrooms together] {You can tell that you|ve
drunk alcohol when on mushrooms\ but there
would be less of an e}ect [ [ [ you could feel it more
than when on LSD|[
DISCUSSION
The present data indicate that the subjective
response to ethanol is strongly attenuated by the
administration of LSD[ Of the 04 LSD users who
reported concurrent use of alcohol\ 02 reported a
complete blockade of alcohol|s subjective e}ects\
while the remaining two cases reported experi!
encing a virtual elimination of subjective alcohol
e}ects when the drug was combined with LSD[ The
_nding that LSD|s antagonism of alcohol|s e}ects
reportedly occurred irrespective of whether the sub!
ject had consumed LSD prior to drinking or the
LSD was ingested when already intoxicated further
supports the conjecture that LSD|s e}ect on the
subjective response to alcohol may be due to a direct
pharmacological interaction[ In contrast to LSD\
the use of psilocybic mushrooms failed to fully anta!
gonize the subjective e}ects of alcohol[ Although
nine of the 04 psilocybin users reported a dimin!
ished response to alcohol\ no participants reported
that the administration of psilocybin completely
blocked the subjective e}ects of alcohol[ Of the
remaining six participants\ _ve reported that psi!
locybin had no impact on their subjective response
to alcohol\ while the _nal subject stated that psi!
locybin actually enhanced the subjective e}ects of
alcohol "i[e[ caused an increase in the subjective
sense of intoxication#[ Thus\ although some par!
ticipants reported a tendency for psilocybin to
weaken the subjective e}ects of alcohol\ this e}ect
was not as pronounced as that associated with LSD^
while 099 per cent of LSD users reported at least
Copyright Þ 1999 John Wiley + Sons\ Ltd[
partially diminished alcohol e}ects\ a full 39 per
cent of psilocybin users failed to report any anta!
gonizing e}ect[ Because very little is known about
the pharmacological actions of psilocybin\ and the
precise nature of the interaction between psilocybin
and alcohol was not clearly revealed by the present
data\ the remainder of the discussion will focus
primarily on _ndings concerning the concurrent
administration of LSD and alcohol[
Prior to commencing a discussion of hypo!
thesized means by which LSD could attenuate sub!
jective alcohol e}ects\ it would seem appropriate to
address some possible limitations of the present
study[ The _rst issue concerns whether or not study
participants could reliably recount their experiences
with the concurrent use of alcohol and hal!
lucinogenic drugs[ There are several indications
that memory is not signi_cantly impaired by the
administration of hallucinogens[ For example\
there are numerous reports that LSD experiences
can be accurately and vividly recalled "e[g[
Hofmann\ 0879^ Abraham et al[\ 0885# suggesting
that LSD intoxication has a negligible impact on
memory storage and retrieval[ The accuracy of rec!
ollections reported by subjects in the present study
is further supported by the fact that most of these
participants had extensive past hallucinogenic use
and reported having used hallucinogens and alco!
hol in combination on several occasions[ Thus\ par!
ticipants| responses to questions concerning
alcoholÐhallucinogen interaction e}ects were based
on numerous experiences rather than a single event
and compared to their own extensive experience
with hallucinogenic drugs alone or in combination[
A second consideration concerns whether par!
ticipants| recollections of alcohol e}ects were sim!
ply overwhelmed by the hallucinogenic properties
of LSD and:or psilocybin[ The observation that
participants were able to reliably distinguish
between LSD and psilocybin in terms of each drug|s
e}ect on the subjective alcohol experience when
taken concurrently argues against this possibility[
In addition\ participants were highly consistent in
their reporting concerning both the nature and
strength of alcoholÐdrug interactions\ despite their
di}erential drug histories and being blind to the
study|s hypotheses[ Finally\ the amount of alcohol
reportedly consumed by some participants while
under the in~uence of LSD argues against the possi!
bility that alcohol e}ects were simply overwhelmed
by hallucinogen intoxication[ For example\ par!
ticipant M described an occasion on which he had
13 drinks following the use of LSD and T recalled
Hum[ Psychopharmacol[ Clin[ Exp[ 04\ 448Ð454 "1999#
 ALCOHOLÐHALLUCINOGEN INTERACTIONS
drinking 07 beers\ a half bottle of liqueur and 02
ounces of vodka while in a state of LSD intoxi!
cation[
While both the consistency and magnitude of
reports of LSD|s e}ect on alcohol intoxication
attest to its reliability\ it is important to note that
in any retrospective study certain issues of potential
bias may arise[ Because subjects were not randomly
selected it remains possible that their experiences
are not characteristic of all hallucinogenic drug
users[ However\ this possibility was minimized by
the fact that participants were recruited from four
di}erent {communities| of drug users through snow!
ball sampling[ It should also be noted that several
additional steps were taken to avoid possible inter!
viewer bias[ First\ questions used for queries about
potential drug interactions were standardized and
neutrally worded[ Second\ three di}erent inter!
viewers were used and all interviews were blindly
rated[ Finally\ raters were instructed to eliminate
cases were interviewer bias was present[
The present data are consistent with the notion
that there is a direct\ pharmacological interaction
between LSD and alcohol[ Although the current
methodology did not directly examine either of
these drugs| pharmacological e}ects\ LSD is known
to act at various serotonergic and dopaminergic
receptor types "e[g[ Peroutka\ 0883^ Watts et al[\
0884# implicated in ethanol reinforcement "e[g[
Koob et al[\ 0887# and discriminative stimulus "e[g[
Kostowski and Bienkowski\ 0888#[ This raises the
possibility that LSD|s e}ect on the subjective
response to alcohol may involve an action at one
or more of these systems[
LSD exerts e}ects at several 4!HT receptor sub!
types\ displaying a.nity for 4!HT0A\ 4!HT0B\ 4!
HT0D\ 4!HT0E\ 4!HT1A\ 4!HT1C\ 4!HT4A\ 4!HT4B\ 4!
HT5\ and 4!HT6 "Peroutka\ 0883^ Bonson et al[\
0885#[ With respect to LSD|s multiple 4!HT
actions\ activity at 4!HT1C and:or 4!HT0B receptors
would seem to represent the best candidates for
LSD|s attenuation of subjective alcohol e}ects\ as
these are the only 4!HT receptor subtypes that have
been directly implicated in the formation of the
ethanol cue "Maurel et al[\ 0887^ Wilson et al[\ 0887^
Kostowski and Bienkowski\ 0888#[ Mixed 4!
HT0B:1C receptor agonists completely generalize to
the ethanol cue in rats "Kostowski and Bienkowski\
0888^ Maurel et al[\ 0887^ Szeliga and Grant\ 0887#\
and are known to produce ethanol!like responses
in humans "Kostowski and Bienkowski\ 0888#[ Evi!
dence also suggests that the blockade of 4!HT0B
and 4!HT1C receptors\ alone or in combination\
Copyright Þ 1999 John Wiley + Sons\ Ltd[
452
interferes with alcohol|s discriminative stimulus
properties "Maurel et al[\ 0887#[ In their review
article\ Kostowski and Bienkowski "0888# refer to
such _ndings\ and conclude that serotonergic
neurotransmission plays a key role in the formation
of the ethanol cue\ and that this cue is primarily
mediated through 4!HT0B and 4!HT1C receptors[
Unfortunately\ the precise nature of LSD|s
action at 4!HT0B remains unknown "Peroutka\
0883#[ The present discussion will therefore focus
on the actions of LSD at 4!HT1C receptors[ LSD
displays partial agonist e}ects at 4!HT1C receptor
sites "Glennon\ 0889^ Fiorella et al[\ 0884^ Egan et
al[\ 0887#[ Thus\ although LSD displays high a.n!
ity\ its agonist actions at 4!HT1C are of low e.cacy[
Because LSD is a partial agonist at 4!HT1C recep!
tors\ the precise nature of its e}ect at these sites will
depend on available 4!HT concentrations and on
the presence of other 4!HT agonists and:or antag!
onists "Glennon\ 0889^ see also Bonson et al[\ 0885#[
At low 4!HT concentrations and:or in the absence
of another agonist\ LSD behaves as a low!e.cacy 4!
HT1C agonist\ achieving approximately 29 per cent
maximal excitation "Marek and Aghajanian\ 0885^
Egan et al[\ 0887#[ In the presence of a high e.cacy
agonist "i[e[ at higher 4!HT concentrations#\ LSD
exerts its own maximal e}ect while suppressing the
receptor|s responsiveness to the other agonist\
thereby blocking the other agonist from achieving
maximal excitation[ Under such conditions\ LSD
may thus appear to function as an antagonist[
LSD|s partial agonist actions are consistent with
the hypothesis that LSD may prevent the level of
4!HT1C excitation required for the alcohol cue to
be subjectively experienced\ and this mechanism
may underlie the _ndings of the present study[
The hypothesis that LSD attenuates the ethanol
cue in humans through such serotonergic mech!
anisms is consistent with the present observation
that this e}ect was diminished or absent following
the administration of psilocybin[ Although LSD
and psilocybin are considered similar in terms of
subjective e}ects\ they di}er with regard to ser!
otonergic pharmacological properties[ For exam!
ple\ LSD is known to bind to various 4!HT sites
with a greater a.nity than psilocybin "Glennon
et al[\ 0874^ McKenna et al[\ 0889#[ Furthermore\
psilocybin is currently believed to act as a full agon!
ist at 4!HT1 receptors "Vollenweider et al[\ 0887#\
whereas LSD acts as a partial agonist at these sites[
If\ as hypothesized\ LSD exerts an e}ect on the
alcohol cue via suppression of the requisite 4!HT1
response\ then one might expect psilocybin to fail
Hum[ Psychopharmacol[ Clin[ Exp[ 04\ 448Ð454 "1999#
453 S[ P[ BARRETT ET AL[
to fully attenuate the subjective e}ects of alcohol[
Aside from its actions at 4HT receptors\ LSD
has also been demonstrated to exert partial agonist
e}ects at dopamine D0 "Watts et al[\ 0884# and
D1 "Giacomelli et al[\ 0887# receptors[ Midbrain
dopaminergic activity is thought to be critical for
the reinforcement of ethanol administration "e[g[
Koob et al[\ 0887#[ Although DA transmission is
implicated in ethanol reinforcement\ there is cur!
rently only limited evidence to suggest that DA
transmission substantially contributes to ethanol|s
subjective e}ects[ Blocking DA neurotransmission
with preferential DA receptor antagonists does not
appear to a}ect either the discriminative stimulus
e}ects of alcohol in rats "Kostowski and Bien!
kowski\ 0888# or the subjective e}ects of alcohol in
humans "Litten\ 0885#[ Although dopamine antag!
onists fail to signi_cantly alter subjective ethanol
e}ects\ there is nevertheless some indication that
dopamine agonists may attenuate aspects of the
ethanol cue[ For example\ amphetamine\ a potent
DA receptor agonist\ has been reported to anta!
gonize ethanol e}ects in rats "Schechter\ 0863# and
cocaine administration has been shown to attenuate
the sedative e}ects of alcohol in humans "e[g[ Foltin
et al[\ 0882#[ Such evidence suggests that LSD|s
blockade of subjective alcohol e}ects may relate to
its agonist activity at DA receptors[ Unlike LSD\
psilocybin does not display an a.nity for DA recep!
tors\ although there is some evidence that it may
increase DA transmission indirectly through ser!
otonergic mechanisms "e[g[ Vollenweider et al[\
0888#[ Nevertheless\ the di}erential a.nity of LSD
and psilocybin for DA receptors may help to
explain reported di}erences in the e}ects of LSD
and psilocybin on the subjective response to alco!
hol[
In summary\ the subjective e}ects of alcohol are
antagonized by LSD and\ to a lesser extent\ by
psilocybin[ Although it is proposed that these
e}ects may be at least partly mediated by ser!
otonergic and:or dopaminergic mechanisms\
actions at either of these systems are likely to in~u!
ence a variety of physiological and neurochemical
processes and the interdependence among these
should not be underestimated[ It should also be
emphasized that the pharmacological pro_les of
alcohol and hallucinogens remain incompletely
understood and more research is needed in order to
fully understand the precise nature of the inter!
actions among these drugs[ This point is par!
ticularly relevant in the case of psilocybin\ which
has not been examined as extensively as either LSD
Copyright Þ 1999 John Wiley + Sons\ Ltd[
or alcohol[ Indeed\ without a fuller characterization
of each of these drugs| e}ects\ interpretation of the
present results must remain largely speculative[
Despite the fact that the present analysis is unable
to fully elucidate the mechanisms governing alco!
holÐhallucinogen interactions\ the present _ndings
are highly relevant for several reasons[ First\ this
is\ to the best of the authors| knowledge\ the _rst
documentation of a recreational drug eliminating
subjective alcohol e}ects in humans[ Further explo!
ration of the interaction between LSD and alcohol
revealed by the present _ndings may ultimately
enhance our understanding of the mechanisms that
mediate the subjective e}ects of ethanol[ Second\
evidence suggests that alcohol is often co!admin!
istered with hallucinogenic drugs "Martin et al[\
0885#[ Given the amounts of alcohol reportedly
consumed by some participants in the present study
while under the in~uence of LSD and the illustrated
potential for LSD to attenuate alcohol e}ects\ this
practice may pose signi_cant health risks[ Third\
this analysis demonstrates that\ despite the fact that
similarity between LSD and psilocybin has been
assumed by some researchers "e[g[ Strassman\
0881#\ there is likely some discordance in the phar!
macological e}ects of these two hallucinogens[
Finally\ this study illustrates a distinctive and e}ec!
tive approach for delineating drugÐalcohol inter!
actions in humans[
REFERENCES
Abraham HD\ Aldridge AM\ Gogia P[ 0885[ The psy!
chopharmacology of hallucinogens[ Neuropsycho!
pharmacolo`y 03] 174Ð187[
Bonson KR\ Buckholtz JW\ Murphy DL[ 0885[ Chronic
administration of serotonergic antidepressants atten!
uates the subjective e}ects of LSD in humans[ Neu!
ropsychopharmacolo`y 03] 314Ð325[
Egan CT\ Herrick!Davis CT\ Miller K\ Glennon RA\
Teitler M[ 0887[ Agonist activity of LSD and lisuride
at cloned 4!HT1A and 4!HT1C receptors[ Psy!
chopharmacol 025] 398Ð303[
Fiorella D\ Rabin RA\ Winter JC[ 0884[ Role of 4!HT1A
and 4!HT1C receptors in the stimulus e}ects of hal!
lucinogenic drugs II] reassessment of LSD false posi!
tives[ Psychopharmacolo`y 010] 246Ð252[
Foltin RW\ Fichman MW\ Pippen PA\ Kelly TH[ 0882[
Behavioral e}ects of cocaine alone and in combination
with ethanol or marijuana in humans[ Dru` Alcohol
Depend 21] 82Ð095[
Giacomelli S\ Palmery M\ Romanelli L\ Cheng CY\ Sil!
vestrini B[ 0887[ Lysergic acid diethylamide "LSD# is a
partial agonist of D1 dopaminergic receptors and it
Hum[ Psychopharmacol[ Clin[ Exp[ 04\ 448Ð454 "1999#
 ALCOHOLÐHALLUCINOGEN INTERACTIONS
potentiates dopamine!mediated prolactin secretion in
lactotrophs in vitro[ Life Sci 52] 104Ð111[
Glennon RA[ 0889[ Do classical hallucinogens act as 4!
HT1 agonists or antagonists< Neuropsychopharma!
colo`y 2] 498Ð406[
Glennon RA\ Titeler M\ McKenney JD[ 0874[ Evidence
for 4!HT1 involvement in the mechanism of action of
hallucinogenic agents[ Life Sci 24] 1494Ð1400[
Hofmann A[ 0879[ LSD] My Problem Child[ McGraw!
Hill] New York[
Jackson W[ 0886[ Methods] Doin` Social Research[ Pren!
tice Hall] Scarborough[
Koob GF\ Roberts AJ\ Schultes G\ Parsons LH\ Heyser
CJ\ Hyytia P\ Merlo!Pich E\ Weiss F[ 0887[ Neuro!
circuitry targets in ethanol reward and dependence[
Alcohol Clin Exp Res 11] 2Ð8[
Kostowski W\ Bienkowski P[ 0888[ Discriminative stimu!
lus e}ects of ethanol] neuropharmacological charac!
terization[ Alcohol 06] 52Ð79[
Litten RZ[ 0885[ Pharmacotherapies for alcohol prob!
lems] a review of research with focus on development
since 0880[ Alcohol Clin Exp Res 19] 748Ð765[
Mangini M[ 0887[ Treatment of alcoholism using psy!
chedelic drugs] a review of the program of research[ J
Psychoactive Dru`s 29] 270Ð307[
Marek GJ\ Aghajanian GK[ 0885[ LSD and the phene!
thylamine hallucinogen DOI are potent partial agon!
ists at 4!HT1A receptors on interneurons in rat piriform
cortex[ J Pharmacol Exp Ther 167] 0262Ð0271[
Martin CS\ Kaczynski NA\ Maaisto SA\ Tarter RE[
0885[ Polydrug use in adolescent drinkers with and
without DSM!IV alcohol abuse and dependence[ Alco!
hol Clin Exp Res 19] 0988Ð0097[
Maurel S\ Schreiber R\ De Vry J[ 0887[ Role of 4!HT0B\
4!HT1A and 4!HT1C receptors in the generalization of
4!HT receptor agonists to the ethanol cue in the rat[
Behav Pharmacol 8] 226Ð232[
Copyright Þ 1999 John Wiley + Sons\ Ltd[
454
McKenna DJ\ Repke DB\ Lo L\ Peroutka SJ[ 0889[
Di}erential interactions of indolealkylamines with 4!
hydroxytryptamine receptor subtypes[ Neuropharma!
colo`y 18] 082Ð087[
Peroutka SJ[ 0883[ 4!Hydroxytryptamine receptor inter!
actions of D!lysergic acid diethylamide[ In 49 Years of
LSD] Current Status and Perspectives of Hallucino`ens\
Plescher A\ Ladewig D "eds#[ Parthenon] New York^
08Ð18[
Schechter MD[ 0863[ E}ects of propranolol\ d!amphet!
amine and ca}eine on ethanol as a discriminative cue[
Eur J Pharmacol 18] 41Ð46[
Strassman RJ[ 0881[ Human hallucinogen interactions
with drugs a}ecting serotonergic neurotransmission[
Neuropsychopharmacolo`y 6] 130Ð132[
Szeliga KT\ Grant KA[ 0887[ Analysis of the 4!HT1
receptor ligands dimethoxy!3!indophenyl!1!amino!
propane and ketanserin in ethanol discriminations[
Alcohol Clin Exp Res 11] 535Ð540[
Vollenweider FX\ Vollenweider!Scherpenhuyzen MFI\
Babler A\ Vogel H\ Hell D[ 0887[ Psilocybin induces
schizophrenia!like psychosis in humans via a sero!
tonin!1 agonist action[ NeuroReport 8] 2786Ð2891[
Vollenweider FX\ Vontobel P\ Hell D\ Leenders KL[
0888[ 4!HT modulation of dopamine release in basal
ganglia in psilocybin!induced psychosis in man * a
PET study with ð00CŁraclopride[ Neuropsycho!
pharmacolo`y 19] 313Ð322[
Watts V\ Lawler CP\ Fox DR\ Neve KA\ Nichols DE\
Mailman RB[ 0884[ LSD and structural analogs] phar!
macological evaluation at D0 dopamine receptors[ Psy!
chopharmacolo`y 007] 390Ð398[
Wilson AW\ Neill JC\ Costall B[ 0887[ An investigation
in to the e}ects of 4!HT agonists and receptor antag!
onists on ethanol self!administration in the rat[ Alcohol
05] 138Ð169[
Hum[ Psychopharmacol[ Clin[ Exp[ 04\ 448Ð454 "1999#