Hallucinogen-like actions of 5-methoxy-N,N-diisopropyltryptamine
in mice and rats
W.E. Fantegrossia,b,⁎, A.W. Harringtonb, C.L. Kiesselb, J.R. Ecklerc, R.A. Rabinc, J.C. Winterc,
A. Coopd, K.C. Ricee, J.H. Woodsb
aDivision of Neuroscience, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA 30322, United States
bDepartment of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, United States
cDepartment of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, United States
dDepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, United States
eLaboratory of Medicinal Chemistry, NIDDK, National Institutes of Health, Bethesda, MD
Received 2 June 2005; received in revised form 7 December 2005; accepted 29 December 2005
Available online 3 February 2006
Few studies have examined the effects of 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) in vivo. In these studies, 5-MeO-DIPT was
tested in a drug-elicited head twitch assay in mice where it was compared to the structurally similar hallucinogen N,N-dimethyltryptamine (N,N-
DMT) and challenged with the selective serotonin (5-HT)2Aantagonist M100907, and in a lysergic acid diethylamide (LSD) discrimination assay
in rats where its subjective effects were challenged with M100907 or the 5-HT1Aselective antagonist WAY-100635. Finally, the affinity of 5-
MeO-DIPT for three distinct 5-HT receptors was determined in rat brain. 5-MeO-DIPT, but not N,N-DMT, induced the head twitch responses in
the mouse, and this effect was potently antagonized by prior administration of M100907. In rats trained with LSD as a discriminative stimulus,
there was an intermediate degree (75%) of generalization to 5-MeO-DIPTand a dose-dependent suppression of response rates. These interoceptive
effects were abolished by M100907, but were not significantly attenuated by WAY-100635. Finally, 5-MeO-DIPT had micromolar affinity for 5-
HT2Aand 5-HT2Creceptors, but much higher affinity for 5-HT1Areceptors. 5-MeO-DIPT is thus effective in two rodent models of 5-HT2agonist
activity, and has affinity at receptors relevant to hallucinogen effects. The effectiveness with which M100907 antagonizes the behavioral actions of
this compound, coupled with the lack of significant antagonist effects of WAY-100635, strongly suggests that the 5-HT2Areceptor is an important
site of action for 5-MeO-DIPT, despite its apparent in vitro selectivity for the 5-HT1Areceptor.
© 2006 Elsevier Inc. All rights reserved.
Keywords: Hallucinogens; Drug-discrimination; Head twitch response; Serotonin receptors
5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT, Fig.
1A) is a synthetic orally active hallucinogenic tryptamine
analogue known by the street names “foxy” and “foxy
methoxy.” The synthesis and hallucinogen-like subjective
effects of this compound were first described in the scientific
literature (Shulgin and Carter, 1980), and expanded upon ten
years later in a book which subsequently gained widespread
dissemination via the internet (Shulgin and Shulgin, 1991).
Since these initial descriptions, the United States Drug
Enforcement Administration (DEA) has documented 5-MeO-
DIPTseizures and reports of abuse in at least nine states, as well
as the District of Columbia (US DEA, 2002). More recent case
reports of 5-MeO-DIPT intoxication (Meatherall and Sharma,
2003; Smolinske et al., 2004; Wilson et al., 2005) suggest that
abuse of this compound may be spreading beyond the
geographic areas initially implicated. Similarly, a search of
The American Association of Poison Control Centers Toxic
Exposure Surveillance System database revealed 41 cases of 5-
MeO-DIPTexposure reports to poison centers over a 15-month
Pharmacology, Biochemistry and Behavior 83 (2006) 122–129
⁎Corresponding author. Division of Neuroscience, Yerkes National Primate
Research Center, Emory University, 954 Gatewood Road, Atlanta, GA 30322,
United States. Tel.: +1 404 727 8512; fax: +1 404 727 1266.
E-mail address: email@example.com (W.E. Fantegrossi).
0091-3057/$ - see front matter © 2006 Elsevier Inc. All rights reserved.
period from April 2002 to the end of June 2003 (Smolinske et
Due to the apparent abuse and toxicity of this compound, 5-
MeO-DIPT was placed temporarily into Schedule I under the
Controlled Substances Act in April of 2003 (Brown, 2003), and
this placement was made permanent in September of 2004
(Leonhart, 2004). Despite these aggressive regulatory measures,
5-MeO-DIPT remains available for purchase from foreign
sources via the internet. Anecdotal reports from human users
posted to internet sites specializing in the dissemination of drug
information (for example, erowid.org and lycaeum.org) further
suggest that 5-MeO-DIPT has profound psychedelic actions in
man, but few studies regarding the effects of this compound in
laboratory animals have been published. However, 5-MeO-
DIPT has been shown to generalize to the interoceptive cue
induced by R-(−)-1-(2,5-dimethoxy-4-methylphenyl)-2-amino-
propane (DOM) in rats (Glennon et al., 1983), although the
pharmacological mechanism for this effect was not explored
using antagonist challenges. A later study reported that related
tryptamine analogues have affinity for 5-HT2receptors, and
suggests that these compound are likely to function as agonists
due to their higher affinity for [3H]4-bromo-2,5-dimethoxy-
phenylisopropylamine (DOB)-labelled receptors than for [3H]
ketanserin-labelled sites (Lyon et al., 1988). These findings,
coupled with the chemical structure of 5-MeO-DIPT and
anecdotal reports of its hallucinogenic activity in man, strongly
suggest that serotonin systems, specifically 5-HT2Areceptors
(Sadzot et al., 1989), may be involved in the mediation of the
behavioral and subjective effects of this compound.
In this regard, the drug-elicited head twitch response
(Corne et al., 1963; Corne and Pickering, 1967) is a selective
behavioral model for 5-HT2agonist activity in the rodent, and
several previous studies have established that direct and
indirect 5-HT agonists induce this effect (Peroutka et al., 1981;
Colpaert and Janssen, 1983; Green et al., 1983; Goodwin and
Green, 1985; Darmani et al., 1990a,b, 1992; Fantegrossi et al.,
2004). Further, 5-HT2receptor antagonists selectively block
head twitch behavior (Lucki et al., 1984; Handley and Singh,
1986; Fantegrossi et al., 2004), and the potency with which
they do so is highly correlated with the antagonist's affinity
for 5-HT2receptors (Peroutka et al., 1981; Ortmann et al.,
1982). Similarly, the strong correlation between discriminative
stimuli in nonverbal species and subjective effects reported by
humans (Schuster and Johanson, 1988; Sanger et al., 1994;
Brauer et al., 1997) allows for a useful characterization of the
interoceptive cues produced by psychedelic drugs using drug
discrimination procedures in laboratory rodents. The discrim-
inative stimulus properties of hallucinogens such as mescaline,
DOM and lysergic acid diethylamide (LSD, Fig. 1C) have
been extensively investigated in several different animal
species and it has been shown that, in agreement with studies
in humans, these drugs generalize with one another (Winter,
1978; Glennon et al., 1983; Fiorella et al., 1995a).
Furthermore, antagonist correlation analysis has determined
that the stimulus effects of phenylisopropylamine and
indolealkylamine hallucinogens are mediated by agonist
activity at 5-HT2A receptors (Fiorella et al., 1995b) and
possibly modulated by agonist activity at 5-HT2C receptors
(Fiorella et al., 1995c).
Thus, in order to compare potency and effectiveness of 5-
MeO-DIPT with the more familiar tryptamine hallucinogens,
we established dose–effect functions for 5-MeO-DIPT and
the structurally similar psychedelic N,N-dimethyltryptamine
(DMT, Fig. 1B) in the head twitch assay in mice. Antagonist
studies were then conducted with the selective 5-HT2A
MDL100907) in order to gauge the involvement of 5-HT2A
receptors in the induction of this behavior. A parallel series
of drug discrimination experiments was conducted in rats in
order to characterize the similarity of the discriminative
stimulus effects of 5-MeO-DIPT with those of LSD. The
effects of M100907 and the selective 5-HT1Aantagonist N-
cyclohexane-carboxamide (WAY-100635) on LSD-appropri-
ate responding were also tested in rats receiving an active
dose of 5-MeO-DIPT. Finally, binding of 5-MeO-DIPT to 5-
HT1A, 5-HT2Aand 5-HT2Creceptors was characterized in rat
brain using a competition binding technique.
All studies were carried out in accordance with the
Declaration of Helsinki and with the Guide for Care and Use
of Laboratory animals as adopted and promulgated by the
National Institutes of Health. Experimental protocols were
approved by the Animal Care and Use Committees at the
University of Michigan and the State University of New York at
2.1. Animals — drug-elicited head twitch response
Male NIH Swiss mice (Harlan Sprague Dawley Inc.,
Indianapolis, IN) weighingapproximately 20–30 gwere housed
12 animals per 44.5×22.3×12.7 cm Plexiglas cage and used in
drug-elicited head twitch experiments. Mice were housed in a
temperature-controlled room at the University of Michigan that
was maintained at an ambient temperature of 22±2 °C at 45–
50% humidity. Lights were set to a 12-h light/dark cycle.
Animals were fed Lab Diet rodent chow (Laboratory Rodent
Diet #5001, PMI Feeds, Inc., St. Louis, MO) and water ad
Fig. 1. Chemical structures of 5-MeO-DIPT (A. left), N,N-DMT (B. middle) and
LSD (C. right). Fantegrossi et al.
123W.E. Fantegrossi et al. / Pharmacology, Biochemistry and Behavior 83 (2006) 122–129
libitum until immediately before testing. Animals were not used
in experiments until at least 2 days after arrival in the laboratory.
Each animal was used only once, and was sacrificed
immediately after use.
2.2. Animals — drug discrimination experiments
Male Fischer-344 rats obtained from Harlan Sprague–
Dawley Inc. (Indianapolis, IN, USA) at an age of approximately
6 weeks were used in LSD discrimination experiments. Rats
were housed in pairs with free access to food and water in a
temperature-controlled room at the State University of New
York at Buffalo under a constant 12-h light/dark cycle (all
experiments were conducted during the light phase.) Caloric
intake was controlled to yield a mean body weight of
approximately 300 g; supplemental feedings of standard rat
chow were provided following experimental sessions.
2.3.1. Drug-elicited head-twitch response in mice
On experimental days, mice were weighed, marked, and
returned to the home cage. Doses were then calculated and
prepared for injection. Individual animals were subsequently
removed from the home cage, injected intraperitoneally (i.p.)
with saline or 0.01 mg/kg M100907, then placed into a
15.24×25.40×12.70 cm Plexiglas mouse cage. Ten minutes
after the initial injection, mice were injected i.p. with various
doses of 5-MeO-DIPT, N,N-DMT or saline and returned to the
small observation cage. Five minutes after this second injection,
a camera mounted above the observation cage began recording
behavior, and continued to do so for 10-min. Videotapes were
later scored by two blind observers for incidence of the head
twitch response, here defined as a rapid rotational jerk of the
head that is not contiguous with any grooming or scratching
behaviors. All experiments were conducted in the colony room
at an ambient temperature of 22±2 °C, and neither food nor
water were available during the tests.
2.3.2. LSD-like discriminative stimulus effects in rats
Six small animal test chambers (Med-Associates Model
ENV-008), each equipped with a house light and an exhaust fan,
and housed in larger lightproof Malaguard sound attenuating
cubicles (Med-Associates Model ENV-022M) were used for
these experiments. The chamber contained two levers mounted
on opposite sides of one wall. Centered between the levers was
a dipper that delivered 0.1 ml of sweetened condensed milk
diluted 2:1 with tap water.
Eleven subjects were trained to discriminate LSD (0.1 mg/
kg, 15 min pretreatment time, i.p. injection) from saline, as
described previously (Fiorella et al., 1995a). A non-resetting
fixed ratio 10 (FR10) schedule of reinforcement was employed
using the MED-PC version IV behavioral programming
application. Drug-induced stimulus control was assumed to be
present when, in five consecutive sessions, 83% or more of all
responses prior to the delivery of the first reinforcer were on the
appropriate lever. The LSD training dose produced approxi-
mately 99.5% drug-appropriate responding. After stimulus
control was established with the training agents, tests with 5-
MeO-DIPT were conducted once per week in each animal so
long as performance did not fall below the criterion level of
83% correct responding in any one of the previous three training
sessions. Half of the test sessions was conducted the day after
saline training sessions with the remainder following LSD
training sessions. During test sessions, no responses were
reinforced and the session was terminated after the emission of
ten responses on either lever. The distribution of responses
between the two levers was expressed as a percentage of total
responses emitted on the drug-appropriate lever. Response rate
was calculated for each session by dividing the total number of
responses emitted on both levers by the elapsed time prior to 10
responses on either lever.
To establish the role of 5-HT2Aand 5-HT1Areceptors in the
stimulus effects of 5-MeO-DIPT, either 0.05 mg/kg M100907
or 0.3 mg/kg WAY-100635 was injected 45 min before 5-MeO-
DIPT, i.e., 60 min before testing. Complete generalization of a
training drug to a test drug is said to be present when (a) a mean
of 80% or more of all test responses occurs on the drug-
appropriate lever; (b) there is no statistically significant
difference between the response distributions of the training
drug and the test drug; and (c) there is a statistically significant
difference between the response distributions of the test drug
and saline control sessions. An intermediate degree of
generalization is defined as being present when response
distributions after a test drug are less than 80% drug-
appropriate, and are significantly different from both training
conditions. Finally, when the response distribution after a test
drug is not statistically significantly different from that in saline
control sessions, an absence of generalization of the training
drug to the test drug is assumed. Similar criteria are applied to
the definitions of full, partial, and no antagonism. Thus, full
antagonism is assumed to be present when (a) less than 20% of
all test responses are on the training drug-appropriate lever; (b)
there is no significant difference between the response
distributions in the test of antagonism and the saline control,
and (c) there is a statistically significant difference between the
response distributions of the test drug alone and in combination
with the antagonist.
2.3.3. Competition binding in rat brain
Frontal cortex (5-HT2Areceptors), hippocampus (5-HT1A
receptors), and brain stem (5-HT2Creceptors) were harvested
from male CDF rats (Charles Rivers Laboratories) and
homogenized (Dounce tissue grinder) in 50 mM Tris–HCl
(pH 7.4). Homogenates were centrifuged at 40,000 ×g for
15 min at 4 °C, and the resulting pellets were resuspended in
the Tris buffer and stored at −80 °C. On the day of the assays,
tissue samples were thawed and centrifuged at 40,000 ×g for
15 min at 4 °C. The resulting pellets were resuspended in
30 ml warm 50 mM Tris–HCl (pH 7.4) and incubated for
10 min at 37 °C to remove endogenous serotonin. Samples were
again centrifuged at 40,000 ×g for 15 min at 4 °C. Final
resuspension of the pellets (frontal cortex: 6.7 mg/ml;
hippocampus: 5 mg/ml; brain stem 13.3 mg/ml) was carried
124 W.E. Fantegrossi et al. / Pharmacology, Biochemistry and Behavior 83 (2006) 122–129
out in Tris assay buffer (50 mM Tris–HCl, pH 7.4, containing
4 mM MgCl2, 10 μM pargyline and 0.1% ascorbate).
binding assays were carried out for 30 min at 37 °C in a final
volume of 0.5 ml Tris assay buffer containing 1 nM radioligand
(129 Ci/mmole; Perkin-Elmer, Boston MA), appropriate drugs
and hippocampal membranes (2 mg wet weight/tube). [3H]
ketanserin binding assays were carried out for 30 min at 30 °C
in a final volume of 0.5 ml Tris assay buffer containing 1.5 nM
radioligand (88 Ci/mmole; Perkin-Elmer, Boston MA), 100 nM
prazosin to prevent binding to α1-adrenergic receptors,
appropriate drugs and frontal cortical membranes (2 mg wet
weight/tube). [3H]mesulergine binding assays were carried out
for 45 min at 37 °C in a final volume of 0.5 ml Tris assay buffer
containing 2 nM radioligand (77 Ci/mmole; Amersham
Biosciences), 100 nM spiperone to prevent binding to 5-HT2A
and dopamine D2receptors, appropriate drugs and membranes
from the brain stem (4 mg wet weight/tube). Reactions were
terminated by rapid vacuum filtration (Brandel harvester)
through GF/B glass fiber filters presoaked in 0.1% polyethy-
lenimine. Filters were washed twice with cold 50 mM Tris–HCl
(pH 7.4), and the amount of bound radioactivity measured by
scintillation spectrophotometry. Nonspecific binding was de-
fined as the difference in the amount of radioligand binding in
the absence and presence of either 10 μM 5-HT ([3H]8-OH-
DPAT binding), 20 μM 5-HT ([3H]mesulergine binding) or
100 μM cinanserin ([3H]ketanserin binding).
2.4. Data analysis
Data from the head twitch response experiments are
presented as mean±SEM and were compared to values
obtained from equivolume saline controls using one way
ANOVA and Tukey's post hoc tests. Drug discrimination data
are expressed as percent drug-appropriate responding, which is
the number of responses emitted on the drug-appropriate lever
as a percentage of the total number of responses emitted.
Response rates are expressed as the number of responses per
minute, calculated for each session by dividing the total number
of responses emitted (prior to the emission of 10 responses on
either lever) by elapsed time. Data for any subjects failing to
emit 10 responses within the constraints of the 10-min test
session were not considered in the calculation of the percent
drug-appropriate responding but were included in the analysis
of response rates. Generalization was said to occur if 80% or
more of the responses were on the drug-appropriate lever. The
statistical significance of the generalization of LSD to 5-MeO-
DIPT in rats trained with LSD and the antagonism of these
effects by M100907 and WAY-100635 were determined using
one-way ANOVA to compare the two training conditions with
5-MeO-DIPT and with 5-MeO-DIPT in the presence of an
antagonist, respectively. Subsequent multiple comparisons were
made by the method of Student–Newman–Keuls. Binding data
were analyzed by nonlinear regression using the program
EBDA/LIGAND (Elsevier BIOSOFT). All differences were
considered to be statistically significant if the probability of
their having arisen by chance was b0.05, and all statistical
analyses were conducted using SigmaStat 2.03 for Windows™
(Jandel Scientific Software, San Rafael, CA).
(+)-LSD, N,N-DMT and 5-MeO-DIPT were supplied by the
National Institute on Drug Abuse (Research Technology
Branch, Research Triangle Park, NC) and dissolved in 0.9%
physiological saline solution. M100907 was synthesized at
Laboratory of Medicinal Chemistry at the National Institutes of
Diabetes, Digestive and Kidney Disorders at the National
Institutes of Health (Bethesda, MD), and dissolved in sterile
water and 0.5 N HCl. WAY-100635 was purchased from Tocris
(Ellisville, MO). With the exception of WAY-100635, which
was administered subcutaneously, all injections were adminis-
tered i.p. at a volume of 1.0 ml/kg (rats) or 1.0 ml/100 g (mice).
3.1. Drug-elicited head-twitch response in mice
5-MeO-DIPT induced a dose-dependent HTR in mice,
producing a maximum of approximately 9 twitches during the
10-min observation period at a dose of 1.0 mg/kg (Fig. 2, closed
circles). Doses of 1.0 and 3.0 mg/kg 5-MeO-DIPT elicited
significantly more head twitchbehavior than did saline (Pb0.05
for both doses). Pretreatment with 0.01 mg/kg M100907
produced a ten-fold rightward shift in the 5-MeO-DIPT HTR
dose–response curve (Fig. 2, open circles). Following antago-
nist pretreatment, 10 mg/kg 5-MeO-DIPT induced significantly
more head twitch behavior than did saline (Pb0.05). At the
highest dose tested (30.0 mg/kg, in the presence of M100907),
5-MeO-DIPT induced convulsions in 3/6 mice; no such
evidence of toxicity was observed at 10.0 mg/kg, either with
or without the antagonist. Interestingly, N,N-DMT did not elicit
Fig. 2. Effects of 5-MeO-DIPT (circles) and N,N-DMT (triangles) on head
twitch behavior in mice treated with M100907 (open symbols) or saline (filled
symbols). Eachpoint represents the mean±SEM (n=6 mice perdose). Ordinate:
mean head twitches/10 min. Abscissa: 5-MeO-DIPTor DMT dose (mg/kg, i.p.).
Asterisks indicate significant differences from saline controls (filled square)
(Pb0.05). Fantegrossi et al.
125 W.E. Fantegrossi et al. / Pharmacology, Biochemistry and Behavior 83 (2006) 122–129
significantly more head twitches than saline at any dose tested
(Fig. 2, filled triangles).
3.2. LSD-like discriminative stimulus effects in rats
An intermediate degree of generalization of LSD to 5-MeO-
DIPT was observed with approximately 52% and 75% LSD-
appropriate responding at doses of 1.0 and 3.0 mg/kg,
respectively (Pb0.05 for both doses) (Fig. 3, left panel, closed
circles); higher doses were not tested due to the greater than
50% reduction in response rates observed at a dose of 3.0 mg/kg
(Fig. 3, right panel, closed circles) — indeed, only 6/11 rats
responded at this dose. The discriminative stimulus effects of
1.0 and 3.0 mg/kg 5-MeO-DIPT were completely blocked
(Pb0.05 for both doses) by the 5-HT2Aselective antagonist
M100907 (Fig. 3, left panel, open circles). In contrast, the
discriminative stimulus effects of 1.0 mg/kg 5-MeO-DIPTwere
non-significantly attenuated (P=0.106) by the 5-HT1Aselective
antagonist WAY-100635, and this effect was overcome at the
3.0 mg/kg dose of 5-MeO-DIPT (Fig. 3, left panel, open
hexagons), although only 5/11 rats responded at this dose.
3.3. Competition binding in rat brain
Because the present behavioral results strongly suggest an
involvement of 5-HT receptors in the effects of 5-MeO-DIPT,
the affinity of this compound at 5-HT2A, 5-HT2C, and 5-HT1A
receptors was determined. 5-MeO-DIPT has micromolar
affinity for 5-HT2Aand 5-HT2Creceptors, and higher affinity
for 5-HT1Areceptors. The equilibrium dissociation constant
(KI) for 5-MeO-DIPTat the 5-HT2Areceptor, as measured using
[3H]ketanserin, was 5620 nM (pKI=5.25). By way of
comparison, the KIfor R(−)-DOI at the 5-HT2Areceptor was
141 nM (pKI=6.85), while the KIfor R(−)-DOM at this site was
513 nM (pKI=6.29) (previously reported in Fantegrossi et al., in
press). The KIfor 5-MeO-DIPTat 5-HT2Creceptors, which was
determined using [3H]mesulergine, was 1700 nM (pKI=5.77).
Binding affinity of 5-MeO-DIPT at the 5-HT1Areceptor, as
measured using [3H]8-OH-DPAT, was appreciably higher with
a KIof 35 nM (pKI=7.44). Binding affinities for 5-MeO-DIPT
at these three 5-HT receptors are summarized in Table 1.
The presently reported results suggest that 5-MeO-DIPT is
behaviorally active in two rodent assays which model
hallucinogen effects. The capacity of this compound to induce
the head twitch response in the mouse, and the potent
antagonism of this effect by prior injection of M100907,
suggests that a primary site of action for 5-MeO-DIPT is the 5-
HT2Areceptor. Similarly, the LSD-like stimulus effects elicited
by 5-MeO-DIPT in the rat, the antagonism by M100907, and
an absence of antagonism by WAY-100635, are also consistent
with a 5-HT2A-mediated mechanism of action for this
compound. This receptor has previously been implicated in
the mediation of hallucinogen effects for the ergoline (LSD-
like), indolealkylamine (DMT-like), and phenylisopropylamine
(DOI-like) hallucinogens (Sadzot et al., 1989; Aghajanian and
Marek, 1999; Nichols, 2004). It should be noted that the dose
of M100907 employed in the present discrimination studies
have previously been shown to completely antagonize LSD-
induced stimulus control (Winter et al., 2004) while the dose
Fig. 3. Left panels — discriminative stimulus effects of 5-MeO-DIPT (closed circles) in rats discriminating between 0.1 mg/kg LSD (closed triangle) and saline (closed
square),andthe effectsof pretreatmentwith 0.05mg/kgM100907(open circles)and0.3mg/kgWAY-100635(open hexagons). Eachpointrepresentsthe mean±SEM.
Ordinate: average percentage of responses on the LSD-associated lever. Abscissa: dose in mg/kg body weight. Right panel — response rate altering effects of 5-MeO-
DIPT. Symbols remain as described for the left panel. Ordinate: average rate of response on either lever. Abscissa: dose in mg/kg body weight. Asterisks indicate
significant differences from saline controls (Pb0.05). Fantegrossi et al.
Affinity of 5-HT1A, 5-HT2Aand 5-HT2Creceptors for 5-MeO-DIPT
7.44±0.04 (35 nM)5.25±0.04
Binding of 5-MeO-DIPT to the various serotonin receptors was carried out as
described in the Methods. Data are expressed as the negative log of the
equilibrium dissociation constant (pKI) and are presented as mean±S.E.M. of 3-
8 separate experiments. Equilibrium dissociation constants, KI, are presented in
the parenthesis. For comparative purposes, see the Results section for a
discussion of the previously determined affinity of the 5-HT2Areceptor for the
phenylisopropylamines R(−)-DOI, and R(−)-DOM.
Fantegrossi et al.
126 W.E. Fantegrossi et al. / Pharmacology, Biochemistry and Behavior 83 (2006) 122–129
of WAY-100635 chosen for use in the present studies has
previously been shown to completely antagonize stimulus
control by the prototypic 5-HT1A agonist, 8-OH-DPAT
(Reissig et al., 2005).
It is notable that effects of 5-MeO-DIPT on head twitch
behavior were less profound than we have previously observed
with the phenylisopropylamine hallucinogens 2,5-dimethoxy-4-
(n)-propylthiophenethylamine (2C-T-7) and DOM (see Fante-
grossi et al., in press). Indeed, the most effective dose of 5-
MeO-DIPT elicited approximately half as much head twitch
behavior as was observed with 2C-T-7 and DOM. While the pKI
values reported herein suggest that the affinity of 5-MeO-DIPT
for the 5-HT2Areceptor is appreciably less than that of the
phenylisopropylamines, one might expect that this would be
reflected in lower potency, but not necessarily effectiveness, in
the head twitch assay. However, the observed range of active
doses for 5-MeO-DIPT was identical to those previously
reported for 2C-T-7 and DOM in the head twitch assay. Indeed,
aside from the effectiveness difference noted above, the dose–
effect curves for all three compounds are quite similar in shape.
Interestingly, 5-MeO-DIPT is more susceptible (shifted further
to the right) to the antagonist actions of M100907 than either of
the phenylisopropylamines previously studied in the head
Another significant finding of these studies is the failure of
N,N-DMT to elicit a significant head twitch response,
particularly given previous reports of its 5-methoxy congener
to induce this behavior in the mouse (e.g., Matsumoto et al.,
1997). The presently reported data, as well as the lack of any
literature reports documenting induction of the head twitch
response by N,N-DMT or N,N-DIPT, suggest that methoxy
substituents might be functionally relevant groups for the
molecular pharmacology of the tryptamine hallucinogens.
Alternatively, this structural modification may impact pharma-
cokinetic variables, resulting in greater bioavailability or brain
penetrance. However, it has previously been shown that i.p.
administration of 10 mg/kg N,N-DMT to rats resulted in greater
and longer lasting brain concentrations of drug than were
observed following an equivalent dose of its 5-methoxy
congener (Sitaram and McLeod, 1990). Clearly, further
behavioral and pharmacokinetic studies of the tryptamine
hallucinogens and their 5-methoxy congeners are warranted.
Of necessity, much of our information regarding the effects
of newer hallucinogens is largely anecdotal in nature.
Nonetheless, accounts of the effects of 5-MeO-DIPT in
human subjects by Shulgin and Shulgin (1991), as well as
those posted online (for example, erowid.org and lycaeum.org),
leave little doubt as to the psychoactive properties of this drug.
Based upon those reports and the previously described
generalization of LSD in LSD-trained rats to R(−)-DOM
(Winter and Rabin, 1988) and vice versa (Glennon et al.,
1983), we would expect 5-MeO-DIPT to substitute for LSD.
The data of Fig. 3 only partially fulfill that prediction. It is seen
that a maximum of 75% LSD-appropriate responding followed
the administration of 3.0 mg/kg 5-MeO-DIPT, with all doses of
this compound producing significant suppression of the rate of
responding, thus precluding the testing of higher doses.
The preferential affinity of 5-MeO-DIPT for 5-HT1A
receptors is not unexpected given the structural similarity of
this compound to other high affinity tryptamines such as 5-
MeO-DMT and psilocin (McKenna et al., 1990). The role of 5-
HT1A receptors in drug-elicited head twitch behavior is
complex, but previous studies have shown that 8-OH-DPAT
inhibits DOI-induced head twitch behavior in the rat (Arnt and
Hyttel, 1989; Schreiber et al., 1995). In comparison to the
phenylisopropylamines (e.g., Fantegrossi et al., 2005) the
decreased effectiveness of 5-MeO-DIPT presently observed in
the head twitch assay may therefore be a consequence of 5-
HT1Areceptor activation, which can function to inhibit effects
mediated by 5-HT2Areceptors (Darmani et al., 1990b; Yocca et
al., 1990). Similarly, 8-OH-DPAT has previously been shown to
occasion LSD-appropriate responding in LSD-trained rats
(Winter and Rabin, 1988), although the reciprocal generaliza-
tion is only partial (Cunningham and Appel, 1987). It may be
the case that 5-HT1A-mediated components of a compound's
stimulus effects are more salient for LSD than for 5-MeO-DIPT.
Furthermore, the present results suggest that, for 5-MeO-DIPT,
these 5-HT1A-mediated interoceptive effects are more salient at
lower doses (i.e., the partial attenuation of LSD-appropriate
responding by WAY-100635 at a dose of 1.0 mg/kg 5-MEO-
DIPT), while the stimulus effects of higher doses are more
likely to be dependent on 5-HT2Areceptors (i.e., no effect on
LSD-appropriate responding at a dose of 3.0 mg/kg 5-MeO-
DIPT by WAY-100635, but complete abolition by M100907).
The appreciable affinities for 5-HT1Areceptors displayed
by the tryptamine-like hallucinogens have long distinguished
them from the phenylisopropylamine hallucinogens (Nichols,
1999; Winter et al., 2000). In light of the present binding
data, one might argue that 5-MeO-DIPT does not act directly
upon 5-HT2Areceptors to partially mimic LSD but instead
acts indirectly via 5-HT1A receptors to influence 5-HT2A
receptors. That this is not the case is indicated by the results
presented in Fig. 3, in which it was seen that the selective 5-
HT1Aantagonist, WAY-100635, did not significantly antag-
onize the effects of 5-MeO-DIPT in LSD-trained rats. These
findings are complete in keeping with an earlier study of the
related tryptamine hallucinogen, 5-MeO-DMT, in which it
was observed that the intermediate mimicry of R(−)-DOM by
5-MeO-DMT was not antagonized by WAY-100635 but was
blocked by pirenperone (Winter et al., 2000). Further
research into these intriguing effects, particularly as they
may relate to subtle differences in the subjective effects
induced by chemically distinct hallucinogens in man, would
This research was supported by by USPHS grants DA 03385
(JRE, RAR, JCW), DA09161 and DA05923 (WEF and JHW),
as well as by the College on Problems of DrugDependence. The
authors express their gratitude to the University of Michigan
Undergraduate Research Opportunity Program, and for the
expert technical assistance provided by the University of
Michigan Unit for Laboratory Animal Medicine staff.
127W.E. Fantegrossi et al. / Pharmacology, Biochemistry and Behavior 83 (2006) 122–129
Aghajanian GK, Marek GJ. Serotonin and hallucinogens. Neuropsychophar-
Arnt J, Hyttel J. Facilitation of 8-OH-DPAT-induced forepaw treading of rats by
the 5-HT2agonist DOI. Eur J Pharmacol 1989;161:45–51.
Brauer LH, Goudie AJ, de Wit H. Dopamine ligands and the stimulus effects of
amphetamine: animal models versus human laboratory data. Psychophar-
Brown JB. Schedules of controlled substances:temporary placement of alpha-
methyltryptamine and 5-methoxy-N,N-diisopropyltryptamine into schedule
I. Fed Regist 2003;68(18):4127–30.
Colpaert FC, Janssen PAJ. The head twitch response to intraperitoneal injection
of 5-hydroxytryptophan in the rat: antagonist effects of purported 5-
hydroxytryptamine antagonists and of pirenperone, an LSD antagonist.
Corne SJ, Pickering RW. A possible correlation between drug-induced
hallucinations in man and a behavioral response in mice. Psychopharma-
Corne SJ, Pickering RW, Warner BT. A method for assessing the effects of drugs
on the central actions of 5-hydroxytryptamine. Brit J Pharmacol
Cunningham KA, Appel JB. Neuropharmacological reassessment of the
discriminative stimulus properties of D-lysergic acid diethylamide (LSD).
Darmani NA, Martin BR, Glennon RA. Withdrawal from chronic treatment with
(±)-DOI causes supersensitivity to 5-HT2 receptor-induced head-twitch
behavior in mice. Eur J Pharmacol 1990a;186:115–8.
Darmani NR, Martin bR, Pandey U, Glennon RA. Do functional relationships
exist between 5-HT1Aand 5-HT2receptors? Pharmacol Biochem Behav
Darmani NA, Martin BR, Glennon RA. Behavioral evidence for differential
adaptation of the serotonergic system after acute and chronic treatment with
(±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) or ketanserin. J
Pharmacol Exp Ther 1992;262(2):692–8.
Fantegrossi WE, Kiessel CL, Leach PT, Martin CV, Karabenick RL, Chen X, et
al. Nantenine: an antagonist of the behavioral and physiological effects of
MDMA in mice. Psychopharmacology 2004;173(3–4):270–7.
Fantegrossi WE, Harrington AW, Eckler JR, Arshad S, Rabin RA, Winter JC,
Coop A, Rice KC, Woods JH. Hallucinogen-like actions of 2,5-dimethoxy-
4-(n)-propylthiophenethylamine (2C-T-7) in mice and rats. Psychopharma-
Fiorella D, Rabin RA, Winter JC. Role of 5-HT2Aand 5-HT2Creceptors in the
stimulus effects of hallucinogenic drugs: II. Reassessment of LSD false
positives. Psychopharmacology 1995a;121(3):357–63.
Fiorella D, Rabin RA, Winter JC. The role of the 5-HT2Aand 5-HT2Creceptors
in the stimulus effects of hallucinogenic drugs: I. Antagonist correlation
analysis. Psychopharmacology 1995b;121(3):347–56.
Fiorella D, Helsley SE, Lorrain DS, Palumbo PA, Rabin RA, Winter JC. The
role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of
hallucinogenic drugs: III. The mechanistic basis for supersensitivity to the
LSD stimulus following serotonin depletion. Psychopharmacology
Glennon RA, Young R, Jacyno JM, Slusher M, Rosecrans JA. DOM-stimulus
generalization to LSD and other hallucinogenic indolealkylamines. Eur J
Goodwin GM, Green AR. A behavioural and biochemical study in mice and rats
of putative selective agonists and antagonists for 5-HT1 and 5-HT2
receptors. Br J Pharmacol 1985;84(3):743–53.
Green AR, O'Shaughnessy K, Hammond M, Schachter M, Grahame-Smith
DG. Inhibition of 5-hydroxytryptamine-mediated behaviours by the
putative 5-HT2 receptor antagonist pirenperone. Neuropharmacology
Handley SL, Singh L. Neurotransmitters and shaking behavior: more than a “gut
bath” for the brain. Trends Pharmacol Sci 1986;7:324–8.
Leonhart MM. Schedules of controlled substances: placement of alpha-
methyltryptamine and 5-methoxy-N,N-diisopropyltryptamine into schedule
I of the controlled substances act. Final rule. Fed Regist 2004;69
Lucki I, Nobler MS, Frazer A. Differential actions of serotonin antagonists on
two behavioral models of serotonin receptor activation in the rat. J
Pharmacol Exp Ther 1984;228:133–9.
Lyon RA, Titeler M, Seggel MR, Glennon RA. Indolealkylamine analogs share
5-HT2binding characteristics with phenylalkylamine hallucinogens. Eur J
Matsumoto K, Mizowaki M, Takayama H, Sakai S-I, Aimi N, Watanabe H.
Suppressive effects of mitragynine on the 5-methoxy-N,N-dimethyltrypta-
mine-induced head-twitch response in mice. Pharmacol Biochem Behav
McKenna DJ, Repke DB, Peroutka SJ. Differential interactions of indolealk-
ylamines with 5-hydroxytryptamine receptor subtypes. Neuropsychophar-
Meatherall R, Sharma P. Foxy, a designer tryptamine hallucinogen. J Anal
Nichols DE. Role of serotonergic neurons and 5-HT receptors in the action of
hallucinogens. In: Baumgarten HG, Gothert M, editors. Serotonergic
neurons and 5-HT receptors in the CNS. Berlin: Springer; 1999. p. 563–85.
Nichols DE. Hallucinogens. Pharmacol Ther 2004;101:131–81.
Ortmann R, Biscoff S, Radeke E, Bueche O, Delini-Stula A. Correlation
between different measures of antiserotonin activity of drugs. Naunyn
Schmiedeberg's Arch Pharmacol 1982;321:265–70.
Peroutka SJ, Lebovitz RM, Snyder SH. Two distinct central serotonin receptors
with different physiological functions. Science (Wash. DC) 1981;212:
Reissig CJ, Eckler JR, Rabin RA, Winter JC. The 5-HT1Areceptor and the
stimulus effects of LSD in the rat. Psychopharmacology 2005;182
Sadzot B, Baraban JM, Glennon RA, Lyon RA. Hallucinogenic drug
treating LSD-induced hallucinogenesis. Psychopharmacology 1989;98
Sanger DJ, Benavides J, Perrault G, Morel E, Cohen C, Joly D, et al. Recent
developments in the behavioral pharmacology of benzodiazepine (omega)
receptors: evidence for functional significance of receptor subtypes.
Neurosci Biobehav Rev 1994;18:355–72.
Schreiber R, Brocco M, Audinot V, Gobert A, Veiga S, Millan MJ. (1-(2,5-
Dimethoxy-4-iodophenyl)-2-aminopropane-induced head-twitches in the rat
are mediated by 5-Hydroxytryptamine (5-HT)2A receptors: modulation
by novel 5-HT2A/2C antagonists, D1 antagonists and 5-HT1A agonists.
J Pharmacol Exp Ther 1995;273:101–12.
Schuster C, Johanson C. Relationship between the discriminative stimulus
properties and subjective effects of drugs. In: Colpaert F, Balster R, editors.
Transduction mechanisms of drug stimuli. Berlin: Springer; 1988.
Shulgin AT, Carter MF. N,N-diisopropyltryptamine (DIPT) and 5-methoxy-N,N-
diisopropyltryptamine (5-MeO-DIPT). Two orally active tryptamine analogs
with CNS activity. Commun Psychopharmacol 1980;4:363–9.
Shulgin A, Shulgin A. TIHKAL: the continuation. Berkley: Transform Press;
1991. p. 527–31.
Sitaram BR, McLeod WR. Observations on the metabolism of the psychoto-
mimetic indolealkylamines: implications for future clinical studies. Biol
Smolinske SC, Rastogi R, Schenkel S. Foxy methoxy: a new drug of abuse. Int J
Med Toxicol 2004;7(1):3 [accessed on 26 May 2005at http://www.acmt.net/
United States Department of Justice / Drug Enforcement Administration.
Drug intelligence brief 02052. Trippin' on tryptamines: the emergence
of Foxy and AMT as drugs of abuse. Microgram Bull 2002;35
Wilson JM, McGeorge F, Smolinske S, Meatherall R. A foxy intoxication.
Forensic Sci Int 2005;148(1):31–6.
Winter JC. Stimulus properties of phenethylamine hallucinogens and lysergic
acid diethylamide: the role of 5-hydroxytryptamine. J Pharmacol Exp Ther
128W.E. Fantegrossi et al. / Pharmacology, Biochemistry and Behavior 83 (2006) 122–129
Winter JC, Rabin RA. Interactions between serotonergic agonists and Download full-text
antagonists in rats trained with LSD as a discriminative stimulus. Pharmacol
Biochem Behav 1988;30:617–24.
Winter JC, Filipink RF, Timineri D, Helsley SE, Rabin RA. The paradox of 5-
methoxy-N,N-dimethyltryptamine: a hallucinogen which induces stimulus
control via 5-HT1Areceptors. Pharmacol Biochem Behav 2000;65:75–82.
Winter JC, Eckler JR, Rabin RA. Serotonergic/glutamatergic interactions: the
effects of mGlu2/3 receptor ligands in rats trained with phencyclidine and
LSD as discriminative stimuli. Psychopharmacology 2004;172:233–40.
Yocca FD, Wright RN, Margraf RR, Eison AS. 8-OH-DPAT and buspirone
analogs inhibit the ketanserin-sensitive quipazine-induced head shakes
response in rats. Pharmacol Biochem Behav 1990;35:251–4.
129 W.E. Fantegrossi et al. / Pharmacology, Biochemistry and Behavior 83 (2006) 122–129