ADIS DRUG EVALUATION Drugs 1998 Oct; 56 (4): 667-690

0012-6667/98/0010-0667/$24.00/0

© Adis International Limited. All rights reserved.

5-Methoxypsoralen
A Review of its Effects in Psoriasis and Vitiligo
Wendy McNeely and Karen L. Goa
Adis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by:

C. Antoniou, University of Athens, Department of Dermatology, ‘A. Sygros’ Hospital, Athens, Greece; F. Aubin,
Department of Functional Dermatology, University Hospital, Besançon, France; P. Calzavara-Pinton,
Department of Dermatology, Bresicia University Hospital, Bresicia, Italy; E.M. Farber, Department of
Dermatology, Stanford University, Stanford, California, USA; S.A. George, Photobiology Unit, Department of
Dermatology, Ninewells Hospital and Medical School, Dundee, Scotland; S.K. Hann, Department of
Dermatology, Yonsei University College of Medicine, Seoul, South Korea; H. Hönigsmann, Division of Special
and Environmental Dermatology, University of Vienna, Vienna, Austria; J.L. Peyron, Dermatologic Clinic,
Saint-Charles Hospital, Montpellier, France; L.M.L. Stolk, Academisch Ziekenhuis Maastricht, Klinische
Farmacie en Toxicologie, Maastricht, The Netherlands; H.M. Studniberg, Skin and Cancer Foundation,
Darlinghurst, New South Wales, Australia; H. Takematsu, Department of Dermatology, Tohoku University
School of Medicine, Sendai, Japan; J.M. Wishart, Department of Dermatology, Auckland Hospital, Auckland,
New Zealand.

Data Selection
Sources: Medical literature published in any language since 1966 on 5-methoxypsoralen, identified using AdisBase (a proprietary database
of Adis International, Auckland, New Zealand), Medline and EMBASE. Additional references were identified from the reference lists of
published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing
the drug.
Search strategy: AdisBase search terms were ‘5-methoxypsoralen’, ‘5-MOP’, ‘bergapten’ and ‘skin disorders’. Medline and EMBASE search
terms were ‘5-methoxypsoralen’, ‘5-MOP’ and ‘bergapten’. Searches were last updated 23 July 1998.
Selection: Studies in patients with psoriasis or vitiligo who received oral or topical 5-methoxypsoralen. Inclusion of studies was based mainly
on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred.
Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: 5-Methoxypsoralen, psoriasis, vitiligo, pharmacokinetics, pharmacodynamics, therapeutic use.

Contents

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668
1. Rationale for the Use of Psoralens in Psoriasis and Vitiligo . . . . . . . . . . . . . . . . . . . . . . . . 671
2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672
2.1 Cutaneous Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673
2.2 Other Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674
3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675
3.1 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675
3.2 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 677
4. Therapeutic Efficacy in Dermatological Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . 677
4.1 Cutaneous Photosensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678
4.2 Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678
4.2.1 Oral Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679
4.2.2 Topical Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681
668 McNeely & Goa

4.3 Vitiligo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681

4.3.1 Sunlamp Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 682
4.3.2 Sunlight Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 682
5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683
5.1 General Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683
5.2 Effects on the Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 684
5.3 Potential for Cutaneous Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 684
6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 685
6.1 Contraindications and Precautions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 685
7. Place of PUVA 5-Methoxypsoralen in the Management of Psoriasis and Vitiligo . . . . . . . . . . . 685

Summary
Abstract 5-Methoxypsoralen, a naturally occurring linear furocoumarin, has been success-
fully used in combination with ultraviolet (UV) A irradiation [psoralen plus UV
(PUVA)] to manage psoriasis and vitiligo.
In patients and volunteers, PUVA 5-methoxypsoralen causes a dose-related
increase in cutaneous photosensitivity. However, mean minimum phototoxic doses
(MPD) were 30 to 50% greater with 5-methoxypsoralen than with 8-methoxy-
psoralen within individuals; this suggests lower photoactivity with 5-methoxy-
psoralen.
In comparative clinical trials of parallel design, psoriasis clearance rates of
>90% or >97% were observed in similar numbers of patients (60 to 77%) receiv-
ing oral PUVA 5-methoxypsoralen (typically 1.2 mg/kg) or oral PUVA 8-methoxy-
psoralen (0.6 mg/kg) treatment. Generally, 5-methoxypsoralen recipients required
a greater total UVA exposure than 8-methoxypsoralen recipients to achieve end-
point. However, study end-point was achieved sooner with oral or topical PUVA
5-methoxypsoralen in a small number of patients with psoriasis who received
both treatments simultaneously and contralaterally.
Up to 56% of patients with vitiligo achieved >75% repigmentation with
5-methoxypsoralen (oral or topical) combined with UV irradiation (lamp or sun);
the face and trunk were the most responsive areas.
Lack of response to PUVA 5-methoxypsoralen treatment was observed in up
to 16% of patients with psoriasis and, in 1 trial, in 22% of those with vitiligo.
Lesion spreading during treatment of vitiligo was also observed in 7 (19%) pa-
tients in 1 study.
The incidence and severity of adverse events was generally lower in PUVA
5-methoxypsoralen 1.2 mg/kg than in PUVA 8-methoxypsoralen 0.6 mg/kg re-
cipients. Nausea and/or vomiting, pruritus and erythema were the most commonly
reported adverse events in the short term; they occurred about 2 to 11 times more
frequently in 8-methoxypsoralen than 5-methoxypsoralen recipients within clin-
ical trials. Adverse hepatic events after oral administration of the drug were un-
common. Long term tolerability data for PUVA 5-methoxypsoralen are scarce;
however, carcinogenicity was not reported during a 14-year observation period
of 413 patients with psoriasis.
Conclusion: Similar lesion clearance rates were observed with oral 5- or
8-methoxypsoralen plus UVA exposure in patients with vitiligo or psoriasis,
although patients given 5-methoxypsoralen often required a greater total UV expo-
sure than 8-methoxypsoralen recipients. The incidence of short term cutaneous

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5-Methoxypsoralen: A Review 669

and gastrointestinal adverse effects is markedly less with 5-methoxypsoralen than

with 8-methoxypsoralen, which is an advantage, although the long term tolerability
of 5-methoxypsoralen has yet to be fully established. Nevertheless, in appropri-
ately selected patients, PUVA 5-methoxypsoralen therapy may be recommended
as an alternative first-line systemic treatment option for the management of vit-
iligo or psoriasis.
Rationale for the Use of The exact mechanisms causing vitiligo are unknown. There is a dysfunction in
Psoralens in Psoriasis the formation of melanin, possibly the result of melanocyte destruction by cyto-
and Vitiligo toxic T lymphocytes. The disease is characterised by the appearance of sponta-
neous, but persistent, depigmented cutaneous patches.
Psoriasis, another chronic condition, is characterised by raised, scaly, red-
dened patches, which result from hyperproliferation of the epidermis and inflam-
mation of both the epidermal and dermal layers.
The rationale for using ultraviolet (UV) A exposure plus oral or topical
psoralen therapy (PUVA) in these 2 conditions is complex. Both the drug and UV
radiation are necessary to obtain the beneficial therapeutic effects (e.g. pigmen-
tation and reduction in cutaneous hyperproliferation) not seen with either therapy
alone. Simultaneously, the psoralen enhances photoadaptation of the skin and
helps protect it from toxic UV effects (e.g severe erythema).
5-Methoxypsoralen is a naturally occurring, linear furocoumarin which has
been isolated from the rinds of citrus fruit, including bergamot and bitter orange,
and the leaves of other plants including celery and parsley.
Oral or topical 5-methoxypsoralen plus UVA irradiation has been used suc-
cessfully in the management of a variety of skin disorders including psoriasis and
vitiligo (see Therapeutic Efficacy summary).
Pharmacodynamic Although the exact mechanism of action is uncertain, 5-methoxypsoralen com-
Properties bined with UV irradiation is thought to form monofunctional or bifunctional
cross-links with pyrimidine bases in DNA strands and thus reduce the charac-
teristic hyperproliferative state of psoriasis. This therapy also generates reactive
oxygen species such as superoxide, which are thought to stimulate melanogenesis
and increase skin pigmentation, as is required for the management of vitiligo.
5-Methoxypsoralen plus UV irradiation appears to have less photosensitising
and pigmenting effects in healthy volunteers than 8-methoxypsoralen plus UV
irradiation. However, erythema observed 72 hours after UVA irradiation in-
creased dose-dependently with the dosage of both 5-methoxypsoralen and UVA.
Under the same UVA conditions the severity of erythema was ‘minimal’ with
5-methoxypsoralen and ‘marked’ with 8-methoxypsoralen.
Pigmentation developed at a faster rate in patients with psoriasis who received
5-methoxypsoralen than in 8-methoxypsoralen recipients (no further details pro-
vided). Higher dosage increments of UVA were therefore permitted in the former
group of patients without notable erythematous reaction. This resulted in fewer
exposures and an overall shorter treatment time (days) with 5- compared with
8-methoxypsoralen. However, total dosages of UVA required to achieve lesion
clearance were not significantly different between treatment groups.
Retinal light sensitivity in volunteers was significantly increased by 5-meth-
oxypsoralen.
Chronopharmacological factors appear to affect the overall activity of the
drug: in healthy volunteers, 5-methoxypsoralen significantly increased plasma
melatonin levels from baseline by about 1.5 times within 2 to 3 hours of admin-

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670 McNeely & Goa

istration; increases in mean maximum plasma melatonin levels were greater after
evening than after morning 5-methoxypsoralen administration.
Pharmacokinetic The overall absorption of orally administered 5-methoxypsoralen is dependent
Properties on the galenic formulation, the fed/fasted state of the recipient and the time of
day that the drug is given. In addition, a wide interindividual variation in general
pharmacokinetic parameters was apparent.
After a standard low fat meal, administration of a micronised compared with
an unmicronised formulation of the drug resulted in 3 to 4 times greater mean
maximum plasma concentrations (Cmax), a reduction in time to Cmax (tmax) of up
to 3 hours, and in 1 study, a significantly higher terminal elimination half-life
value (t1⁄2β). However, the Cmax of 5-methoxypsoralen was reduced compared
with that during the fed state when the drug was given after a ≥8-hour fast irre-
spective of the formulation given.
Cmax and area under the plasma concentration-time curve values were approx-
imately doubled after evening compared with morning administration of the un-
micronised formulation.
5-Methoxypsoralen metabolites were detected in the urine as early as 2 hours
after oral administration in volunteers. One-third of a dose of 5-[ 14C-methoxy]-
psoralen was recovered in the faeces and two-thirds in the urine in 2 human
volunteers within 5 days of administration. The metabolised drug excreted via
the urine comprised predominantly glucuronic acid conjugates.
Therapeutic Efficacy In clinical trials, investigators generally compared the effects of oral 5-methoxy-
psoralen 1.2 mg/kg and 8-methoxypsoralen 0.6 mg/kg. Many trials were nonblind
and few were randomised.
The level of cutaneous photosensitivity is dependent on the dose of 5-methoxy-
psoralen. Mean minimum phototoxic doses (MPD; an indicator of photosensitiv-
ity) of UVA were significantly higher with 5-methoxypsoralen 1.2 mg/kg than
with 8-methoxypsoralen 0.6 mg/kg in patients with psoriasis who received
8-methoxypsoralen for 1 year and the alternative drug in the second consecutive
year. MPD values within individuals were 30 to 50% greater with 5-methoxy-
psoralen than with 8-methoxypsoralen, which suggests a lower extent of photo-
sensitisation with the former.
Psoriasis clearance rates of >97% were observed in 60 and 64% of 5- and
8-methoxypsoralen recipients in 1 double-blind parallel study; correspondingly,
in another double-blind parallel study 62 and 77% of patients achieved >90%
clearance. The total UVA exposure and number of treatments required to reach
these end-points showed wide interstudy variation, and in several studies 8-
methoxypsoralen recipients required less total UVA exposure than patients given
5-methoxypsoralen. However, in a small number of patients who received both
treatments simultaneously and contralaterally, study end-point was achieved sooner
with oral 5-methoxypsoralen.
Patients receiving the micronised compared with the unmicronised tablet for-
mulation of 5-methoxypsoralen required significantly less total UVA and a lower
number of exposures to achieve a >90% reduction in the psoriasis area and
severity index in 1 study.
Treatment failure (<50% clearance of psoriasis) occurred in up to 16% of
patients receiving PUVA 5-methoxypsoralen and up to 8% of patients receiving
PUVA 8-methoxypsoralen (2 to 4 patients per treatment per study).

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5-Methoxypsoralen: A Review 671

The comparative efficacies of 5- and 8-methoxypsoralen, administered via a

water-bath, in patients with psoriasis are unclear.
5-Methoxypsoralen (oral or topical) combined with UV light exposure (lamp
or sun) induced >75% repigmentation in up to 56% of patients with vitiligo in a
number of nonblind studies. Areas of vitiligo located on the face and trunk were
the most responsive to treatment. In 1 study, 22% of patients did not respond to
therapy; also, 19% of patients (responders and nonresponders) exhibited spread-
ing lesions during treatment. Treatment success was not associated with dosage,
patient age or the duration of vitiligo.
The addition of phenylalanine to 5-methoxypsoralen treatment may enhance
repigmentation; this has yet to be confirmed.
Tolerability The incidence of short term adverse events in patients with psoriasis or vitiligo
was generally lower in those receiving PUVA 5-methoxypsoralen 1.2 mg/kg than
in those who received PUVA 8-methoxypsoralen 0.6 mg/kg. Adverse events oc-
curring after oral administration of these drugs can be generally classified as
gastrointestinal (caused by the psoralen) or cutaneous (caused by the combination
of psoralen and UVA exposure): nausea and/or vomiting, pruritus and erythema
were the most commonly reported adverse events. Within trials the incidence of
nausea and/or vomiting (severity not stated) was about 2 to 11 times greater in
8-methoxypsoralen than in 5-methoxypsoralen recipients; the incidence of pru-
ritus (severity not stated) and moderate to severe erythema was about 2 to 6 times
greater.
The formulation of 5-methoxypsoralen appears to influence the occurrence
and severity of adverse events. For example, nausea and vomiting (severity not
stated) were reported in up to 26% of recipients of the tablet formulation, but
nausea was observed only in a mild form in 7.7% of patients taking the drug as
a liquid suspension in soft gelatin capsules. Further comparative trials of the
different drug formulations are necessary to confirm this.
Adverse events associated with the liver after short term oral administration
of the drug were uncommon. Long term tolerability data for PUVA 5-methoxy-
psoralen, particularly with respect to cutaneous carcinogenicity, are scarce. How-
ever, there were no reports of carcinogenicity during a 14-year observation period
in which 413 patients with psoriasis received the treatment 1 to 3 times weekly.
Dosage and As part of PUVA therapy for psoriasis or vitiligo, the standard dosage of oral
Administration 5-methoxypsoralen is 1.2 mg/kg. Tablets (formulation not specified) should be
taken 2 hours before UVA exposure. Generally, it is necessary to complete 20
sessions at a rate of 2 to 4 per week. The duration of UV irradiation should be
carefully logged. Additional exposure to the sun should be avoided; so too should
other photosensitising medication such as sulfonamides, phenothiazides and
tetracyclines.

1. Rationale for the Use of Psoralens
in Psoriasis and Vitiligo
The use of psoralens (natural or synthetic) in
combination with ultraviolet (UV) light for the treat-
ment of vitiligo has been under investigation world-
wide since the late 1940s.[1] 8-methoxypsoralen
was the psoralen originally used in the treatment of
vitiligo, a skin condition characterised by patches
of depigmentation resulting from the destruction of
melanocytes. However, the melanogenic and photo-
toxic doses of the drug were similar, and this initi-
ated fears of potential erythematous reactions from
overexposure to UV light. Therefore, both the

 Adis International Limited. All rights reserved. Drugs 1998 Oct; 56 (4)
672
psoralen and the UV light source were further in-
vestigated in an effort to find a combination ther-
apy with a more acceptable risk to benefit ratio. As
a result, long wave (320 to 400nm; UVA) UV irra-
diation has been used [in combination with a pso-
ralen (PUVA)] in preference to UVB irradiation
since 1974.[2]
5-Methoxypsoralen is a naturally occurring,
linear furocoumarin which has been isolated from
the rinds of citrus fruit, including bergamot, lime,
grapefruit and bitter orange, and also from the leaves
of the fig tree, celery and parsley.[3] Oral or topical
5-methoxypsoralen plus UVA irradiation treatment
(PUVA 5-methoxypsoralen) has been used success-
fully in the management of a variety of skin disor-
ders including psoriasis and vitiligo (sections 4.2
and 4.3), which are the focus of this review.
Psoriasis and vitiligo have very different pre-
sentations and pathologies. The spontaneous, but
persistent and often progressive, appearance of
depigmented patches of skin in vitiligo is not re-
stricted to persons with highly pigmented skin,
although the patches are more obvious on dark
skin. The exact mechanisms causing vitiligo are
unknown, although there is an obvious dysfunction
of the melanocyte system and the subsequent for-
mation of melanin.[4] There is some evidence to
suggest that cytotoxic T lymphocytes are involved,
in an autoimmune capacity, in the destruction of
melanocytes in patients with this disorder.[5]
Psoriasis is also a chronic condition, subject to
periods of spontaneous remission and relapse. The
characteristic raised, scaly, reddened patches (or
plaques), are the result of hyperproliferation of the
epidermis and inflammation of both the epidermal
and dermal layers.[6]
The rationale for using UV exposure plus oral
or topical psoralen therapy in vitiligo and psoriasis
is complicated. It is based on the dual abilities of
the psoralen to enhance the sensitivity of the skin
to the beneficial effects of UV light (e.g pigmenta-
tion and hypoproliferation resulting from photo-
excited psoralen molecules), while simultaneously
provoking photoadaptation (e.g pigmentation) and
thus protecting the skin from toxic UV effects (e.g.
 Adis International Limited. All rights reserved.
McNeely & Goa
erythema, oedema and exfoliation).[1] Generally, the
therapeutic benefit resulting from combining pso-
ralen and UV exposure is not observed with either
therapy alone.
In vitiligo, repigmentation of lesions after PUVA
therapy is thought to occur as a result of melano-
cyte migration from hair follicles.[7] Cytokines re-
leased in the skin after exposure to UV radiation
are thought to stimulate this migration.[8]In addi-
tion, PUVA is known to destroy T lymphocytes,[9]
which could lead to a reduction in melanocyte
destruction and thus prevent the development of
further vitiligous lesions.
Photoprotection, which is thought to be con-
ferred by an increase in epidermal thickness and
the increase in melanin production,[1] may help to
shield the skin, particularly the sensitive depig-
mented areas, from the toxic effects of UV expo-
sure during therapy.
For the management of psoriasis, the hypopro-
liferative effects of photo-excited psoralen mole-
cules on the epidermal cells are required (section
2),[10] but not at the expense of causing erythema,
oedema and exfoliation. The photosensitising ef-
fect of 5-methoxypsoralen allows increased mela-
nin formation which in turn confers photoprotec-
tion against the unwanted effects of the prolonged
UV exposure that may be required to manage this
condition. Care should be taken not to induce too
much melanin production because it may interfere
with UV penetration through the epidermis and
thus reduce treatment efficacy.
2. Pharmacodynamic Properties
Although the exact mechanisms of action of PUVA
therapy are uncertain; the proposed mechanisms
are comprehensively documented elsewhere.[4,10-15]
Briefly, photoactivated psoralens form monofunc-
tional or bifunctional adducts (cross-links) between
their 4′,5′-double bond and/or their 3,4-double bond
and pyrimidine bases (thymine, cytosine) within
strands of DNA (fig. 1).[10] These cross-links are
thought to prevent DNA replication and thus re-
duce the hyperproliferative cutaneous state charac-
teristic of psoriasis. In addition, photoactivation of
Drugs 1998 Oct; 56 (4)
5-Methoxypsoralen: A Review 673

O O O action by which PUVA 5-methoxypsoralen can help

(1)
manage diseases with such diverse aetiologies and
pathologies as psoriasis and vitiligo remain specu-
(2)
lative.
O CH3
The pharmacodynamic properties of 5-methoxy-
5-Methoxypsoralen psoralen have been examined extensively in vitro
and in vivo and are summarised in table I. Some of
the more clinically relevant effects demonstrated
DNA (3) in human volunteers are discussed below.
C
(4) 2.1 Cutaneous Effects

T At equal doses, 5-methoxypsoralen appears to

(4)
T
(3)
C
Fig. 1. Structure of 5-methoxypsoralen and potential binding
sites with DNA. The 4′,5′ (1) and/or the 3,4 (2) double bonds of
the 5-methoxypsoralen molecule are thought to form mono- or
bi-functional adducts with the pyrimidine bases cytosine (3) and
thymine (4) within strands of DNA.[10]
the psoralen results in the generation of reactive
oxygen species such as superoxide; this is thought
to stimulate melanocyte proliferation and increase
pigmentation. Furthermore, the effects of UV ex-
posure on cutaneous cytokine release (section 1)
may be enhanced by the addition of 5-methoxy-
psoralen which may be beneficial in patients with
vitiligo.[8] Nonetheless, the exact mechanisms of
have less photosensitising and pigmenting effects
than 8-methoxypsoralen in volunteers with[16] or
without psoriasis.[16,17]
Fewer 5-methoxypsoralen than 8-methoxypsor-
alen (both 0.6 to 0.8 mg/kg orally) recipients ex-
hibited erythema (a marker of cutaneous sensitisa-
tion) 72 hours after UVA exposure (0 to 14% vs 42 to
72%; fig. 2); although statistical analysis was not
reported.[16] Erythema increased dose-dependently
with the dose of 5-methoxypsoralen and/or the
total UVA exposure (J/cm2) [fig. 2]. The mean
maximum severity of erythema was notably less
with 5-methoxypsoralen than with 8-methoxy-
psoralen [arbitrary score of 1+ (minimal percepti-
ble erythema) vs 3+ (marked erythema: red, but no
oedema)].
In patients with psoriasis, pigmentation devel-
oped at a much faster rate (no further details pro-
vided) with 5-methoxypsoralen 1.2 to 1.6 mg/kg
than with 8-methoxypsoralen 0.6 to 0.8 mg/kg.[16]
This allowed greater UVA dosage increments with
5-methoxypsoralen (up to 6.0 J/cm2) without caus-
ing a notable erythematous reaction in 18 of 19
5-methoxypsoralen recipients (no further details
given); the incidence of notable erythematous re-
action was similar in 8-methoxypsoralen recipients
(6 vs 5% with 5-methoxypsoralen) whose dosage
increments were limited to ≤2.0 J/cm2. Although
the number of days (17.1 vs 27.8) and the number
of exposures (9.0 vs 14.3) required for clearing the
lesions was significantly shorter with 5- compared
with 8-methoxypsoralen (p < 0.02 for both), there
was no statistically significant difference between

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674 McNeely & Goa

Table I. Summary of the pharmacodynamic properties of orally administered 5-methoxypsoralen in healthy volunteers or human-derived
tissues (unless stated otherwise)

In healthy volunteers
Increases cutaneous photosensitivity and pigmentation after oral[16] or topical[17,18] application (p-values not available)
Increases retinal light sensitivity (p < 0.05 vs baseline) and enhances the early phase of dark adaptation without affecting the ‘slow’ phase
(p < 0.05)[19,20]
Increases plasma melatonin levels (p < 0.01 vs baseline);[19,21,22] efficacy depends on the time of day the drug is given[22]
Compared with placebo, increases evening sleepiness (p < 0.001),[21] possibly via increased plasma melatonin levels

In vitro
In combination with UVA irradiation, forms photoadducts within DNA strands comprising 1 molecule of psoralen and 2 pyrimidine
bases[10-12,15]
Combined with UVA irradiation, releases soluble factors that suppress delayed and contact hypersensitivity in cultured mouse
keratinocytes[23]
UVA = ultraviolet A light.

the groups regarding total UVA required (105 vs 93
J/cm2 ).
These results are important with respect to the
management of psoriasis and vitiligo with PUVA
therapy. They indicate a greater margin between
the photosensitising, and therefore potentially
phototoxic, dosage (as indicated by erythema) and
the therapeutic dosage (as indicated by a more
rapid pigmentation), and thus a more favourable
risk to benefit ratio, with 5-methoxypsoralen than
with 8-methoxypsoralen.
In 10 volunteers, topical 5-methoxypsoralen also
appeared to be less phototoxic than topical 8-
methoxypsoralen (both 0.1% solutions) as indicated
by the development of blistering and depigmenta-
tion in 3 of 5 volunteers receiving 8-methoxy-
psoralen and in none of those who received 5-
methoxypsoralen.[17]
2.2 Other Effects
Retinal light sensitivity was significantly in-
creased with 5-methoxypsoralen in volunteers (p <
0.05 vs baseline). The early phase of dark adapta-
tion was enhanced without affecting the ‘slow’
phase (p < 0.05).[19,20] Therefore, it is important to
minimise ocular exposure to UV light (lamp or sun)
both during and between irradiation sessions (sec-
tion 6.1).
A series of studies in volunteers by Souêtre et
al.[19,21,22] indicated that chronopharmacological
factors may be important in the overall efficacy of
5-methoxypsoralen: plasma melatonin levels sig-
nificantly (p < 0.01) increased from baseline by
about 1.5 times within 2 to 3 hours of morning or
evening administration of a single dose of 5-meth-
oxypsoralen 40mg.[19] After 1 week’s daily admin-
istration of 5-methoxypsoralen 40mg at 4pm, both
plasma levels of melatonin and subjective assess-
ment of sleepiness were significantly increased when
measured 5 hours after the dose (i.e. at 9pm; p <
0.01 vs placebo).[21] Furthermore, mean maximum
plasma melatonin levels were increased from base-
line (131 ng/L) to a greater extent after evening
(9pm; 293 ng/L) than after morning (9am; 163 ng/L)
administration of the drug (p < 0.01 for evening
administration vs baseline).[22] The amplitude of
diurnal changes in plasma melatonin levels was also
enhanced by evening administration of 5-methoxy-
psoralen: values were 37, 31 and 107 ng/L, respec-
tively, for baseline (no treatment), morning and
evening treatment. These data suggest that 5-
methoxypsoralen has a greater overall pharmaco-
logical effect when given in the evening than in the
morning. However, this does not appear to be con-
sidered in the dosage recommendations (section 6).
Diseases such as psoriasis and vitiligo are thought
to involve the immune system.[23] In in vitro mouse
keratinocyte preparations, PUVA 5-methoxypso-
ralen exposure resulted in the release of a soluble
factor that suppressed both contact and delayed
type hypersensitivity, which does suggest a link be-
tween PUVA therapy, keratinocytes and the immune
system;[23] however, this is yet to be confirmed.

 Adis International Limited. All rights reserved. Drugs 1998 Oct; 56 (4)
5-Methoxypsoralen: A Review 675

100 5-MOP (0.6-0.8 mg/kg) ent on the galenic formulation, the fed/fasted state
of the recipient and the time of day that the drug is
80 given.
5-Methoxypsoralen is poorly soluble in water
60
(1.5 mg/L at 20°C[24])[2,25] and therefore the parti-
cle size of the drug is an important factor regard-
40
ing dissolution and absorption.[24,25] However,
particle size was given in 1 of the studies reviewed
20
for the micronised formulation only;[24] neither
0
this study,[24] nor any of the others reviewed gave
Patients with positive response for erythema (%)

this information for the unmicronised formula-

100 5-MOP (1.2-1.6 mg/kg)
80
60
40
20
0 Time to Cmax (tmax) was reduced by up to 3 hours
100 8-MOP (0.6-0.8 mg/kg)
80
60
40
20
0
1 2 3 5
UVA exposure (J/cm2)
Fig. 2. Percentage of patients with psoriasis exhibiting erythema
72 hours after oral 5-methoxypsoralen (5-MOP) 0.6 to 0.8 mg/kg
(n = 7) or 1.2 to 1.6 mg/kg (n = 4) or 8-methoxypsoralen (8-MOP)
0.6 to 0.8 mg/kg (n = 7; no p-values provided).[16] Maximum
erythema scores (for all doses) were 1+ (minimal perceptible
erythema) with 5-methoxypsoralen and 3+ (marked erythema:
red, but no oedema) with 8-methoxypsoralen.
3. Pharmacokinetic Properties
3.1 Absorption and Distribution
The overall rate and extent of absorption of
orally administered 5-methoxypsoralen is depend-
tion.[25-27]
The pharmacokinetics of micronised and unmic-
ronised oral formulations of 5-methoxypsoralen
(1.2 mg/kg dose) are summarised in table II. After
a standard low fat meal, mean maximum plasma
drug concentrations (Cmax) were about 3 to 4 times
greater with the micronised (range 249 to 322
µg/L) than with the unmicronised formulation
(range 68 to 108 µg/L; p < 0.01).[24-26]
with the micronised formulation (p < 0.01[25,26]);[29]
mean tmax ranges were 0.86 to 2.7 hours (micronised)
and 3.04 to 3.82 hours (unmicronised; table II).
Predicting tmax is important because, ideally, UVA
exposure should coincide with the time of maxi-
mum cutaneous psoralen concentration.[30-32] Cu-
taneous tmax values have been shown to be similar
to plasma tmax values; they are also influenced by
the galenic formulation of the drug (fig. 3).[26]
7 9 Reports from several studies remarked on the
wide interindividual variation in 5-methoxypso-
ralen pharmacokinetic parameters.[27,29,33,34] For
example, Aubin et al.[25] and Treffel et al.[26] inves-
tigated the same micronised formulation of 5-
methoxypsoralen in their individual studies, yet re-
spective mean tmax values were 0.86 and 1.45 hours
(table II). Indeed, a Cmax range of 2 to 750 µg/L
(mean 110 µg/L) and a tmax range of 1 to 5 hours
(mean 3 hours) was shown by another group (drug
formulation not specified).[35] These latter data
suggest that UVA exposure may be more effective
if given 3 instead of the recommended 2 hours after
oral 5-methoxypsoralen (section 6). For a more
effective treatment, perhaps pharmacokinetic

 Adis International Limited. All rights reserved. Drugs 1998 Oct; 56 (4)
676 McNeely & Goa

Table II. Summary of pharmacokinetic data pertaining to oral 5-methoxypsoralen (5-MOP) 1.2 mg/kg given as a micronised (M) or an
unmicronised (UM) formulation to patients with psoriasis (pts) or healthy volunteers (vts) in crossover trials (unless otherwise stated)
Reference No. and type of recipients Formulation Pharmacokinetic parameter (mean value)
Cmax (µg/L) tmax (h) AUC (µg/L • h) t1⁄2β(h)

5-MOP given after a standard low fat meal

Aubin et al.[25] 13 ptsa M 320.36*** 0.86*** NR NR
15 ptsa UM 85.82 3.82 NR NR
Stolk et al.[24] 7 pts M 322** 2.7 942** NR
7 pts UM 108 3.3 276 NR
Treffel et al.[26] 12 vts M 249** 1.45** 890** 3.2**
12 vts UM 68 3.04 272 2.23

5-MOP given after a ≥8-hour fast

Brodie et al.[27] 6 vts M 177b 1.6b 433b 1.4b
6 vts UM 19 3.4 64 2c
[28] d e
Nitsche & Mascher 6 vts M 31.8 2.0 140.4 1.69
6 vts LGd 70.8 2.0e 262* 2.27
a Nonblind, randomised, parallel study.
b Statistical analysis not performed.
c Measured in 2 volunteers only.
d Standard 40mg dose of psoralen given.
e Presented graphically.
AUC = area under the plasma concentration-time curve; Cmax = maximum plasma concentration; LG = liquid suspension of 5-MOP in soft
gelatin capsules; NR = not reported; t1⁄2β = terminal elimination half-life; tmax = time to Cmax; * p < 0.05, ** p < 0.01, *** p < 0.001 vs comparator
formulation.

parameters should be measured for each patient be-
fore PUVA therapy begins; costs and time manage-
ment will obviously determine the practicality of
this.
Tanew and colleagues[36] showed that serum con-
centrations of 5-methoxypsoralen were linearly re-
lated to the dose of the drug given. Two hours after
oral administration of liquid-filled (5-methoxy-
psoralen in suspension) gelatin capsules to patients
with psoriasis, the respective mean serum concen-
trations for 5-methoxypsoralen 0.6 and 1.2 mg/kg
were 81 and 164 µg/L. The authors compared these
values with that obtained in another study of the
same formulation of 8-methoxypsoralen 0.6 mg/kg
(305 µg/L[37]). This finding (i.e. much higher se-
rum concentrations with 8-methoxypsoralen than
with the same dose of 5-methoxypsoralen) was sug-
gested as an explanation for the lower photosen-
sitising effect of 5-methoxypsoralen (section 4.1).
Results from separate studies suggest that the
pharmacokinetics of 5-methoxypsoralen are al-
tered if the drug is given after a ≥8-hour fast:[27,28]
Cmax and area under the plasma concentration-time
curve (AUC) values were markedly reduced in the
fasted compared with the fed state (table II). This
phenomenon is supported by results from a com-
parative study in which mean plasma 5-methoxy-
psoralen concentrations measured 2 hours after
oral administration of 1.2 mg/kg were 4 times
lower in fasted than in fed volunteers (14.3 vs 56.7
µg/L; p = 0.004).[33] After a 10-hour fast, plasma
concentrations measured 2 hours after psoralen ad-
ministration (1.2 mg/kg) were below the assay de-
tection limit (<1 µg/L) in 6 of 9 volunteers. Simi-
larly, Cmax values were detectable in only 4 of 9
fasted volunteers and ranged from 15 to 88 µg/L,
whereas the corresponding range detectable in all
9 fed volunteers was 37 to 144 µg/L (p = 0.004).
Cmax and AUC values significantly increased
when 5-methoxypsoralen 1.2 mg/kg (unmicro-
nised) was administered at 7pm (175 µg/L and 196.9
mg/L • h) compared with 7am (82 µg/L and 105.2
mg/L • h; both p < 0.001).[38] These AUC values
appear very high compared with values reported in

 Adis International Limited. All rights reserved. Drugs 1998 Oct; 56 (4)
5-Methoxypsoralen: A Review
other studies (table II); nevertheless, the relative
changes give further evidence to suggest that cir-
cadian rhythms ought to be taken into consider-
ation when implementing PUVA treatment regi-
mens.
Distribution of 5-methoxypsoralen into the ocu-
lar lens was negligible in guinea-pigs. Two hours
after oral administration, respective concentrations
for serum, epidermis and lens were 308 mg/L, 303
mg/kg and 21 mg/kg.[39] Although this suggests
that 5-methoxypsoralen is not present in high con-
centrations in lens tissue, some evidence of retinal
light sensitivity has nonetheless been seen in vol-
unteers (section 2.2).
3.2 Metabolism and Elimination
5-Methoxypsoralen metabolites have been de-
tected in the urine as early as 2 hours after oral
administration in healthy volunteers.[29] It has been
suggested that these rapid changes are the result
of biotransformation within the intestine wall,[29]
or, more likely, within the liver.[40] A saturable
first-pass effect has been demonstrated for 8-
methoxypsoralen in volunteers;[40,41] similar pub-
Plasma concentrations
Micronised
Unmicronised
**
Cutaneous concentrations
*
0 1 2 3 4 5
tmax (h)
Fig. 3. Mean values for time to maximum plasma and cutaneous
5-methoxypsoralen concentrations (tmax) after oral administra-
tion of 2 different galenic formulations to 12 healthy volun-
teers.[26] Cutaneous concentrations were determined in
mechanically induced (by suction) blister fluid. * p< 0.05; ** p <
0.01 vs micronised formulation.
 Adis International Limited. All rights reserved.
677
lished data for 5-methoxypsoralen are not avail-
able. However, since these 2 agents have a similar
chemical structure, it would be reasonable to sup-
pose that 5-methoxypsoralen is affected in a sim-
ilar manner by first-pass metabolism.
Approximately two-thirds of a 50mg dose of
5-[14C-methoxy]psoralen was recovered in the urine
and one-third in the faeces in 2 human volunteers
within 5 days of administration.[42] Trace amounts
of unchanged 5-methoxypsoralen were excreted in
the urine;[29,42] the majority was excreted as glucu-
ronic acid conjugates.
In 1 study, the terminal elimination half-life
value was significantly lower with the unmicro-
nised than with the micronised formulation (3.2
vs 2.23 hours; p < 0.01)[26] [table II]. However,
after a ≥8-hour fast the value was lower with the
micronised formulation (1.4 vs 2.0 hours; statisti-
cal analysis not performed).[27]
4. Therapeutic Efficacy in
Dermatological Disorders
The quality of the available data for the effi-
cacy of PUVA 5-methoxypsoralen in psoriasis and
vitiligo is variable. Fewer than half of the studies
were double-blind and fewer than one-third were
randomised. The duration of studies was not al-
ways clearly stated; in many studies patients con-
tinued therapy until a predetermined reduction in
the symptoms of the disease had been attained
(e.g. ≥75% clearance of psoriatic lesions). The
number of patients receiving 5-methoxypsoralen
ranged from 16 to 198 per study, but in half of the
studies the group size was <30.
Initial doses of UVA lamp irradiation were de-
termined by calculating the minimum phototoxic
dose (MPD) according to methods described else-
where.[43] Briefly, small defined areas of skin are
exposed to increasing levels of UVA irradiation 2
hours after oral administration of the psoralen; the
MPD is the lowest level of UVA which causes a
barely perceptible but well defined erythema 72
hours after UVA irradiation. A percentage of this
dose (50 to 75%) is used as the starting dosage for
the UVA treatment. UVA dosages are increased
Drugs 1998 Oct; 56 (4)
678
with consideration given to the skin type and the
observed reaction to PUVA therapy.
Generally, patients were given the oral psoralen
in the morning after a low fat meal and 2 hours
before UVA lamp exposure (PUVA) or ≤2 hours
before exposure to sunlight (UVA and UVB;
PUVASOL). In the studies reviewed, a variety of
oral 5-methoxypsoralen formulations were used.
Where stated, these included ‘tablets’ (micronised
state not usually defined),[44-47] microcrystalline
tablets[48] and liquid-filled (psoralen in suspen-
sion) soft gelatin capsules.[36,49]
4.1 Cutaneous Photosensitivity
An increase in cutaneous photosensitivity after
oral psoralens is an important aspect of the thera-
peutic activity of the drug. It is linked to both pig-
mentation and the reduction of epidermal hypopro-
liferation (sections 1 and 2). However, if cutaneous
sensitivity is increased without a photoprotective
component, it may result in phototoxicity, a term
commonly used in the trials reviewed to describe
undesirable cutaneous effects such as severe ery-
thema (section 5.1).
Because of the importance of photosensitivity
to the overall treatment rationale (section 1), it is
relevant to discuss it here rather than treating it as
a tolerability issue.
The 1 available study which compared the MPDs
of UVA for 2 different doses of 5-methoxypsoralen
in patients with psoriasis showed an inverse dose
relationship:[36] respective MPDs for 0.6 and 1.2
mg/kg were 6.4 and 3.5 J/cm2. In the same study,
the MPD for 8-methoxypsoralen 0.6 mg/kg was 2.7
J/cm2, which is similar to that for the higher dose
of 5-methoxypsoralen.
One reason suggested for the apparently lower
photosensitisation observed with 5-methoxypso-
ralen than with 8-methoxypsoralen is that, at the
same dosage, the former has a lower serum concen-
tration after oral administration (section 3.1).[36]
Nevertheless, mean total UVA dosages required
to achieve complete remission in patients with
psoriasis were 45, 132 and 53 J/cm2, respectively,
for 8-methoxypsoralen 0.6 mg/kg and 5-methoxy-
 Adis International Limited. All rights reserved.
McNeely & Goa
psoralen 0.6 or 1.2 mg/kg (p < 0.05 for 5-methoxy-
psoralen 0.6 mg/kg vs the other groups).[36] These
data suggest similar efficacies for 8-methoxypso-
ralen 0.6 mg/kg and 5-methoxypsoralen 1.2 mg/kg
with respect to the total amount of UV exposure
required to achieve the same level of therapeutic
efficacy,[36] and it is these dosages that have been
compared in clinical trials. In the same study, [36]
phototoxicity, described as severe erythema reac-
tion, occurred in 19, 0 and 3%, respectively, of
patients receiving 8-methoxypsoralen 0.6 mg/kg
and 5-methoxypsoralen 0.6 or 1.2 mg/kg. This sug-
gests that 5-methoxypsoralen compared with 8-
methoxypsoralen causes a reduced phototoxic ef-
fect.
In another study, mean MPDs were significantly
higher with 5-methoxypsoralen 1.2 mg/kg than
with 8-methoxypsoralen 0.6 mg/kg in 25 patients
with psoriasis who received 5-methoxypsoralen a
year after they had been treated with 8-methoxy-
psoralen (5.4 vs 3.1 J/cm2; p < 0.01).[48] The intra-
individual variability for each drug was wide (3 to
10 J/cm2 with 5-methoxypsoralen vs 2 to 7 J/cm2
with 8-methoxypsoralen), but the MPD values
within individuals were 30 to 50% higher with 5-
methoxypsoralen than with 8-methoxypsoralen,
which again indicates a lower phototoxic effect
with the former psoralen. Although these data sup-
port the findings in volunteers (section 2.1), they
do not take into account cutaneous photoadapta-
tion, if any, caused by the initial 8-methoxypsoralen
PUVA therapy.
4.2 Psoriasis
Psoriasis presents in several distinct forms. The
most common is the plaque type: this may involve
small areas of the skin or may cover almost the
entire body. Less common is the guttate form,
which comprises numerous small lesions located
on the trunk; this form is more common in children.
The thickened plaques of scaly epidermal tissue
seen in psoriasis are thought to result from uncon-
trolled epidermal growth coupled with rapid cellu-
lar turnover.[2]
Drugs 1998 Oct; 56 (4)
5-Methoxypsoralen: A Review 679

Where reported in the studies reviewed,[36,44,46-48] Good/very good

patients receiving 5-methoxypsoralen most com- Fair/minimal
Failure
monly had chronic plaque-type psoriasis and skin
Not indicated
type II to IV (constant sunburn, sometimes fol- 5-Methoxypsoralen
lowed by pigmentation[46]). 1.2 mg/kg (n = 56)
77%
4.2.1 Oral Formulations
Several studies have compared the effects of
PUVA 5-methoxypsoralen 1.2 mg/kg and 8-
methoxypsoralen 0.6 mg/kg in patients with pso-
riasis: the overall effects of the 2 treatments were
not statistically significantly different. Psoriasis
clearance rates of >97% were observed in 60% of 14%
5-methoxypsoralen recipients and 64% of those
receiving 8-methoxypsoralen in 1 double-blind stu- 7%
2%
dy.[46] Similar results were seen in a second ran-
domised, double-blind study in which 77 and 62% 8-Methoxypsoralen
62%
of patients, respectively, who received 5- and 8- 0.6 mg/kg (n = 61)
methoxypsoralen 3 to 5 times weekly achieved
>90% clearance (fig. 4).[47] However, data were
not available for 14% of 5-methoxypsoralen recip-
ients and 21% of patients receiving 8-methoxy-
psoralen.
Furthermore, in another study the psoriasis area
and severity index (PASI) was similarly reduced in
patients who received 5-methoxypsoralen (by 96%)
or 8-methoxypsoralen (by 97%) once weekly.[48] 21%
Although overall clinical efficacy was not sig- 13%
3%
nificantly different between treatment groups in
Fig. 4. Clearance rates in patients with psoriasis (typically
these studies, as measured by clearance rates and plaque-t y p e ) w h o r e c e iv e d 5 - m e th o x y p s o r a le n o r 8 -
reductions in PASI scores, the total UVA irradia- methoxypsoralen orally 3 to 5 times weekly in combination with
tion (J/cm2) and the number of exposures required ultraviolet (UV) A irradiation (duration not provided).[47]
Psoralens were given 2 hours before UVA exposure. Good/very
to achieve this level of efficacy were the more good represents >90% clearance of lesions (no further details
commonly expressed end-points. provided).
In several studies the total UVA irradiation re-
quired was 11 to 34% less in 8-methoxypsoralen from 117.7 to 305 J/cm2 for 8-methoxypsoralen;
than in 5-methoxypsoralen recipients (table III); the corresponding ranges for the total number of
the difference was significant in some studies (p < exposures were 18 to 22.1 and 18 to 29.6 (table III).
0.05).[44,48] This suggests a greater efficacy for 8-
Therefore, results from studies in which patients
methoxypsoralen. However, the total UVA irradia-
received PUVA each psoralen simultaneously and
tion and number of treatments required to reach
end-point showed wide interstudy variation. With contralaterally are perhaps more indicative of the
the tablet formulation, including microcrystalline true comparative effect of these 2 drugs. For exam-
preparation (excluding the liquid-filled capsules), ple, Hönigsmann et al.[16] reported that study end-
the total UVA irradiation required ranged from point (i.e. complete flattening of psoriatic lesions)
136.9 to 187 J/cm2 for 5-methoxypsoralen and was achieved sooner with 5-methoxypsoralen 1.2

 Adis International Limited. All rights reserved. Drugs 1998 Oct; 56 (4)
680 McNeely & Goa

Table III. Summary of comparative trials with oral PUVA 5-methoxypsoralen 1.2 mg/kg (5-MOP) or PUVA 8-methoxypsoralen 0.6 mg/kg
(8-MOP) therapy in patients with psoriasis
Reference Design No. of evaluable Psoralen administereda Treatment required for psoriasis clearance or
patients (no. of treatments/wk) reduction in PASIb
total UVA difference between no. of
(J/cm2) groups in total UVA exposures
Berg & Ros[44] db, dd, r 16 5-MOP (2) 187* 18
15 8-MOP (2) 155 17%* 18
Calzavara-Pinton et al.[48] nb, co 25 5-MOPc (1) 179.1** 22.1
25 8-MOPc (1) 117.7 34%** 22.6
Grupper & Berretti[50] nb, con 198 5-MOP (NR) 148 20.6
1259 8-MOP (NR) 131 11% 21.1
Kalis et al.[47] db, mc, r 56 5-MOP (3-5) 136.9 19.4
61 8-MOP (3-5) 119.5 13% 18.3
Peyron & Meynadier[46] db 26 5-MOP (3-5) 163 19.6
25 8-MOP (3-5) 305 -47% 29.6
Tanew et al.[36] r 63d 5-MOPe (4) 53 15*
48d 8-MOPe (4) 45 15% 12
a Psoralens given 2 hours before UVA exposure as tablet formulation (microcrystalline state not given) unless stated otherwise.
b End-points were defined as follows: psoriasis healing (no further details);[44] >90% reduction in PASI;[48] lesion clearance of >75%[50],
>90%[47], ≥97%[46] or 100%[36]
c Drugs given as microcrystalline formulation.
d Patients with chronic plaque type psoriasis (≈66%) also received etretinate 5 days prior to the start of and during the entire period of UVA
therapy.
e Drugs given as liquid suspension in soft gelatine capsules; 8-methoxypsoralen given 1 hour before UVA exposure.
co = crossover; con = consecutive patients; db = double-blind; dd = double-dummy; mc = multicentre; nb = nonblind; NR = not reported;
PASI = psoriasis area and severity index; PUVA = psoralen plus ultraviolet A irradiation; r = randomised; UVA = ultraviolet A * p < 0.05; ** p
< 0.01 vs comparator drug.

to 1.6 mg/kg than with 8-methoxypsoralen 0.6 to
0.8 mg/kg when separate sides of the body were
treated with UVA after administration of each drug
on alternate days in 6 patients with generalised
psoriasis; the mean number of irradiations required
with 5-methoxypsoralen was 6.1 (no further details
provided). Further studies of this design with larger
patient numbers are warranted to determine more
accurately the comparative efficacies of these 2
psoralens.
The type of oral formulation used alters the ef-
ficacy of the drug: patients receiving the micron-
ised compared with the unmicronised tablet formu-
lation of 5-methoxypsoralen required significantly
less total UVA (145.89 vs 231.11 J/cm2) and fewer
exposures (10.64 vs 17.27; both p < 0.05) to
achieve a >90% reduction in PASI.[25] This may be
the result of a more rapid dissolution and greater
cutaneous absorption with the smaller micronised
particles (section 3.1). In another study, which ex-
amined the effects of psoralens given as a liquid
suspension in gelatin capsules,[36] the total UVA
required for 100% remission of psoriasis was 53
J/cm2 with 5-methoxypsoralen and 45 J/cm2 with
8-methoxypsoralen. These values appear low in com-
parison with results from trials which used tablet
formulations and are more within the range seen
with topical formulations (section 4.2.2). However,
since this study did not include a tablet comparator,
the results should be interpreted with caution.[36] In
addition, patients in this study with plaque-type
psoriasis (approximately 66%) also received etret-
inate 1 mg/kg 5 days before and throughout the
entire PUVA therapy; this additional drug may
have influenced the absolute, but not relative, effi-
cacy of the psoralens.[36]
Treatment failure (<50% clearance of psoria-
sis[46]) occurred in up to 16% of patients (3 to 4
patients per study) receiving PUVA 5-methoxy-
psoralen 0.6 or 1.2 mg/kg and up to 8% of patients

 Adis International Limited. All rights reserved. Drugs 1998 Oct; 56 (4)
5-Methoxypsoralen: A Review 681

(2 to 3 patients per study) receiving 8-methoxy- 5-methoxypsoralen are required before this can be
psoralen 0.6 mg/kg.[36,46,47] confirmed.

4.2.2 Topical Formulations 4.3 Vitiligo

The severity of palmar psoriasis (assessed by
PASI score) was significantly reduced by about 90%
after water-bath application of 0.0003% (wt/vol)
of 5-methoxypsoralen or 8-methoxypsoralen 15 to
20 minutes immediately prior to UVA irradiation
(p < 0.01 vs baseline; no significant difference be-
tween treatment groups). However, the total UVA
irradiation (30.2 vs 46.3 J/cm2; p < 0.01) and num-
ber of exposures (17 vs 21; p = 0.02) were signifi-
cantly lower with 5-methoxypsoralen than with
8-methoxypsoralen.[51] Each of the 10 patients was
randomised to simultaneously receive 1 of the
psoralens on either hand.
Widespread plaque-type psoriasis was also sig-
nificantly reduced by about 94% with each pso-
ralen (p < 0.01 vs baseline; no significant differ-
ence between treatment groups) after water-bath
application (0.0003% wt/vol) in 22 patients, but in
this case total UVA irradiation (56.8 vs 59.1 J/cm2)
and number of exposures (20 vs 21.6) were similar
in each treatment group.[51] When compared with
oral use, topical application of these drugs appears
to reduce the overall exposure to UVA required to
attain a satisfactory effect. However, studies which
directly compare topical and oral administration of
The characteristic depigmented patches of viti-
ligo may be localised (i.e. restricted to 1 area), gen-
eralised (i.e. depigmented areas scattered over the
entire body surface) or universal (i.e. the entire cu-
taneous area is depigmented, with occasional hyper-
pigmented spots on areas exposed to sunlight).
Regularly exposed areas of skin (e.g. hands, face
and feet) are commonly the first sites to develop
the condition.
Where reported,[52,53] patients enrolled in the
clinical trials reviewed in this section had vitiligo
for up to 30 years, which covered up to 70% of their
body, and had skin type II to VI (constant sunburn,
sometimes followed by pigmentation to racially
black[46]).
Although 8-methoxypsoralen was the original
psoralen used in combination with UV irradiation
to treat vitiligo, there is only 1 study currently avail-
able that has investigated the comparative effects
of 5- and 8-methoxypsoralen (section 4.3.2).[45]
5-Methoxypsoralen combined with UV light ex-
posure induced >75% repigmentation in up to 56%
of patients with vitiligo as shown in a number of
nonblind studies. Some studies used the previously
described PUVA technique (i.e. UVA from a lamp;

Table IV. Summary of nonblind trials with oral 5-methoxypsoralen (5-MOP) given 2 hours prior to ultraviolet A (UVA) lamp exposure in patients
with vitiligo
Reference No. of evaluable Dosage (no. of treatments/wk) Patients achieving Treatment required
patients repigmentation (%)
50 -75% >75% total total UVA no. of duration
total area area (J/cm2) exposures (mo)
Berretti et al.[52] 15a PA 50 mg/kg PO 30 min pre UVA 0 0 NR NR NR
(3)
50a 5-MOP 1 mg/kg (3) 32 16 1080b 196b 31
60 a
5-MOP 1 mg/kg + PA 50 mg/kg 25 25 588 121 20
PO 30 min pre UVA (3)
Hann et al.[53] 36 5-MOP 40-60mg (1-2) 25 31 332-356c 42-45c 5-6c
a All 15 patients in the PA group were included in the 5-MOP group; 28 patients in the 5-MOP group were included in the 5-MOP + PA
group.
b Statistical analysis not reported for any between-group comparisons.
c Values given for 50-75% repigmentation and >75% repigmentation groups.
NR = not reported; PA = phenylalanine; PO = orally.

 Adis International Limited. All rights reserved. Drugs 1998 Oct; 56 (4)
682 McNeely & Goa

table IV);[52,53] others examined the effects of the in 25 and 16% of patients receiving oral treat-
drug given orally[45] or topically[54] as PUVASOL ment, respectively, with and without phenylalanine
therapy [i.e. with exposure to natural sunlight (p-values not provided).[52] The time taken (121 vs
(UVA and UVB); table V]. 196 exposures) and total UVA (588 vs 1080 J/cm2)
required to achieve this level of repigmentation
4.3.1 Sunlamp Exposure were also reduced by the addition of phenylalanine.
In a study of PUVA 5-methoxypsoralen (40 to Indeed, in some patients who had previously re-
60mg orally per session),[53] areas of vitiligo lo- ceived PUVA 5-methoxypsoralen treatment and
cated on the face and trunk were more responsive who had no further improvement in their lesions
to treatment than areas located on the distal parts for at least 2 months, repigmentation resumed
of limbs. Although 31% of 36 patients achieved when phenylalanine was added to the regimen.[52]
>75% repigmentation, 8 patients (22%) did not re- Phenylalanine plus UVA alone did not induce
spond to therapy at all. In addition, 7 patients (19%) repigmentation. These results should be interpreted
exhibited spreading lesions during treatment; 3 of with caution, however, because the benefit of add-
these were nonresponders, and the others showed ing phenylalanine to PUVA treatment has not been
spreading lesions within well-repigmented areas, confirmed.
particularly on the hands. Overall, improvement
was not associated with patient age or the duration 4.3.2 Sunlight Exposure
of vitiligo before treatment intervention. More patients receiving oral 5-methoxypso-
In another study, the addition of phenylalanine ralen 0.6 or 1.2 mg/kg (n = 26 and 25) than those
50 mg/kg 30 minutes before UVA exposure en- receiving oral 8-methoxypsoralen 0.6 mg/kg (n =
hanced the PUVA 5-methoxypsoralen repigmenta- 27) achieved >50% repigmentation (56, 54 and
tion process: >75% repigmentation was achieved 41%, respectively; no p-values provided) when the
drugs (both micronised formulations) were given
orally 1.5 to 2 hours prior to a 30-minute period of
Table V. Summary of nonblind trials using 5-methoxypsoralen (5- sun exposure (15 minutes each prone and supine)
MOP) or 8-methoxypsoralen (8-MOP) prior to sun exposure in 3 times weekly (fig. 5).[45]
patients with vitiligo
Exposure to sunlight is not as reliable as con-
Reference No. of Dosage (no. of Patients achieving
evaluable treatments/wk) >50% trolled UVA lamp exposure.[45] Generally, caution
patients repigmentation (%) is needed when treating fair skinned and/or undis-
Orecchia & 27 5-MOP 14.8 ciplined patients to prevent risk of severe burns.
Malagoli[54] 0.001%a
Indeed, the authors of the above study in Indian
Pathak et 25 5-MOP 0.6 56
al.[45] mg/kg PO patients[45] highlighted factors which complicated
1.5-2h pre 30 treatment compliance. These included lack of sun-
min sun shine (because of unseasonal weather) and insuf-
exposure (3)
26 5-MOP 1.2 54
ficient time and privacy during the day (because
mg/kg PO of work constraints and cultural limitations) to
1.5-2h pre 30 achieve the necessary exposure time on the re-
min sun
exposure (3)
quired body areas. Nevertheless, this treatment
27 8-MOP 0.6 41 regimen was successful in more than 50% of the
mg/kg PO 5-methoxypsoralen-treated group. In this study,
1.5-2h pre 30 response to treatment did not appear to be dose-
min sun
exposure (3) related.
a 5-MOP applied as a solution 15 minutes prior to sun exposure Preliminary results indicate that 5-methoxy-
(abstract report; frequency not defined). psoralen (0.001% solution) applied topically fol-
PO = orally.
lowed by sunlight exposure induces repigmenta-

 Adis International Limited. All rights reserved. Drugs 1998 Oct; 56 (4)
5-Methoxypsoralen: A Review
54%
23%
23%
5-Methoxypsoralen
1.2 mg/kg (n = 26)
Fig. 5. Repigmentation rates in Indian patients with vitiligo who received oral psoralens 1.5 to 2 hours before a 30-minute exposure
to sunlight (15 minutes each prone and supine) 3 times weekly (duration not reported).[45] Excellent/good represents >50 to 99%,
minimal/fair represents >5 to 50%, poor/worse represents <5% repigmentation or vitiligo exacerbated.
tion in patients with vitiligo (table V).[54] Topical
application may reduce the gastrointestinal ad-
verse events associated with oral application of 5-
methoxypsoralen (section 5.1).
5. Tolerability
5.1 General Profile
Generally, the incidence of adverse events in
patients with psoriasis or vitiligo was lower in those
receiving PUVA 5-methoxypsoralen 1.2 mg/kg than
in those who received PUVA 8-methoxypsoralen
0.6 mg/kg, although the clinical trials reviewed did
not provide statistical analysis.[36,44-47,50,51,55]
In clinical studies, adverse events associated
with use of PUVA or PUVASOL therapy may be
divided into 2 major categories: gastrointestinal
(caused by the oral psoralen alone) and cutaneous
[caused by the combination of psoralen and UVA
irradiation (many of these relate to phototoxicity,
which is discussed in section 4.1)]. The most com-
monly occurring gastrointestinal events were nau-
sea and/or vomiting, although obstipation/diarrhoea
was also reported in 1 study.[44] Pruritus and ery-
thema were the most common cutaneous adverse
 Adis International Limited. All rights reserved.
683
Excellent/good
Minimal/fair
Poor/worse
56% 41%
12%
33%
26%
32%
5-Methoxypsoralen 8-Methoxypsoralen
0.6 mg/kg (n = 25) 0.6 mg/kg (n = 27)
reactions; headache and giddiness were also re-
ported in some trials.[44,45,47]
Frequencies for individual adverse events var-
ied widely. The incidence of pruritus, for example,
ranged from 2 to 63% in oral 5-methoxypsoralen
1.2 mg/kg recipients and from 11 to 42% in those
receiving oral 8-methoxypsoralen 0.6 mg/kg (both
tablet formulations).[36,44-47,50,51] The incidence of
nausea and/or vomiting (severity not stated) ranged
from 0 to 26% in oral 5-methoxypsoralen recipi-
ents and from 8 to 63% in those receiving oral
8-methoxypsoralen, however, within each trial, the
incidence was about 2 to 11 times greater in 8-
methoxypsoralen than in 5-methoxypsoralen recip-
ients. Correspondingly, the incidence of pruritus
(severity not stated) and moderate to severe ery-
thema was about 2 to 6 times greater.
The formulation of 5-methoxypsoralen may
influence the occurrence and severity of adverse
events: mild (in 7.7% of patients) but not moderate
to severe nausea was observed in patients taking
5-methoxypsoralen as a liquid suspension in soft
gelatin capsules; mild, moderate and severe pruri-
tus occurred in, respectively, 30.8, 7.7 and 5.1% of
patients (fig. 6).[55] The incidence of all levels of
nausea was significantly higher in 8-methoxy-
Drugs 1998 Oct; 56 (4)
684 McNeely & Goa

35 5-Methoxypsoralen
8-Methoxypsoralen
30 *
*
Incidence (% of patients)

25

20
*

15
*
*
10

re
re
e

e
ild

ild
at

at

ve
ve
M

M
er

er

Se
Se
od

od
M

Nausea Pruritus
Fig. 6. Comparative incidence of nausea and pruritus in patients with psoriasis who received 5-methoxypsoralen 1.2 mg/kg (n = 39)
or 8-methoxypsoralen 0.6 mg/kg (n = 39) PUVA for 8 sessions.[55] Psoralens were given as liquid suspensions in soft gelatine capsules.
* p < 0.01 vs 5-methoxypsoralen.

psoralen recipients, as were moderate and severe 5.3 Potential for Cutaneous Carcinogenicity
pruritus (p < 0.01 for all vs 5-methoxypsoralen).
Nausea/vomiting and pruritus were not apparent There are many reports in which the long term
after topical application of 5-methoxypsoralen to use of PUVA is associated with an increased risk
patients with psoriasis (drug applied via a water- for the latent development (up to 15 years after
bath).[51] However, direct comparisons between initial PUVA exposure[58]) of cutaneous carcinoma
micronised and liquid suspension formulations and including malignant melanoma.[59] Most of the re-
oral and topical formulations of 5-methoxypsoralen ports, however, refer to the use of 8- and not 5-
are warranted to determine whether a true difference methoxypsoralen.[58,60-66] Similar published data for
in the incidence of short term adverse events exists. the use of PUVA 5-methoxypsoralen are not avail-
able. Nevertheless, because both of these agents are
5.2 Effects on the Liver linear psoralens, it would be prudent to view the
long term use of 5-methoxypsoralen PUVA with
Psoralens are metabolised in the liver, and high caution (as with 8-methoxypsoralen PUVA) until
doses have been shown to cause hepatocyte changes evidence to the contrary is available.
in animals.[56] Adverse events associated with the In the 2 published reports pertaining to com-
liver after 5-methoxypsoralen administration in bined exposure to 5-methoxypsoralen and UVA light,
humans were uncommon. Transient elevated serum there was no occurrence of carcinogenicity during
transaminase levels (>33 IU/L) were reported in a 14-year observation period in which 413 patients
5% of patients (4 of 80) with vitiligo or psoriasis with psoriasis received PUVA 5-methoxypsoralen
within 3.5 to 20 months of starting PUVA 5- treatment 1 to 3 times weekly (duration of contin-
methoxypsoralen treatment 2 to 3 times weekly in uous treatment not stated).[67] Furthermore, an Ital-
1 study;[57] levels returned to within normal ranges ian study concluded that the incidence of carci-
4 to 10 weeks after treatment cessation. noma was age-linked rather than being associated

 Adis International Limited. All rights reserved. Drugs 1998 Oct; 56 (4)
5-Methoxypsoralen: A Review
with exposure to 5-methoxypsoralen (a component
of bergamot oil) and sunlight in workers involved
in the bergamot essential oil industry.[68] Clearly,
further long term tolerability studies are required
to disclose more fully the potential, if any, for
cutaneous carcinoma with use of PUVA 5-meth-
oxypsoralen therapy in patients with psoriasis and
vitiligo.
6. Dosage and Administration
The standard dosage of oral 5-methoxypsoralen
as part of PUVA therapy for psoriasis or vitiligo is
1.2 mg/kg. Each tablet (formulation details not de-
fined) contains 20mg active drug; therefore adults
of 60kg need 2 to 3 tablets and adults of 80kg need
2.5 to 4 tablets.[69] Tablets should be taken 2 hours
before UVA irradiation. Generally it is necessary
to complete 20 sessions at a rate of 2 to 4 per
week.[69]
The UVA dosage should be given with consid-
eration to the skin type.
6.1 Contraindications and Precautions
Contraindications for the use of 5-methoxy-
psoralen include:
• renal or hepatic failure
• skin diseases which are aggravated by the sun
(e.g. lupus erythematosus)
• cataracts and glaucoma
• epithelioma and melanoma.[69]
It is also contraindicated in infants, pregnant
women and lactating mothers.[69]
Because of the speculated carcinogenic poten-
tial with PUVA therapy, it is prudent to avoid this
treatment in patients with precancerous skin con-
ditions and in patients previously treated with ar-
senic compounds (notably Fowler’s liqueur).[69]
The duration of UV irradiation should be care-
fully logged. Additional exposure to the sun should
be avoided. In the case of local treatment, UV
block should be worn on the untreated areas during
the irradiation sessions. In addition, UV block
glasses should be worn during and up to 8 hours
after the UVA irradiation sessions.[69]
 Adis International Limited. All rights reserved.
685
Concomitant photosensitising medication such
as sulfonamides, phenothiazides and tetracyclines
should be avoided.[69]
7. Place of PUVA 5-Methoxypsoralen
in the Management of Psoriasis
and Vitiligo
The therapeutic use of psoralens for vitiligo has
a long and fascinating history; it dates back to
Ancient Egyptian times and is recorded in such
revered literature as the Koran and Atharva Veda
(the sacred Indian book circa 1400 BC). The psor-
alens were originally extracted from plant sources
including Ammi majus and Psoralea corylifolea.[2]
Today the combination of psoralens (natural or
synthetic) and UVA irradiation is commonly used
in the management of vitiligo and psoriasis. It has
also been used to treat other dermatological condi-
tions including atopic eczema,[70] cutaneous T cell
lymphoma[49] and alopecia areata.[71]
Psoriasis and vitiligo each occur in less than 3%
of the world’s population.[4,6] Neither is commonly
life threatening, but both have an effect on the
emotional, social and economic well-being of the
patient that is often underestimated by healthcare
professionals.
Several approaches are available for the man-
agement of both vitiligo and psoriasis (table VI),
including the option of no treatment. Many of the
therapeutic regimens are accompanied by a range,
in both severity and type, of adverse events; there-
fore, as with any other therapy, the risk to benefit
ratio must be considered. Ultimately, the choice of
treatment should be determined by the emotional
as well as the physical needs of the patient. [6,73]
Often, commitment to extensive therapy is re-
quired for a condition that is not life threatening.
In both conditions, treatment is initially topical,
unless ≥20% body surface area is involved,[2,6,72]
before proceeding to systemic treatments. For vit-
iligo, surgical options are also available; these in-
clude autologous epidermal grafts, blister-induced
epidermal grafts, autologous melanocyte trans-
plants and micropigmentation by tattoo.
Drugs 1998 Oct; 56 (4)
686
Table VI. Summary of currently available medical options for the
management of psoriasis and vitiligo[6,72-74]
Therapy Comment
Psoriasis
Systemic
Oral PUVA Generally considered the systemic
treatment of choice. Suitable for large areas
of lesions. Risk of developing skin cancer
linked to high UVA irradiation
Methotrexate For severe, uncontrolled, unresponsive
psoriasis. Suppresses bone marrow and is
hepatotoxic; thus regular laboratory
analysis required
Acitretin For severe, extensive, resistant psoriasis
and palmoplantar pustular psoriasis.
Prescription by consultant dermatologist
required. Conception contraindicated during
and for 2 years after therapy
Cyclosporin For severe psoriasis, long term therapy
required. Potential for renal impairment and
increased risk of cancer
Topical
Calcipotriol Treatment of choice for home use. Not
appropriate for facial use
Dithranol Staining of clothes/skin avoided by ‘short
contact’ application. Efficacy enhanced
when combined with coal tar baths and UVA
irradiation
Coal tar Effective for mild localised areas. Efficacy
enhanced when followed by UVA irradiation
Corticosteroids Potent steroids useful on palms and soles,
also for inflamed lesions. Potential for
cutaneous atrophy and/or adrenal
suppression curtails long term use
Vitiligo
Systemic
Oral PUVA Most effective noninvasive therapy. Severity
of short term adverse events reduced by
replacing 8-MOP with 5-MOP
Topical
Corticosteroids 4-6 months duration advised; only low
potency preparations used on face.
Potential for cutaneous atrophy
Topical PUVA Generally recommended if <20% of body
involved. Potential for treated areas to
blister depending on psoralen used
MOP = methoxypsoralen; PUVA = psoralen plus exposure to UVA;
UVA = ultraviolet A light.
Oral PUVA therapy is the systemic treatment of
choice.[73] 8-Methoxypsoralen has been used suc-
cessfully for the management of both vitiligo[4]
and psoriasis;[75] however, short term cutaneous and
gastrointestinal adverse events were often severe.[75]
 Adis International Limited. All rights reserved.
McNeely & Goa
5-Methoxypsoralen and 8-methoxypsoralen each
stimulate repigmentation in vitiligous lesions and
clear psoriatic lesions to a similar extent in clinical
trials. In the 1 trial that compared the 2 psoralens
in combination with sunlight in patients with viti-
ligo, 5-methoxypsoralen tended to induce repig-
mentation in more patients than 8-methoxypsoralen
(section 4.3.2). However, in comparative trials in
patients with psoriasis there was no significant dif-
ference between the 2 treatment groups regarding
lesion clearance after oral or topical application of
the 2 drugs (sections 4.2.1 and 4.2.2). In parallel
group studies of patients with psoriasis, however,
those given 8-methoxypsoralen required up to one-
third less total UVA exposure than 5-methoxypso-
ralen recipients to achieve the therapeutic end-point,
although there was wide interstudy variation. This
suggests that 8-methoxypsoralen is a more effec-
tive photosensitising agent than 5-methoxypso-
ralen in the management of psoriasis and this may
have long term tolerability implications (see be-
low). However, in 2 small studies (n = 6 and 10)
that compared both psoralens, either orally or top-
ically, simultaneously on contralateral sides of the
body, 5-methoxypsoralen recipients required fewer
treatment sessions, and in the topical study, a sig-
nificantly lower total UVA exposure to achieve
end-point. These studies are perhaps indicative of
the true differences between 5- and 8-methoxy-
psoralen and further similarly designed studies
with larger patient numbers are warranted.
Results from pharmacokinetic studies have
indicated that individual Cmax 5-methoxypsoralen
values should be assessed to determine the optimal
time between oral drug administration and expo-
sure to UVA. The overall absorption, and conse-
quently the efficacy, of the drug is affected by the
galenic formulation. The micronised formulation
appears more effective than the unmicronised; this
may be related to the dissolution and subsequent
cutaneous absorption of each formulation. Further
data pertaining to the liquid-filled gelatin capsules
are required. Results from chronopharmacological
studies have demonstrated that the drug has a
greater effect when given in the evening than in the
Drugs 1998 Oct; 56 (4)
5-Methoxypsoralen: A Review
morning (indicated by the difference in plasma
melatonin levels; section 2.2). This factor might
also be a consideration when determining treat-
ment schedules which would minimise the amount
of UVA irradiation required without compromising
the therapeutic effect, although it does not cur-
rently feature in the dosage recommendations.
Clinical trials reviewed in section 4 infrequently
specified whether the formulation used was micro-
nised or not and usually used a regimen involving
morning administration of the drug.
5-Methoxypsoralen 1.2 mg/kg appears to be
superior to 8-methoxypsoralen 0.6 mg/kg regard-
ing tolerability in the short term. Nausea and/or
vomiting, erythema and pruritus were the most
common adverse events reported. Although many
studies did not provide statistical analyses, within
trials the incidence of gastrointestinal effects was
up to 11 times greater in 8-methoxypsoralen recip-
ients and the incidence of cutaneous adverse events
was up to 6 times greater. 5-Methoxypsoralen 1.2
mg/kg does not appear to have a greater overall
therapeutic efficacy than 8-methoxypsoralen 0.6
mg/kg. However, the lower incidence of erythema
with the former psoralen suggests it does have less
phototoxic effect on the skin, which may be bene-
ficial during prolonged treatment.
It is generally accepted that the development of
skin cancer is associated with exposure to UV
irradiation.[76] More specifically, the risk of de-
veloping cutaneous malignancy is related to high
cumulative doses of UVA irradiation.[73]
Data from long term follow-up in patients who
received PUVA 8-methoxypsoralen therapy indi-
cate that there is an increased risk of developing
cutaneous carcinoma, including melanoma, in
PUVA recipients than in the general population
(section 5.3). Of concern is the fact that there ap-
pears to be a long latency period (up to 15 years
from initial exposure) before the carcinomas are
detected.[58] Additional risk factors associated with
the development of cutaneous carcinoma in PUVA
recipients include exposure to previous ionising
radiation, history of cutaneous carcinoma, total
number of PUVA treatments and having skin type
 Adis International Limited. All rights reserved.
687
I or II compared with III to VI.[77] Published data
specifically concerning the long term tolerability
effects of PUVA 5-methoxypsoralen are limited.
Therefore, since these 2 agents probably have a
similar mechanism of action, caution should be
applied to the use of PUVA 5-methoxypsoralen
therapy.
Reports from 2 studies suggest that carcino-
genicity has not been linked with either long term
5-methoxypsoralen PUVA treatment in patients
(observed for up to 14 years; duration of continu-
ous treatment not stated), or combined exposure to
5-methoxypsoralen and sunshine in workers in the
bergamot essential oil industry (section 5.3). How-
ever, until results from appropriately designed long
term studies become available, these current re-
sults should be interpreted with caution.
It appears that the risk of developing skin cancer
resulting from PUVA therapy may be reduced by
careful patient selection (e.g. restricting its use in
patients with previous exposure to arsenic com-
pounds) and observing other precautionary meas-
ures during therapy such as preventing additional
UV exposure by use of appropriate clothing and
UV block creams.
Interestingly, the use of bergamot essential oil
(Citrus auranthium ssp. bergamia) is recommended
to alleviate stress and depression and to induce
sleep.[78,79] There is limited evidence of these thera-
peutic effects with oral 5-methoxypsoralen: Souêtre
et al.[80] showed that oral 5-methoxypsoralen 40
mg/day for 7 days (without UV irradiation) im-
proved Hamilton depression rating scores by 21%
in 24 patients with major depressive disorder (p <
0.05 vs placebo). If confirmed, this may prove an
additional benefit in the management of psoriasis
and vitiligo, which often involve an emotional as-
pect and consequently the potential for developing
stress and insomnia.
In conclusion, available data suggest that there
is no significant difference in the overall lesion clear-
ance rates for PUVA 5- and 8-methoxypsoralen
therapy in patients with psoriasis or vitiligo, even
though 8-methoxypsoralen required less total UVA
exposure in several studies.
Drugs 1998 Oct; 56 (4)
688
One advantage with 5-methoxypsoralen is that
the incidence of short term cutaneous and gastro-
intestinal adverse effects is markedly less than with
8-methoxypsoralen, although the long term toler-
ability of 5-methoxypsoralen has yet to be fully
established. Nevertheless, in appropriately se-
lected patients PUVA 5-methoxypsoralen therapy
may be recommended as an alternative first-line
systemic treatment option for the management of
vitiligo or psoriasis, two dermatological conditions
that are notoriously difficult to treat.
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Correspondence: Wendy McNeely, Adis International Lim-
ited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay,
Auckland 10, New Zealand.
E-mail: demail@adis.co.nz
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